实施例
实施例1:硬化性骨化病作图到人第17号染色体长臂
造成人硬化性骨化病的缺陷的遗传作图将造成此疾病的基因定位于人第17号染色体中编码新TGF-β结合蛋白家族成员的区域。在硬化性骨化病人群中,骨骼的矿物质密度相对于未患病人员而言展示出较大的增加。头部的骨同样呈现出生长过度。硬化性骨化病患者通常是健康的,尽管他们可能显示出出生时不同程度的并指(趾)现象和不同程度的头颅压迫以及头骨中的神经压迫。
与硬化性骨化病相关的基因缺陷的连锁分析通过对采集自有此病史的24个南非Afrikaaner家族的DNA样品进行纯合性作图来完成。(Sheffield等,1994,Human Molecular Genetics 3:1331-1335.“3号染色体上Bardet-Biedl综合症位点的鉴定以及有效同源性作图方法的评估(Identification of a Bardet-Biedl syndrome locus onchromosome 3 and evaluation of an efficient approach tohomozygosity mapping)”)。南非Afrikaaner人群从遗传上说是均一的;该人群是从几个世纪前殖民于此地区的少数建立者繁衍而来的,并且,自从建立以来他们已由于地理和社会屏障而被隔离。在Afrikaaner群落之外的世界各地,硬化性骨化病都是罕见的,这显示出该建立者群体中存在基因突变,且后来随着人口的增多,突变的数目也有所增加。纯合性作图的应用是以一定的假设为基础的,即在来自同血缘家族和隔离人群的受影响个体中邻近隐性突变的DNA作图标记很可能是纯合的。
选择来自常染色体的一组371个微型卫星标记(ResearchGenetics,Set 6)测定取自硬化性骨化病患者样品的DNA集合的类型。用于此项分析的DNA样品来自24个家庭的29名硬化性骨化病患者、59名未患病的家庭成员和同一种群的一组无关对照个体。所述集合由4-6个个体组成,他们或者是患病个体、来自血亲家族的患病个体、父母和未患病的兄弟姐妹,或者是无关的对照。在无关个体组和大部分患病个体或家庭成员组中,所述标记的分析显示各个标记有几种等位基因大小。标记之一,即D17S1299呈现出纯合的迹象:在数个患病个体集合中都是一条带。
用D17S1299区(在17q12-q21)的总共19个标记对所有24个硬化性骨化病家族进行了分型。来自每个家族的患病个体显示出在此区域是纯合的,而29个个体中有25个对于核心单倍体是纯合的;他们各自在D17S1787和D17S930之间具有相同的等位基因。其它四个个体具有匹配此单倍体的一条染色体和不匹配的另一条染色体。总而言之,这些数据有力的显示了此3 megabase区域包含了硬化性骨化病突变。对此3 megabase区域中大部分外显子的序列分析识定出了新TGF-β结合蛋白编码序列中的无义突变(在SEQ ID NO:1的序列第117位C突变成T产生了终止密码子)。此突变显示出对于硬化性骨化病患者和Afrikaaner后代携带者而言是独特的。此基因的特性通过鉴定其内含子中的突变(内含子+3位置处A突变成T)得到进一步的证实,所述突变导致已确诊为硬化性骨化病的单个无关患者中mRNA加工不正确。
实施例2:TGF-β结合蛋白基因表达的组织特异性
A.利用RT-PCR进行人beer基因表达:
利用商品化的试剂盒(“用于第一条cDNA链合成的Superscript预扩增体系(Preamplification System for First-Strand cDNASynthesis)”,Life Technologies,Rockville,MD)从以下总RNA样品中制备第一链cDNA:人脑、人肝、人脾、人的胸腺、人的胎盘、人的骨骼肌、人的甲状腺、人的垂体、人的成骨细胞(NHOst,来自Clonetics Corp.,San Diego,CA)、人骨肉瘤细胞系(Saos-2,ATCC#HTB-85)、人的硬骨、人的骨髓、人的软骨、长尾黑颚猴(vervet monkey)的骨骼、酿酒酵母和人外周血单核细胞。除了以下种类是自己制备的之外,所有的RNA样品均购买获得(Clontech,Palo Alto,CA):人的成骨细胞、人的骨肉瘤细胞系、人的硬骨、人的软骨和长尾黑颚猴的骨骼。这些自备的RNA样品是使用商品化的试剂盒(“TRI试剂”,Molecular Research Center,Inc.,Cincinnati,OH)制备。
对这些样品进行PCR,并另外用人基因组样品进行PCR作为对照。有义Beer寡核苷酸引物的序列为:5’-CCGGAGCTGGAGAACAACAAG-3’(SEQ ID NO:19)。反义Beer寡核苷酸引物的序列为:5’-GCACTGGCCGGAGCACACC-3’(SEQ ID NO:20)。此外,用针对人β-肌动蛋白基因的引物进行PCR作为对照。有义β-肌动蛋白寡核苷酸引物的序列为:5’-AGGCCAACCGCGAGAAGATGA CC-3’(SEQ ID NO:21)。反义β-肌动蛋白寡核苷酸引物的序列为:5’-GAAGTCCAGGGCGACGTAGCA-3’(SEQ ID NO:22)。用标准条件在25μl反应体系中进行PCR,退火温度为61℃。用Beer引物进行32个循环的PCR,而用β-肌动蛋白引物则进行24个循环。
扩增后,将来自各次反应的12μl样品通过琼脂糖凝胶电泳和溴化乙锭染色进行分析。参阅图2A。
B.小鼠胚胎切片的RNA原位杂交:
用制造商的方案,以反义和有义方向将全长小鼠Beer cDNA(Sequence ID No.11)克隆入pCR2.1载体(Invitrogen,Carlsbad,CA)中。用Ambion,Inc(Austin,TX)提供的体外转录试剂合成35S-α-GTP-标记的cRNA有义和反义转录产物。按照Lyons等的方案(J.CellBiol.111:2427-2436,1990)进行原位杂交。
小鼠Beer cRNA探针检测正在发育的小鼠胚胎的神经管、肢芽、血管和硬化软骨中表达的特异信息。图3的模块A显示了肢(1)芽顶端外胚层脊背(apical ectodermal ridge,aer)、血管(bv)和神经管(nt)中的表达。模块B显示了大脑第4脑室(4)中的表达。模块C显示了下颚(ma)颈椎骨(cv)中、枕骨(oc)、上颚(pa)和血管(bv)中的表达。模块D显示了肋骨(r)和心脏瓣膜(va)中的表达。模块A是10.5dpc胚胎的横切片。模块B是12.5dpc胚胎的纵切片,而模块C和D是15.5dpc胚胎的纵切片。
ba=鳃弓,h=心脏,te=端脑(前脑),b=脑,f=额鼻块,g=肠,h=心脏,j=颚,li=肝,lu=肺,ot=耳泡(otic vesicle),ao=,sc=脊髓,skm=骨骼肌,ns=鼻窦,th=胸腺,to=舌,fl=前肢,di=横膈膜
实施例3:重组Beer蛋白质的表达和纯化
A.在COS-1细胞中的表达:
用以下PCR寡核苷酸引物扩增编码全长人Beer蛋白的DNA序列:5’寡核苷酸引物的序列为5’-AAGCTTGGTACCATGCAGCTCCCAC-3’(SEQ ID NO:23),并且包含HindIII限制性酶切位点(粗体),之后是Beer基因的19个核苷酸,其在推测的氨基末端起始密码子(ATG)之前6bp开始。3’寡核苷酸引物的序列为5’-AAGCTTCTACTTGTCATCGTCGTCCTTGTAGTCGTAGGCGTTCTCCAGCT-3’(SEQ ID NO:24),并包含HindIII限制性酶切位点(粗体),之后是反向互补终止密码子(CTA),其后是FLAG表位的反向互补序列(下划线,Sigma-Aldrich Co.,St.Louis,MO),该互补序列侧翼是Beer羧基末端5个氨基酸的编码核苷酸的反向互补序列。经TA克隆PCR产物(“原创的TA克隆试剂盒”,Invitrogen,Carlsbad,CA)并通过DNA测序筛选各个克隆。然后将序列已证实的克隆用HindIII消化,并用商品化的试剂(“QIAquick Gel Extraction Kit”,Qiagen Inc.,Valencia,CA)在1.5%琼脂糖凝胶上进行纯化。然后用T4 DNA连接酶将此片段连接至经HindIII消化、磷酸酶处理的pcDNA3.1质粒(Invitrogen,Carlsbad,CA)上。转化大肠杆菌DH10B,并铺在含100μg/ml氨苄青霉素的LB平板上。通过基于PCR的筛选鉴定携带正确定向的预期重组子的菌落,所用5’引物相应于pcDNA3.1中的T7启动子/启动位点,而3’引物具有序列5’-GCACTGGCCGGAGCACACC-3’(SEQ ID NO:25),其相应于内在Beer序列的反向互补序列。已克隆片段的序列通过DNA测序证实。
利用COS-1细胞(ATCC#CRL-1650)进行转染。按制造商提供的方案,利用商品化的试剂盒(“DEAE-葡聚糖转染试剂盒”,SigmaChemical Co.,St.Louis,MO)转染50μg表达质粒pcDNA-Beer-Flag。转染后的最终培养基是含0.1%胎牛血清的DMEM(Life Technologies,Rockville,MD)。培养4天后,去掉培养基。利用抗-FLAG
M2单克隆抗体(Sigma-Aldrich Co.,St.Louis,MO)通过SDS-PAGE和Western印迹分析重组Beer的表达。用抗-FLAG M2亲和柱(“哺乳动物瞬时表达体系”,Sigma-Aldrich Co.,St.Louis,MO)进行重组BEER蛋白质的纯化。用抗-FLAG M2单克隆抗体通过SDS-PAGE和Western印迹分析柱层析产物。
B.在SF9昆虫细胞中的表达:
用标准条件和以下引物经PCR扩增人Beer基因序列:
有义引物:
5’-GTCGTCGGATCCATGGGGTGGCAGGCGTTCAAGAATGAT-3’(SEQ ID NO:26)
反义引物:
5’-GTCGTCAAGCTTCTACTTGTCATCGTCCTTGTAGTCGTA
GGCGTTCTCCAGCTCGGC-3’(SEQ ID NO:27)
产生的cDNA包含具有两个修饰的Beer编码区。N末端分泌信号被去除,并将FLAG表位标签(Sigma)读框一致地融合入插入片段C-末端。添加BamH1和HindIII克隆位点,并将基因亚克隆入pMelBac载体(Invitrogen)中,以便用标准方法转移入杆状病毒表达载体中。
用Bac-N-Blue转染试剂盒(Invitrogen)制备表达Beer蛋白质的重组杆状病毒并按照制造商的说明书进行纯化。
将SF9细胞(Invitrogen)保持在含10%胎牛血清的TNM_FH培养基(Invitrogen)中。为了进行蛋白质表达,以大于10的MOI感染旋转烧瓶中的SF9培养物。5天内每天采集培养基和细胞样品,用抗-FLAGM2单克隆抗体(Sigma)或抗-Beer兔多克隆抗血清通过蛋白质印迹监测Beer的表达。
5天后,离心收获杆状病毒感染的SF9细胞,并用高盐抽提缓冲液(1.5M NaCl,50mM Tris pH 7.5)从细胞沉淀中提取细胞相关蛋白质。离心使提取物(每300ml培养物20ml)澄清,用4升Tris缓冲盐(150mM NaCl,50mM Tris pH 7.5)透析3次,并再次离心澄清。将此高盐组分加到Hitrap Heparin(Pharmacia;床体积5ml)上,柱子用HEPES缓冲盐水(25mM HEPES 7.5,150mM NaCl)粗洗,并用150mM NaCl至1200mM NaCl梯度洗脱被结合的蛋白质。在大约800mMNaCl处观察到Beer洗脱。在含Beer的组分中加入10%甘油和1mM DTT并冻存于-80℃。
实施例4:抗Beer、Gremlin和Dan的多克隆抗体的制备和检测
A.抗原的制备:
用标准方法扩增人Beer、人Gremlin和人Dan的DNA序列,所用的寡核苷酸引物如下:
H.Beer
有义:5′-GACTTGGATCCCAGGGGTGGCAGGCGTTC-3′(SEQ ID NO:28)
反义:5′-AGCATAAGCTTCTAGTAGGCGTTCTCCAG-3′(SEQ ID NO:29)
H.Gremlin
有义:5′-GACTTGGATCCGAAGGGAAAAAGAAAGGG-3′(SEQ ID NO:30)
30)
反义:5′-AGCATAAGCTTTTAATCCAAATCGATGGA-3′(SEQ ID NO:31)
H.Dan
有义:5′-ACTACGAGCTCGGCCCCACCACCCATCAACAAG-3′(SEQ ID NO:32)
反义:5′-ACTTAGAAGCTTTCAGTCCTCAGCCCCCTCTTCC-3′(SEQ ID NO:33)
在各情况下,所列举的引物扩增除了分泌信号序列之外的整个编码区。其中,对于Beer和Gremlin而言,包含在位点BamHI/HindIII处、对于Dan而言包含在位点SacI/HindIII亚克隆入细菌表达载体pQE-30(Qiagen Inc.,Valencia,CA)的限制性切点。pQE30在克隆区的5’末端包含了6×His标签的编码序列。将完成的构建体转化入大肠杆菌菌株M-15/pRep(Qiagen Inc)并测序查证各个克隆。在M-15/pRep中的蛋白质表达和纯化(与偶联在琼脂糖上的Ni-NTA结合的6×组氨酸亲和标签)依照制造商的说明书(Qiagen,TheQIAexpressionist)进行。
利用增溶作用在6M胍中大量回收大肠杆菌来源的Beer蛋白质,并透析至2-4M胍中,以防止在贮存期间沉淀。Gremlin和Dan蛋白质则通过溶解于6M胍中得到更大量的回收,纯化后的胍浓度达到0.5M。
B.多克隆抗体的产生和检测:
按照标准方案(R & R抗体,Stanwood,WA;用于兔免疫和抗血清回收的标准方案(standard protocol for rabbit immunization andantisera recovery);分子生物学中的简洁方法(Short Protocolsin Molecular Biology).第二版1992.11.37-11.41,投稿人HelenM.Cooper和Yvonne Paterson;用重要的生物溶液产生鸡抗血清(chicken antisera was generated with Strategic Biosolutions),Ramona,CA)在兔子和鸡宿主中产生针对三种抗原中每一种的多克隆抗体。
通过Western印迹法筛选兔抗血清和鸡蛋Igy组分的活性。经PAGE分离三种抗原中的每一种并转染至0.45um的硝酸纤维素膜(Novex,San Diego,CA)上。将膜切成条,每条包含大约75ng抗原。将这些膜条用3%的Blotting Grade Block(Bio-Rad Laboratories,Hercules,CA)封闭并在1X Tris缓冲盐水(TBS)/0.02% TWEEN缓冲液中洗3次。将这些膜条与一抗(免疫前放血,将兔抗血清或鸡蛋IgY用封闭缓冲液稀释,稀释范围为1∶100至1∶10,000)一起温和摇动保温1小时。再用1X TBS/0.02%TWEEN洗三次,然后与二抗(缀合了驴抗兔抗体的过氧化物酶,Amersham Life Science,Piscataway,NJ;或缀合了驴抗鸡抗体的过氧化物酶,Jackson ImmunoResearch,WestGrove,PA)一起保温1小时。最后再用1X TBS/0.02%TWEEN洗三次,并将膜条用Lumi-Light Western印迹底物显色(Roche MolecularBiochemicals,Mannheim,Germany)。
C.抗体交叉反应性检测:
在完成以上章节所描述的流程之后,将Beer、Gremlin或Dan的硝酸纤维素膜条与它们各自的兔抗血清或鸡蛋IgY稀释液(1∶5000和1∶10,000)以及剩余两种抗原的抗血清或鸡蛋Igy(稀释1∶1000和1∶5000倍)一起保温。提高不匹配抗体的水平以检测只有在提高浓度下才可能被观察到的那些抗体的低亲和力结合。按照上述流程,所用方案和呈色时间对于所有三种结合情况而言都是相同的。对于任一种被检测抗原而言都未观察到抗原交叉反应性。
实施例5:Beer与TGF-β超家族蛋白质的相互反应
用免疫沉淀方法研究Beer与来自不同系统发生支的TGF-β超家族蛋白质的相互作用。已纯化的TGFβ-1、TGFβ-2、TGFβ-3、BMP-4、BMP-5、BMP-6和GDNF获自商品化途径(R&D systems;Minneapolis,MN)。代表性方案如下。将部分纯化的Beer在HEPES缓冲盐水(25mM HEPES 7.5,150mM NaCl)中透析。在300μl IP缓冲液(150mM NaCl,25mM TrispH 7.5,1mM EDTA,1.4mM β-巯基乙醇,0.5% triton X 100和10%甘油)中进行免疫沉淀。在存在或缺失500ng FLAG表位-标记Beer的条件下将30ng重组人BMP-5蛋白质(R&D systems)加到15μl FLAG亲和基质(Sigma;St Louis MO)中。将蛋白质在4℃保温4小时,并随后用IP缓冲液洗涤与亲和基质相联的蛋白质5次(每次1ml)。用60μl 1X SDS PAGE样品缓冲液从亲和基质上洗脱被结合的蛋白质。用SDS PAGE拆分蛋白质并用抗-BMP-5抗血清(Research Diagnostics,Inc)通过western印迹检测与Beer相连的BMP-5(见图5)。
BEER配体结合试验:
将FLAG-Beer蛋白质(20ng)加入100μl PBS/0.2%BSA中,并吸附于预先用抗FLAG单克隆抗体(Sigma;St Louis MO)包被并用含10%BSA的PBS封闭的96孔微量滴定板的各个孔中。这一过程在室温进行60分钟。除去此蛋白质溶液并漂洗各孔以去除未结合的蛋白质。在各孔中加入浓度范围从10pM至500nM的溶于PBS/0.2%BSA的BMP-5,并在室温保温2小时。去除结合溶液并用200μl体积的PBS/0.2%BSA漂洗平板三次。然后用BMP-5抗血清通过ELISA(F.M.Ausubel etal(1998)分子生物学通用方法(Current Protocols in Mol Biol.)卷211.2.1-11.2.22)检测BMP-5的水平。通过从总的结合中扣除非特异性结合来计算特异性结合,并用LIGAND软件(Munson和Podbard,Anal.Biochem.,107,p220-239,(1980)进行分析。
在此方法的修饰方案中,将Beer进行改造并表达为人Fc融合蛋白。同样的,改造配体BMP并将其表达为小鼠Fc融合蛋白。将这些蛋白质一起保温并如Mellor等所述用均一时间解析荧光检测法进行检测(G.W.Mellor等,J of Biomol Screening,3(2)91-99,1998)。
实施例6:有关TGF-β结合蛋白与TGF-β家族成员结合的抑制作用的筛选试验
重复上述试验,其中有两处不同。首先,BMP浓度固定为先前所确定的Kd。其次,拮抗剂候选物的集合以固定浓度加入(如果是小有机分子集合则为20μM,在抗体研究中则为1μM)。这些TGF-β结合蛋白结合的候选分子(拮抗剂)包括商品化来源的有机化合物或代表不同化学结构的内部合并物。用DMSO将这些化合物制备成贮液并在标准实验条件下以小于1%的终体积加入检测孔中。将它们与BMP和BEER一起室温保温2小时,去除溶液并如前所述对被结合的BMP进行定量。在缺乏化合物或抗体的条件下观察到抑制了40%的BMP结合的试剂被认为是此相互作用的拮抗剂。这些试剂基于滴定试验被进一步评估为潜在的抑制剂,所述的滴定试验用于测定它们的抑制作用常数以及它们对TGF-β结合蛋白结合亲和力的影响。还可进行可比较的特异性对照试验以确定已经鉴定的拮抗剂的选择性特征,该研究使用了依赖于BMP配体作用的检测法(例如,BMP/BMP受体竞争性试验)。
实施例7:对TGF-β结合蛋白定位于骨基质的抑制作用
对Nicolas的方法(Nicolas,V.Calcif Tissue Int 57:206,1995)加以修改,用于评估对定位于骨基质(羟磷灰石)的抑制作用。简而言之,如Nicolas(同上文)所述制备125I-标记的TGF-β结合蛋白。将羟磷灰石加入装备了聚丙烯滤膜(Polyfiltroninc,Weymouth MA)的96孔微量滴定板的各孔中。将TGF-β结合蛋白加入含0.2%白蛋白的PBS缓冲液中。用此缓冲液将含有基质的孔漂洗3次。被吸附的TGF-β结合蛋白用0.3M NaOH洗脱并定量。
通过将TGF-β结合蛋白与待测分子一起保温并如上所述将混合物施加到基质上来进行抑制剂的鉴定。用含0.2%白蛋白的PBS缓冲液将基质洗3次。被吸附的TGF-β结合蛋白用0.3M NaOH洗脱并定量。在无化合物或抗体的条件下观察到抑制了40%TGF-β结合蛋白结合的试剂被认为是骨定位抑制剂。这些抑制剂通过剂量反应试验测定其抑制常数及其对TGF-B结合蛋白结合亲和力的影响而被进一步定性。
实施例8:TGF-β结合蛋白突变体的构建
A.诱变:
pBluescript SK中的全长TGF-β结合蛋白cDNA被用作诱变的模板。简而言之,利用适当的引物(参阅上文讨论部分)以及Vent DNA聚合酶(New England Biolabs,Beverly,MA)通过聚合酶链式反应产生DNA片段。在57℃退火温度下利用制造商提供的缓冲液进行聚合酶链式反应23个循环。然后将产物暴露于两种限制性酶中,并在用琼脂糖凝胶电泳进行分离后,连接回其中的匹配序列已通过酶促消化去除的pRBP4-503中。通过DNA测序检验突变体的完整性。
B.突变体TGF-β结合蛋白的哺乳动物细胞表达和分离
将突变体TGF-β结合蛋白cDNAs转移入实施例3中所述的pcDNA3.1哺乳动物表达载体。在核实序列后,将产生的构建体转染入COS-1细胞,并如实施例3所述纯化分泌的蛋白质。
实施例9
动物模型-I
过表达BEER基因的转基因小鼠的产生
利用分离自CITB小鼠基因组DNA文库(由Research Genetics,Huntsville,AL分装)的大约200kb BAC克隆15G5测定小鼠Beer基因的全序列及其5′和3′侧翼区。将包含完整基因体以及大约17kb的5′侧翼区和大约20kb的3′侧翼序列的41kb SalI片段亚克隆入SuperCosI粘粒载体(Stratagene,La Jolla,CA)的BamHI位点,并于大肠杆菌菌株DH10B中增殖。然后用常规方式分别凝胶纯化来自此粘粒构建体且包括完整小鼠Beer基因以及17kb和14kb的5′和3′侧翼序列的35kb MluI-AviII限制性片段(Sequence No.6),并将它用于小鼠受精卵的显微注射(DNX Transgenics;US Patent No.4,873,191)。以存活后代中有5-30%的频率获得其中所克隆的DNA片段随机整合入基因组中的建立者动物。通过对提取自诸如尾端等小量小鼠组织的基因组DNA进行Southern印迹分析来确定转基因的存在。用以下方案提取DNA:在55℃用含200mM NaCl,100mM Tris pH8.5,5mM EDTA,0.2% SDS和0.5mg/ml蛋白酶K的裂解缓冲液消化组织过夜。次日,将DNA用酚/氯仿(50∶50)抽提一次,用氯仿/异戊醇(24∶1)抽提一次并用酒精沉淀。将各DNA样品8-10μg重悬于TE(10mM TrispH7.5,1mM EDTA)中,用诸如EcoRI等限制性内切酶消化,进行凝胶电泳并转移至诸如HyBondN+(Amersham,Arlington Heights,IL)等带电荷的尼龙膜上。然后将所产生的滤膜与来自小鼠Beer基因座的DNA的放射性标记片段杂交,所述片段能识别来自内源基因座的片段和来自转基因的不同大小的片段二者。将建立者动物与正常非转基因小鼠交配产生足够数目的转基因和非转基因后代,在其中测定Beer基因过表达的效应。为了进行这些试验,用各个年龄(例如,1天、3周、6周、4个月)的动物进行许多不同的试验,所述试验被设计成探知总的骨骼形成、骨矿物质密度、骨矿物质含量、破骨细胞和成骨细胞的活性、软骨内骨化的程度、软骨形成等。转基因的转录活性可通过从各种组织中提取RNA并借助RT-PCR检测法进行测定,该RT-PCR检测法利用了转基因所来源的小鼠株系(129Sv/J)和用于DNA显微注射的小鼠株系[(C57BL5/J x SJL/J)F2]之间单核苷酸多态性的优势。
动物模型-II
通过同源重组破坏小鼠Beer基因
可用胚胎干(ES)细胞同源重组灭活内源小鼠Beer基因并随后产生具有功能丧失的突变的动物。将诸如大肠杆菌β-半乳糖苷酶基因等报道基因插入打靶载体中,从而使其表达受内源Beer基因启动子和翻译起始信号的调控。以此方式,可以测定携带目标等位基因的动物中Beer基因表达的空间和时间模式。
打靶载体的构建首先是将来自pGT-N29(New England Biolabs,Beverly,MA)的药物可筛选的由磷酸甘油酸激酶(PGK)启动子驱动的新霉素抗性基因(neo)盒克隆入克隆载体pSP72(Promega,Madson,WI)中。利用PCR使PGKneo盒的两侧具有噬菌体P1 loxP位点,它是P1 Cre重组酶的识别位点(Hoess et al.,PNAS USA,79:3398,1982)。这使得后来可以去除打靶ES细胞或ES细胞来源动物中的neo-抗性标记(US Patent 4,959,317)。PCR引物包含34个核苷酸(ntd)的loxP序列、与PGKneo盒5′和3′末端互补的15-25ntd以及用于克隆入pSP72的限制性酶识别位点(在有义引物中是BamHI,而在反义引物中是EcoRI)。有义引物是5′-AATCTGGATCCATAACTTCGTATAGCATACATTATACGAAGTTATCTGCAG GATTCGAGGGCCCCT-3′(SEQ ID NO:34);反义引物是5′-AATCTGAATTCCACCGGTGTTAATTAAATAACTTCGTATAATGTATGCTATACGA AGTTATAGATCTAGAG TCAGCTTCTGA-3′(SEQ ID NO:35)。
下一步是将含有大肠杆菌β-半乳糖苷酶基因和来自pSVβ(Clontech,Palo Alto,CA)的SV40聚腺苷酸化信号的3.6kbXhoI-HindIII片段克隆入pSP72-PGKneo质粒。通过由BAC克隆15G5扩增2.4kb片段得到来自小鼠Beer基因座的同源物的“短臂”。该片段的3′末端与Beer基因的翻译起始位点一致,且PCR中所用的反义引物还包括与β-半乳糖苷酶基因5’末端互补的30ntd,从而使其编码区能与Beer起始位点读框一致地融合。将“短臂”引入pSP72-βgal-PGKneo质粒所采用的方法是在β-gal基因上游的位点线性化质粒,然后将此片段与“短臂”PCR产物一起共转化,并选择其中PCR产物通过同源重组被整合了的质粒。用于“短臂”扩增的有义引物包括与pSP72载体互补的30ntd,从而使得此重组得以进行。有义引物的序列是5′-ATTTAGGTGACACTATAGAACTCGAGCAGCTGAAGCTTAAC CACATGGTGGCTCACAACCAT-3′(SEQ ID NO:36),而反义引物的序列是5′-AACGACGGCCAGTGAATCCGTAATCATGGTCATGCTGCCAGGTGGAGGAGGGCA-3′(SEQ ID NO:37)。
通过由BAC克隆15G5扩增6.1kb片段而得到Beer基因座的“长臂”,所用引物中还引入了切点稀有的限制性酶位点SgrAI、FseI、AscI和PacI。具体而言,有义引物的序列是5′-ATTACCACCGGTGACACCCGCTTCCTGACAG-3′(SEQ ID NO:38);反义引物的序列是5′-ATTACTTAATTAAACATGGCGCGCCATATGGCCGGCCCCTAATTGCGGCGCATCGTTAATT-3′(SEQ ID NO:39)。将所产生的PCR产物克隆入TA载体(Invitrogen,Carlsbad,CA)中作为中间产物。
小鼠Beer基因打靶构建体还包括第二个可选择标记,即在劳氏肉瘤病毒长末端重复元件(RSV LTR)调控下的单纯疱疹病毒胸苷激酶基因(HSVTK)。此基因的表达使得哺乳动物细胞对gancyclovir敏感(且不能生存);因此它是用于对抗选择其中所述构建体通过非重组活动发生整合的新霉素抗性细胞的便利方法(美国专利5,464,764)。使用使其随后可克隆入“长臂”-TA载体质粒的FseI和AscI位点内的引物,自pPS1337扩增RSVLTR-HSVTK盒。对于此PCR而言,有义引物的序列是5′-ATTACGGCCGGCCGCAAA GGAATTCAAGA TCTGA-3′(SEQ ID NO:40);反义引物的序列是5′-ATTACGGCGCGCCCCTCACAGGCCGCACCCAGCT-3′(SEQ ID NO:41)。
打靶载体构建中的最后步骤包括将含“长臂”和RSVLTR-HSVTK基因的8.8kb SgrAI-AscI片段克隆入pSP72-“短臂”-βgal-PGKneo质粒的SgrAI和AscI位点。在电穿孔进入ES细胞之前用AscI或PacI消化将此打靶载体线性化。
实施例10:反义链介导的Beer失活
以重叠格式制备17-个核苷酸的反义寡核苷酸,以此方式,第一寡核苷酸的5′末端与Beer转录物的翻译起始AUG重叠,接连着的寡核苷酸的5’末端相对于Beer AUG而言沿5’方向滚动增加的5个核苷酸处(最多在离其50个核苷酸处)。设计并制备对应的对照寡核苷酸,所用的碱基组成相当,但在序列中重新分布以抑制其与编码mRNA的任何显著杂交。通过阳离子脂质投递而将试剂投递至待测细胞体系(P.L.Felgner,Proc.Natl.Acad.Sci.USA 84:7413,1987)。将2μg反义寡核苷酸加入100μl简化血清培养基(Opti-MEM I简化血清培养基,Life Technologies,Gaithersburg MD)中,并在100μl简化血清培养基中与Lipofectin试剂(6μl)(Life Technologies,Gaithersburg MD)混合。将这些试剂混合后,在室温络合30分钟,并将混合物加入预先接种的MC3T3E21或KS483细胞中。培养这些细胞并回收mRNA。利用RT-PCR并结合Beer特异引物监测Beer mRNA。此外,收集分开的实验孔并如实施例4所述通过western印迹法鉴定蛋白质水平。收获细胞后,重悬于裂解缓冲液(50mM Tris pH 7.5,20mM NaCl,1mM EDTA,1% SDS)中并收集可溶性蛋白。将此材料加至10-20%梯度变性SDS PAGE中。将被分开的蛋白质转移至硝酸纤维素滤膜上,并利用如上所述的抗体试剂进行western印迹分析。平行地,将对照寡核苷酸加入相同的培养物中并重复实验操作。如果与对照混合的寡核苷酸相比,在各情况下用反义寡核苷酸处理导致50%的改变,则BeermRNA或蛋白质水平的降低被认为是显著的。此方法能使得选择性失活基因并随后对组织培养模型中的矿物化结节进行表型表征。
实施例11:硬化素核心区的模型模拟
同源性识别技术(例如,PSI-BLAST(Altschul等,Nucleic AcidsRes.25:3389-402(1997))、FUGUE(Shi等,J.Mol.Biol.310:243-57(2001))暗示SOST(SOST_Core)的核心区采取了胱氨酸结折叠的形式。FUGUE是检测序列与结构之间同源性的灵敏方法。实验测定的3D结构已知的人绒毛膜促性腺激素β(hCG-β)通过FUGUE(Shi等,同上)被确定为SOST_Core最接近的同源物。因此,hCG-β被用作结构模板来构建SOST_Core的3D模型。
SOST_Core与其密切同源物的序列比对如图7中所示。在序列比对所显示的同源物中,只有hCG-β(CGHB)具有已知的3D结构。SOST_Core和hCG-β之间的序列同一性大约为25%。在整个家族中有8个CYS残基是保守的,加强了SOST_Core和hCG-β之间整体结构的相似性。在“结”构型中三对胱氨酸(1-5,3-7,4-8)形成二硫键(在图7中以实心线表示),它是胱氨酸-结折叠的特征。在图7中显示为虚线的一个额外二硫键(2-6)对于此家族而言是独特的,将此家族蛋白质与其它胱氨酸-结家族蛋白质(例如,TGF-β,BMP)区别开来。
用PDB(Berman等,Acta Crystallogr.D.Biol.Crystallogr.58(Pt 6 Pt1):899-907(2002))登录号1HCN,以hCG-β的3D结构(Wuet al.,Structure 2:545-58(1994))作为结构模板模拟SOST_Core。用MODELER(Sali & Blundell,J.Mol.Biol.234:779-815(1993))对模型进行计算。最佳模型的快照如图8中所示。
大部分胱氨酸-结蛋白质形成二聚体,因为在单体中缺乏疏水核心(Scheufler等,同上;Schlunegger和Grut ter,J.Mol.Biol.231:445-58(1993));Wu等,同上)。SOST很可能遵循相似的规则并形成均二聚体以提高其稳定性。构建二聚体化SOST_Core区的模型有几个难题,因为(1)SOST_Core和hCG-β之间的序列相似性较低(25%);(2)hCG-β不形成均二聚体,而是与hCG-α形成杂二聚体;且(3)在来自不同家族的二聚体化胱氨酸-结蛋白质中观察到许多相对构象不同的单体(例如,PDGF,TGF-β,神经营养蛋白,IL-17F,促性腺激素),这表明SOST的二聚体构象可能明显与hCG-α/β杂二聚体构象不同。在构建模型时,用结构叠加技术与手工调整相结合,将hCG-α置换为来自杂二聚体结构(1HCN)的hCG-β,然后按照假hCG-β均二聚体结构建立SOST_Core均二聚体。最后的模型如图9中所示。
实施例12:模拟SOST-BMP相互作用
此实施例描述了BMP上I型和II型受体的蛋白质模拟,其中涉及BMP和SOST之间的相互作用。
竞争性研究证实了SOST与I型和II型受体竞争性结合BMP。在基于ELISA的竞争性试验中,BMP-6与硬化素-包被的表面(300ng/孔)以高亲和力(KD=3.4nM)选择性地相互作用。提高量的BMP受体IA(FC融合构建体)可与硬化素竞争结合BMP-6(11nM)(IC50=114nM)。10倍摩尔浓度过量的BMP受体足以使硬化素与BMP-6的结合减少大约50%。用BMP受体II-FC融合蛋白(IC50=36nM)和DAN(IC50=43nM)也观察到此竞争作用。该检测法的特异性表现为在硬化素和rActivinR1B-FC融合蛋白之间缺乏与BMP-6结合的竞争作用,所述的rActivinR1B-FC融合蛋白是不结合BMP的TGF-β受体家族成员。
BMP多肽上的I型和II型受体结合位点已被作图,并且在空间上是分离的(Scheufler等,同上文;Innis等,同上文;Nickel等,同上文;Hart等,同上文)。头蛋白是以高亲和力与BMP结合的另一种BMP拮抗剂,它通过头蛋白的N末端部分在I型和II型受体结合位点处都与BMP接触(Groppe等,同上文)。在接近C末端的核心区内的两条β-链也在II型受体结合位点处接触BMP。
手工调校的头蛋白和SOST的序列比对显示这两种多肽在蛋白质N末端部分之间和核心区之间共有序列相似性。氨基酸序列比对如图10中所示。形成特征性cys-结的半胱氨酸残基在头蛋白和SOST之间是保守的。总体序列同一性是24%,而N末端结合区(序列比对位置1-45)内的序列同一性是33%。在头蛋白N-末端结合区内的两个残基,即在序列比对中第21位的Leu(L)和第23位的Glu(E),据报道在BMP结合中起重要作用(Groppe等,同上文)。这两个残基在SOST中也是保守的。核心区(序列比对的第131-228位)内的序列相似性大约为20%,但cys-结骨架被保持,且足够数目的关键残基是保守的,这证实了头蛋白和SOST之间的同源性。
此外还将头蛋白结构与SOST比较以了解两个SOST单体是如何二聚体化的。正如图11中所示的,头蛋白结构暗示N末端区和核心区之间的接头不仅在连接这两个区域之间起作用,还形成了两头蛋白单体之间二聚化界面的部分。头蛋白和SOST之间的一个主要差异是N末端区和核心区之间的接头在SOST中要低得多。
SOST的C末端区可能在SOST二聚化的过程中发挥作用。头蛋白的序列结束于核心区,而SOST则有一额外的C末端区。在头蛋白结构中,两个头蛋白单体的C末端以二硫键连接。因而,SOST的C末端区开始向两个单体的界面靠近,并且可能有助于二聚化。此外,二级结构预测显示SOSR C末端区的某些部分有形成螺旋的趋势。SOST中的该区域可能负责二聚化活性,有可能是通过螺旋-螺旋堆积实现的,这模拟了头蛋白中较长接头的功能。头蛋白和SOST结构之间的另一差异是在SOST核心区内序列比对的第169-185位的氨基酸插入序列(见图10)。此插入延长了β-发夹,它指向头蛋白结构中的二聚化界面(在图11中显示为在单体中间且在C末端半胱氨酸残基上方的环形区)。此延长的β-发夹还可能有助于SOST二聚化。
实施例13:SOST肽免疫原的设计和制备
此实施例描述了SOST肽免疫原的有关设计,所述免疫原用于免疫动物并产生阻断BMP和SOST之间相互作用以及阻止SOST单体形成二聚体的抗体。
BMP结合片段
SOST和头蛋白之间的总体相似性以及这两种多肽在N末端区之间的相似性显示SOST可能以类似头蛋白的方式与BMP相互作用。即,SOST的N末端区可能与BMP上I型和II型受体结合位点都相互作用,而核心区的部分(图10中氨基酸序列比对的第190-220位)可能与II型受体结合位点相互作用,从而使得特异于这些SOST区的抗体可能阻断或削弱BMP对SOST的结合。
大鼠和人SOST的这些SOST多肽片段的氨基酸序列提供如下。
SOST_N_接头:N末端区(包括与核心区连接的短接头)
人:QGWQAFKNDATEIIPELGEYPEPPPELENNKTMNRAE
NGGRPPHHPFETKDVSEYS(SEQ ID NO:92)
大鼠:QGWQAFKNDATEIIPGLREYPEPPQELENNQTMNRAEN
GGRPPHHPYDTKDVSEYS(SEQ ID NO:93)
SOST_核心_结合:可能在其II型受体结合位点处接触BMP的核心区部分(在两个末端处都稍有延长以包含CYS残基锚):
人:CIPDRYRAQRVQLLCPGGEAPRARKVRLVASC(SEQ ID NO:94)
大鼠:CIPDRYRAQRVQLLCPGGAAPRSRKVRLVASC(SEQ ID NO:95)
SOST二聚化片段
SOST的C末端区域有可能涉及SOST均二聚体的形成(见实施例12)。延长的β-发夹也可能在均二聚体的形成中发挥作用。特异性地结合这些区域的抗体可阻止或削弱SOST单体的二聚化,这可能反过来干扰SOST和BMP之间的相互作用。在大鼠和人SOST中相应于这些区域的多肽片段如下。
SOST_C:C末端区域
人:LTRFHNQSELKDFGTEAARPQKGRKPRPRARSAKANQA
ELENAY(SEQ ID NO:96)
大鼠:LTRFHNQSELKDFGPETARPQKGRKPRPRARGAKANQAE
LENAY(SEQ ID NO:97)
SOST_核心_二聚体:SOST二聚化中可能涉及的核心区部分(在两个末端处都稍有延长以包含CYS残基锚):
人:CGPARLLPNAIGRGKWWRPSGPDFRC(SEQ ID NO:98)
大鼠:CGPARLLPNAIGRVKWWRPNGPDFRC(SEQ ID NO:99)
SOST N-末端的BMP结合片段
以头蛋白/BMP-7复合物结构(蛋白质数据库录入号:1M4U)和氨基酸序列比对(见图10)为基础模拟关键的SOSTN末端结合区(图10中序列比对的第1-35位)以鉴定有可能与BMP相互作用的SOST N末端氨基酸残基。SOST模型如图12中所示。在比较模型中,SOST序列中序列比对第8位(见箭头所指和附属的文字说明)处的苯丙氨酸(Phe,F)伸入BMP二聚体表面上的疏水性口袋内。在BMP和I型受体复合物结构中观察到同样的“结入孔”特征(Nickel等,同上文),其中受体的Phe85嵌入同一口袋中,这是针对TGF-β超家族成员的配体-I型受体识别中的关键特征(包括例如TGF-β家族、BMP家族,等等)。依照该模型,脯氨酸(Pro)介导的转角也是保守的,它使N末端结合片段沿BMP二聚体表面延伸,从I型受体结合位点运动至复合物另一侧的II型受体结合位点。接近结合片段羧基末端的另一Pro介导的转角也是保守的,它与接头区连接。在图12中可明显显示了SOST和BMP之间的广泛接触。
肽免疫原
将肽设计成包含预计与BMP蛋白质相接触的SOST N-末端区。肽序列如下所示。为了免疫动物,将肽序列设计成交迭的,并将一额外的半胱氨酸加至C末端以便于与KLH交联。然后将所述肽用于免疫动物。免疫原的肽序列如下。
人SOST:
QGWQAFKNDATEIIPELGEY(SEQ ID NO:47)
TEIIPELGEYPEPPPELENN(SEQ ID NO:48)
PEPPPELENNKTMNRAENGG(SEQ ID NO:49)
KTMNRAENGGRPPHHPFETK(SEQ ID NO:50)
RPPHHPFETKDVSEYS(SEQ ID NO:51)
具有额外半胱氨酸的人SOST肽:
QGWQAFKNDATEIIPELGEY-C(SEQ ID NO:52)
TEIIPELGEYPEPPPELENN-C(SEQ ID NO:53)
PEPPPELENNKTMNRAENGG-C(SEQ ID NO:54)
KTMNRAENGGRPPHHPFETK-C(SEQ ID NO:55)
RPPHHPFETKDVSEYS-C(SEQ ID NO:56)
大鼠SOST:
QGWQAFKNDATEIIPGLREYPEPP(SEQ ID NO:57)
PEPPQELENNQTMNRAENGG(SEQ ID NO:58)
ENGGRPPHHPYDTKDVSEYS(SEQ ID NO:59)
TEIIPGLREYPEPPQELENN(SEQ ID NO:60)
具有额外半胱氨酸的大鼠SOST肽:
QGWQAFKNDATEIIPGLREYPEPP-C(SEQ ID NO:61)
PEPPQELENNQTMNRAENGG-C(SEQ ID NO:62)
ENGGRPPHHPYDTKDVSEYS-C(SEQ ID NO:63)
TEIIPGLREYPEPPQELENN-C(SEQ ID NO:64)
以下肽被设计成包含预计与BMP蛋白质接触的核心区部分的氨基酸。将半胱氨酸加到各肽的C末端以便与KLH连接,并将连接后的肽用于免疫动物。在停泊性核心N末端肽中,内部的半胱氨酸被改变成丝氨酸以避免与KLH的双重连接。
针对人SOST:
未添加半胱氨酸残基的氨基酸序列:
停泊_核心_N-末端_肽:IPDRYRAQRVQLLCPGGEAP(SEQ ID NO:66)
停泊_核心_C末端_肽:QLLCPGGEAPRARKVRLVAS(SEQ ID NO:67)
停泊_核心_N-末端_肽:IPDRYRAQRVQLLCPGGEAP-C(SEQ IDNO:68)
停泊_核心_C末端_肽:QLLCPGGEAPRARKVRLVAS-C(SEQ ID NO:69)
针对大鼠SOST:
无半胱氨酸残基添加或取代的氨基酸序列:
停泊_核心_N-末端_肽:IPDRYRAQRVQLLSPGG(SEQ ID NO:70)
停泊_核心_C末端_肽:PGGAAPRSRKVRLVAS(SEQ ID NO:71)
有半胱氨酸加入和取代的肽免疫原:
停泊_核心_N-末端_肽:IPDRYRAQRVQLLSPGG-C(SEQ ID NO:72)
停泊_核心_C末端_肽:PGGAAPRSRKVRLVAS-C(SEQ ID NO:73)
SOST内有可能相互作用而形成SOST均二聚体的两个区域包括头蛋白中不存在的SOST核心区域的氨基酸。被设计成包含此序列的人SOST肽具有与KLH缀合的C末端或N末端半胱氨酸。对于大鼠SOST肽而言,将一半胱氨酸加到序列(SEQ ID NO:76)的羧基末端。用与KLH缀合的肽免疫动物。
对于人SOST:
CGPARLLPNAIGRGKWWRPS(SEQ ID NO:74)
IGRGKWWRPSGPDFRC(SEQ ID NO:75)
对于大鼠SOST:
PNAIGRVKWWRPNGPDFR(SEQ ID NO:76)
添加了半胱氨酸的大鼠SOST肽
PNAIGRVKWWRPNGPDFR-C(SEQ ID NO:77)
SOST内有可能相互作用而形成SOST均二聚体的第二个区域包括C末端区。将肽免疫原设计成包括此区域内的氨基酸序列(见下文)。为了与KLH缀合,将一半胱氨酸残基加至C末端,并用缀合后的肽免疫动物。
适于人SOST:
KRLTRFHNQS ELKDFGTEAA(SEQ ID NO:78)
ELKDFGTEAARPQKGRKPRP(SEQ ID NO:79)
RPQKGRKPRP RARSAKANQA(SEQ ID NO:80)
RARSAKANQA ELENAY(SEQ ID NO:81)
在C末端添加了半胱氨酸的肽免疫原:
KRLTRFHNQS ELKDFGTEAA-C(SEQ ID NO:82)
ELKDFGTEAA RPQKGRKPRP-C(SEQ ID NO:83)
RPQKGRKPRP RARSAKANQA-C(SEQ ID NO:84)
RARSAKANQA ELENAY-C(SEQ ID NO:85)
对于大鼠SOST:
KRLTRFHNQSELKDFGPETARPQ(SEQ ID NO:86)
KGRKPRPRARGAKANQAELENAY(SEQ ID NO:87)
SELKDFGPETARPQKGRKPRPRAR(SEQ ID NO:88)
在C末端添加了半胱氨酸的肽免疫原:
KRLTRFHNQSELKDFGPETARPQ-C(SEQ ID NO:89)
KGRKPRPRARGAKANQAELENAY-C(SEQ ID NO:90)
SELKDFGPETARPQKGRKPRPRAR-C(SEQ ID NO:91)
实施例14:检测抗体与TGF-β结合蛋白的结合的检测法
此实施例描述了用于检测例如抗体或抗体片段等配体与硬化素的结合的检测法。
依照制造商(Sigma Aldrich,St.Louis,MO)的方案并如美国专利6,395,511中所述制备FLAG-硬化素融合蛋白。用抗FLAG-单克隆抗体(Sigma Aldrich)包被96孔微量滴定板的各孔,然后用溶于PBS的10%BSA封闭。将融合蛋白(20ng)加入100μl PBS/0.2%BSA中并在室温吸附于96孔板上60分钟。去除此蛋白质溶液,并漂洗各孔,以去除未结合的融合蛋白质。将诸如BMP-4、BMP-5、BMP-6或BMP-7等BMP稀释于PBS/0.2%BSA中,并以10pM至500nM范围的浓度加入各孔中。室温保温2小时后,去除结合溶液,并用200μl体积的PBS/0.2%BSA漂洗平板三次。依照标准ELISA技术用特异于BMP的多克隆抗血清或单克隆抗体以及适当酶缀合的第二步试剂检测BMP与硬化素的结合(参阅,例如,Ausubel等,分子生物学通用方法(CurrentProtocols in Mol Biol.)Vol 2 11.2.1-11.2.22(1998))。通过从总结合量中扣除非特异性结合来计算特异性结合并用LIGAND软件进行分析(Munson和Podbard,Anal.Biochem.107:220-39(1980))。
此外还用均一时间解析荧光检测法探测硬化素与BMP的结合(Mellor等,J Biomol.Screening,3:91-99(1998))。依照本领域已知及本文所述方法将编码硬化素的多核苷酸序列与重组核酸构建体中的人免疫球蛋白恒定区有效连接,并表达为人Fc-硬化素融合蛋白。同样的,改造BMP配体并表达为BMP-小鼠Fc融合蛋白。将这两个融合蛋白一起保温并如Mellor等所述进行检测。
实施例15:针对抑制TGF-β家族成员与TGF-β结合蛋白相结合的抗体的筛选试验
此实施例描述了用于检测抑制TGF-β家族成员与硬化素相结合的抗体的方法。基本上如实施例14中所述进行ELISA,不同之处在于BMP浓度固定为其Kd值(例如,通过BIAcore分析测定)。此外,将抗体或抗体文库或集合以1μM的浓度加入孔中。将抗体与BMP和硬化素在室温保温2小时,去除溶液,如上文所述对结合的BMP进行定量(参阅实施例14)。抑制无抗体存在情况下所观察到的BMP结合达40%的抗体被认为是此相互作用的拮抗物。通过进行滴定试验测定其抑制常数以及它们对TGF-B结合蛋白结合亲和力的作用,将这些抗体作为潜在的抑制剂进一步评估。还可用依赖于BMP配体作用的检测法(例如,BMP/BMP受体竞争性试验)进行可比较的特异性对照试验,以确定已鉴定的拮抗物的选择性曲线。
实施例16:对TGF-β结合蛋白定位于骨基质的抑制
利用Nicolas(Calcif.Tissue Int.57:206-12(1995))方法的修改版本进行骨基质定位的抑制作用的评估。简而言之,如Nicolas(同上文)所述制备125I-标记的TGF-β结合蛋白。将羟磷灰石加入配备了聚丙烯滤膜(Polyfiltroninc,Weymouth MA)的96孔微量滴定板的各孔中。将TGF-β结合蛋白稀释于含0.2%白蛋白的PBS缓冲液中并随后加入孔中。用含0.2%白蛋白的PBS缓冲液漂洗包含基质的孔三次。用0.3M NaOH洗脱被吸附的TGF-β结合蛋白并随后进行定量。
通过将TGF-β结合蛋白与抗体一起保温并如上所述将此混合物施加到基质中来鉴定抑制或削弱硬化素TGF-β结合蛋白与羟磷灰石结合的抗体。将所述基质用含0.2%白蛋白的PBS缓冲液洗3次。用0.3M NaOH洗脱被吸附的硬化素并随后进行定量。与无抗体存在条件下观察到的结合水平相比,对硬化素与羟磷灰石的结合水平至少抑制40%的抗体被认为是骨定位的抑制剂。在剂量反应试验中对这种抗体进一步定性,以测定其抑制常数和它对TGF-B结合蛋白结合亲和力的影响。
综上所述,尽管为了便于说明的目的在此描述了本发明的特殊实施方案,但是可以对它们进行各种修改而并不偏离本发明的精神和范围。因此,本发明并不只局限于所附的权利要求。
序列表
<110>Brunkow,Mary E.
Galas,David J.
Kovacevich,Brian
Mulligan,John T.
Paeper,Bryan W.
Van Ness,Jeffrey
Winkler,David G.
<120>用于增加骨矿化的组合物和方法
<130>60117-136
<140>
<141>2004-06-15
<150>US 10/463,190
<151>2003-06-16
<160>143
<170>FastSEQ for Windows Version 3.0
<210>1
<211>2301
<212>DNA
<213>Homo sapien
<400>1
agagcctgtg ctactggaag gtggcgtgcc ctcctctggc tggtaccatg cagctcccac 60
tggccctgtg tctcgtctgc ctgctggtac acacagcctt ccgtgtagtg gagggccagg 120
ggtggcaggc gttcaagaat gatgccacgg aaatcatccc cgagctcgga gagtaccccg 180
agcctccacc ggagctggag aacaacaaga ccatgaaccg ggcggagaac ggagggcggc 240
ctccccacca cccctttgag accaaagacg tgtccgagta cagctgccgc gagctgcact 300
tcacccgcta cgtgaccgat gggccgtgcc gcagcgccaa gccggtcacc gagctggtgt 360
gctccggcca gtgcggcccg gcgcgcctgc tgcccaacgc catcggccgc ggcaagtggt 420
ggcgacctag tgggcccgac ttccgctgca tccccgaccg ctaccgcgcg cagcgcgtgc 480
agctgctgtg tcccggtggt gaggcgccgc gcgcgcgcaa ggtgcgcctg gtggcctcgt 540
gcaagtgcaa gcgcctcacc cgcttccaca accagtcgga gctcaaggac ttcgggaccg 600
aggccgctcg gccgcagaag ggccggaagc cgcggccccg cgcccggagc gccaaagcca 660
accaggccga gctggagaac gcctactaga gcccgcccgc gcccctcccc accggcgggc 720
gccccggccc tgaacccgcg ccccacattt ctgtcctctg cgcgtggttt gattgtttat 780
atttcattgt aaatgcctgc aacccagggc agggggctga gaccttccag gccctgagga 840
atcccgggcg ccggcaaggc ccccctcagc ccgccagctg aggggtccca cggggcaggg 900
gagggaattg agagtcacag acactgagcc acgcagcccc gcctctgggg ccgcctacct 960
ttgctggtcc cacttcagag gaggcagaaa tggaagcatt ttcaccgccc tggggtttta 1020
agggagcggt gtgggagtgg gaaagtccag ggactggtta agaaagttgg ataagattcc 1080
cccttgcacc tcgctgccca tcagaaagcc tgaggcgtgc ccagagcaca agactggggg 1140
caactgtaga tgtggtttct agtcctggct ctgccactaa cttgctgtgt aaccttgaac 1200
tacacaattc tccttcggga cctcaatttc cactttgtaa aatgagggtg gaggtgggaa 1260
taggatctcg aggagactat tggcatatga ttccaaggac tccagtgcct tttgaatggg 1320
cagaggtgag agagagagag agaaagagag agaatgaatg cagttgcatt gattcagtgc 1380
caaggtcact tccagaattc agagttgtga tgctctcttc tgacagccaa agatgaaaaa 1440
caaacagaaa aaaaaaagta aagagtctat ttatggctga catatttacg gctgacaaac 1500
tcctggaaga agctatgctg cttcccagcc tggcttcccc ggatgtttgg ctacctccac 1560
ccctccatct caaagaaata acatcatcca ttggggtaga aaaggagagg gtccgagggt 1620
ggtgggaggg atagaaatca catccgcccc aacttcccaa agagcagcat ccctcccccg 1680
acccatagcc atgttttaaa gtcaccttcc gaagagaagt gaaaggttca aggacactgg 1740
ccttgcaggc ccgagggagc agccatcaca aactcacaga ccagcacatc ccttttgaga 1800
caccgccttc tgcccaccac tcacggacac atttctgcct agaaaacagc ttcttactgc 1860
tcttacatgt gatggcatat cttacactaa aagaatatta ttgggggaaa aactacaagt 1920
gctgtacata tgctgagaaa ctgcagagca taatagctgc cacccaaaaa tctttttgaa 1980
aatcatttcc agacaacctc ttactttctg tgtagttttt aattgttaaa aaaaaaaagt 2040
tttaaacaga agcacatgac atatgaaagc ctgcaggact ggtcgttttt ttggcaattc 2100
ttccacgtgg gacttgtcca caagaatgaa agtagtggtt tttaaagagt taagttacat 2160
atttattttc tcacttaagt tatttatgca aaagtttttc ttgtagagaa tgacaatgtt 2220
aatattgctt tatgaattaa cagtctgttc ttccagagtc cagagacatt gttaataaag 2280
acaatgaatc atgaccgaaa g 2301
<210>2
<211>213
<212>PRT
<213>Homo sapien
<400>2
Met Gln Leu Pro Leu Ala Leu Cys Leu Val Cys Leu Leu Val His Thr
1 5 10 15
Ala Phe Arg Val Val Glu Gly Gln Gly Trp Gln Ala Phe Lys Asn Asp
20 25 30
Ala Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro
35 40 45
Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg
50 55 60
Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser Cys
65 70 75 80
Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg Ser
85 90 95
Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala
100 105 110
Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser
115 120 125
Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val
130 135 140
Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg
145 150 155 160
Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln
165 170 175
Ser Glu Leu Lys Asp Phe Gly Thr Glu Ala Ala Arg Pro Gln Lys Gly
180 185 190
Arg Lys Pro Arg Pro Arg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu
195 200 205
Leu Glu Asn Ala Tyr
210
<210>3
<211>2301
<212>DNA
<213>Homo sapien
<400>3
agagcctgtg ctactggaag gtggcgtgcc ctcctctggc tggtaccatg cagctcccac 60
tggccctgtg tctcgtctgc ctgctggtac acacagcctt ccgtgtagtg gagggctagg 120
ggtggcaggc gttcaagaat gatgccacgg aaatcatccc cgagctcgga gagtaccccg 180
agcctccacc ggagctggag aacaacaaga ccatgaaccg ggcggagaac ggagggcggc 240
ctccccacca cccctttgag accaaagacg tgtccgagta cagctgccgc gagctgcact 300
tcacccgcta cgtgaccgat gggccgtgcc gcagcgccaa gccggtcacc gagctggtgt 360
gctccggcca gtgcggcccg gcgcgcctgc tgcccaacgc catcggccgc ggcaagtggt 420
ggcgacctag tgggcccgac ttccgctgca tccccgaccg ctaccgcgcg cagcgcgtgc 480
agctgctgtg tcccggtggt gaggcgccgc gcgcgcgcaa ggtgcgcctg gtggcctcgt 540
gcaagtgcaa gcgcctcacc cgcttccaca accagtcgga gctcaaggac ttcgggaccg 600
aggccgctcg gccgcagaag ggccggaagc cgcggccccg cgcccggagc gccaaagcca 660
accaggccga gctggagaac gcctactaga gcccgcccgc gcccctcccc accggcgggc 720
gccccggccc tgaacccgcg ccccacattt ctgtcctctg cgcgtggttt gattgtttat 780
atttcattgt aaatgcctgc aacccagggc agggggctga gaccttccag gccctgagga 840
atcccgggcg ccggcaaggc ccccctcagc ccgccagctg aggggtccca cggggcaggg 900
gagggaattg agagtcacag acactgagcc acgcagcccc gcctctgggg ccgcctacct 960
ttgctggtcc cacttcagag gaggcagaaa tggaagcatt ttcaccgccc tggggtttta 1020
agggagcggt gtgggagtgg gaaagtccag ggactggtta agaaagttgg ataagattcc 1080
cccttgcacc tcgctgccca tcagaaagcc tgaggcgtgc ccagagcaca agactggggg 1140
caactgtaga tgtggtttct agtcctggct ctgccactaa cttgctgtgt aaccttgaac 1200
tacacaattc tccttcggga cctcaatttc cactttgtaa aatgagggtg gaggtgggaa 1260
taggatctcg aggagactat tggcatatga ttccaaggac tccagtgcct tttgaatggg 1320
cagaggtgag agagagagag agaaagagag agaatgaatg cagttgcatt gattcagtgc 1380
caaggtcact tccagaattc agagttgtga tgctctcttc tgacagccaa agatgaaaaa 1440
caaacagaaa aaaaaaagta aagagtctat ttatggctga catatttacg gctgacaaac 1500
tcctggaaga agctatgctg cttcccagcc tggcttcccc ggatgtttgg ctacctccac 1560
ccctccatct caaagaaata acatcatcca ttggggtaga aaaggagagg gtccgagggt 1620
ggtgggaggg atagaaatca catccgcccc aacttcccaa agagcagcat ccctcccccg 1680
acccatagcc atgttttaaa gtcaccttcc gaagagaagt gaaaggttca aggacactgg 1740
ccttgcaggc ccgagggagc agccatcaca aactcacaga ccagcacatc ccttttgaga 1800
caccgccttc tgcccaccac tcacggacac atttctgcct agaaaacagc ttcttactgc 1860
tcttacatgt gatggcatat cttacactaa aagaatatta ttgggggaaa aactacaagt 1920
gctgtacata tgctgagaaa ctgcagagca taatagctgc cacccaaaaa tctttttgaa 1980
aatcatttcc agacaacctc ttactttctg tgtagttttt aattgttaaa aaaaaaaagt 2040
tttaaacaga agcacatgac atatgaaagc ctgcaggact ggtcgttttt ttggcaattc 2100
ttccacgtgg gacttgtcca caagaatgaa agtagtggtt tttaaagagt taagttacat 2160
atttattttc tcacttaagt tatttatgca aaagtttttc ttgtagagaa tgacaatgtt 2220
aatattgctt tatgaattaa cagtctgttc ttccagagtc cagagacatt gttaataaag 2280
acaatgaatc atgaccgaaa g 2301
<210>4
<211>23
<212>PRT
<213>Homo sapien
<400>4
Met Gln Leu Pro Leu Ala Leu Cys Leu Val Cys Leu Leu Val His Thr
1 5 10 15
Ala Phe Arg Val Val Glu Gly
20
<210>5
<211>2301
<212>DNA
<213>Homo sapien
<400>5
agagcctgtg ctactggaag gtggcgtgcc ctcctctggc tggtaccatg cagctcccac 60
tggccctgtg tctcatctgc ctgctggtac acacagcctt ccgtgtagtg gagggccagg 120
ggtggcaggc gttcaagaat gatgccacgg aaatcatccg cgagctcgga gagtaccccg 180
agcctccacc ggagctggag aacaacaaga ccatgaaccg ggcggagaac ggagggcggc 240
ctccccacca cccctttgag accaaagacg tgtccgagta cagctgccgc gagctgcact 300
tcacccgcta cgtgaccgat gggccgtgcc gcagcgccaa gccggtcacc gagctggtgt 360
gctccggcca gtgcggcccg gcgcgcctgc tgcccaacgc catcggccgc ggcaagtggt 420
ggcgacctag tgggcccgac ttccgctgca tccccgaccg ctaccgcgcg cagcgcgtgc 480
agctgctgtg tcccggtggt gaggcgccgc gcgcgcgcaa ggtgcgcctg gtggcctcgt 540
gcaagtgcaa gcgcctcacc cgcttccaca accagtcgga gctcaaggac ttcgggaccg 600
aggccgctcg gccgcagaag ggccggaagc cgcggccccg cgcccggagc gccaaagcca 660
accaggccga gctggagaac gcctactaga gcccgcccgc gcccctcccc accggcgggc 720
gccccggccc tgaacccgcg ccccacattt ctgtcctctg cgcgtggttt gattgtttat 780
atttcattgt aaatgcctgc aacccagggc agggggctga gaccttccag gccctgagga 840
atcccgggcg ccggcaaggc ccccctcagc ccgccagctg aggggtccca cggggcaggg 900
gagggaattg agagtcacag acactgagcc acgcagcccc gcctctgggg ccgcctacct 960
ttgctggtcc cacttcagag gaggcagaaa tggaagcatt ttcaccgccc tggggtttta 1020
agggagcggt gtgggagtgg gaaagtccag ggactggtta agaaagttgg ataagattcc 1080
cccttgcacc tcgctgccca tcagaaagcc tgaggcgtgc ccagagcaca agactggggg 1140
caactgtaga tgtggtttct agtcctggct ctgccactaa cttgctgtgt aaccttgaac 1200
tacacaattc tccttcggga cctcaatttc cactttgtaa aatgagggtg gaggtgggaa 1260
taggatctcg aggagactat tggcatatga ttccaaggac tccagtgcct tttgaatggg 1320
cagaggtgag agagagagag agaaagagag agaatgaatg cagttgcatt gattcagtgc 1380
caaggtcact tccagaattc agagttgtga tgctctcttc tgacagccaa agatgaaaaa 1440
caaacagaaa aaaaaaagta aagagtctat ttatggctga catatttacg gctgacaaac 1500
tcctggaaga agctatgctg cttcccagcc tggcttcccc ggatgtttgg ctacctccac 1560
ccctccatct caaagaaata acatcatcca ttggggtaga aaaggagagg gtccgagggt 1620
ggtgggaggg atagaaatca catccgcccc aacttcccaa agagcagcat ccctcccccg 1680
acccatagcc atgttttaaa gtcaccttcc gaagagaagt gaaaggttca aggacactgg 1740
ccttgcaggc ccgagggagc agccatcaca aactcacaga ccagcacatc ccttttgaga 1800
caccgccttc tgcccaccac tcacggacac atttctgcct agaaaacagc ttcttactgc 1860
tcttacatgt gatggcatat cttacactaa aagaatatta ttgggggaaa aactacaagt 1920
gctgtacata tgctgagaaa ctgcagagca taatagctgc cacccaaaaa tctttttgaa 1980
aatcatttcc agacaacctc ttactttctg tgtagttttt aattgttaaa aaaaaaaagt 2040
tttaaacaga agcacatgac atatgaaagc ctgcaggact ggtcgttttt ttggcaattc 2100
ttccacgtgg gacttgtcca caagaatgaa agtagtggtt tttaaagagt taagttacat 2160
atttattttc tcacttaagt tatttatgca aaagtttttc ttgtagagaa tgacaatgtt 2220
aatattgctt tatgaattaa cagtctgttc ttccagagtc cagagacatt gttaataaag 2280
acaatgaatc atgaccgaaa g 2301
<210>6
<211>213
<212>PRT
<213>Homo sapien
<400>6
Met Gln Leu Pro Leu Ala Leu Cys Leu Ile Cys Leu Leu Val His Thr
1 5 10 15
Ala Phe Arg Val Val Glu Gly Gln Gly Trp Gln Ala Phe Lys Asn Asp
20 25 30
Ala Thr Glu Ile Ile Arg Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro
35 40 45
Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg
50 55 60
Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser Cys
65 70 75 80
Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg Ser
85 90 95
Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala
100 105 110
Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser
115 120 125
Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val
130 135 140
Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg
145 150 155 160
Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln
165 170 175
Ser Glu Leu Lys Asp Phe Gly Thr Glu Ala Ala Arg Pro Gln Lys Gly
180 185 190
Arg Lys Pro Arg Pro Arg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu
195 200 205
Leu Glu Asn Ala Tyr
210
<210>7
<211>2301
<212>DNA
<213>Homo sapien
<400>7
agagcctgtg ctactggaag gtggcgtgcc ctcctctggc tggtaccatg cagctcccac 60
tggccctgtg tctcgtctgc ctgctggtac acacagcctt ccgtgtagtg gagggccagg 120
ggtggcaggc gttcaagaat gatgccacgg aaatcatccg cgagctcgga gagtaccccg 180
agcctccacc ggagctggag aacaacaaga ccatgaaccg ggcggagaac ggagggcggc 240
ctccccacca cccctttgag accaaagacg tgtccgagta cagctgccgc gagctgcact 300
tcacccgcta cgtgaccgat gggccgtgcc gcagcgccaa gccggtcacc gagctggtgt 360
gctccggcca gtgcggcccg gcgcgcctgc tgcccaacgc catcggccgc ggcaagtggt 420
ggcgacctag tgggcccgac ttccgctgca tccccgaccg ctaccgcgcg cagcgcgtgc 480
agctgctgtg tcccggtggt gaggcgccgc gcgcgcgcaa ggtgcgcctg gtggcctcgt 540
gcaagtgcaa gcgcctcacc cgcttccaca accagtcgga gctcaaggac ttcgggaccg 600
aggccgctcg gccgcagaag ggccggaagc cgcggccccg cgcccggagc gccaaagcca 660
accaggccga gctggagaac gcctactaga gcccgcccgc gcccctcccc accggcgggc 720
gccccggccc tgaacccgcg ccccacattt ctgtcctctg cgcgtggttt gattgtttat 780
atttcattgt aaatgcctgc aacccagggc agggggctga gaccttccag gccctgagga 840
atcccgggcg ccggcaaggc ccccctcagc ccgccagctg aggggtccca cggggcaggg 900
gagggaattg agagtcacag acactgagcc acgcagcccc gcctctgggg ccgcctacct 960
ttgctggtcc cacttcagag gaggcagaaa tggaagcatt ttcaccgccc tggggtttta 1020
agggagcggt gtgggagtgg gaaagtccag ggactggtta agaaagttgg ataagattcc 1080
cccttgcacc tcgctgccca tcagaaagcc tgaggcgtgc ccagagcaca agactggggg 1140
caactgtaga tgtggtttct agtcctggct ctgccactaa cttgctgtgt aaccttgaac 1200
tacacaattc tccttcggga cctcaatttc cactttgtaa aatgagggtg gaggtgggaa 1260
taggatctcg aggagactat tggcatatga ttccaaggac tccagtgcct tttgaatggg 1320
cagaggtgag agagagagag agaaagagag agaatgaatg cagttgcatt gattcagtgc 1380
caaggtcact tccagaattc agagttgtga tgctctcttc tgacagccaa agatgaaaaa 1440
caaacagaaa aaaaaaagta aagagtctat ttatggctga catatttacg gctgacaaac 1500
tcctggaaga agctatgctg cttcccagcc tggcttcccc ggatgtttgg ctacctccac 1560
ccctccatct caaagaaata acatcatcca ttggggtaga aaaggagagg gtccgagggt 1620
ggtgggaggg atagaaatca catccgcccc aacttcccaa agagcagcat ccctcccccg 1680
acccatagcc atgttttaaa gtcaccttcc gaagagaagt gaaaggttca aggacactgg 1740
ccttgcaggc ccgagggagc agccatcaca aactcacaga ccagcacatc ccttttgaga 1800
caccgccttc tgcccaccac tcacggacac atttctgcct agaaaacagc ttcttactgc 1860
tcttacatgt gatggcatat cttacactaa aagaatatta ttgggggaaa aactacaagt 1920
gctgtacata tgctgagaaa ctgcagagca taatagctgc cacccaaaaa tctttttgaa 1980
aatcatttcc agacaacctc ttactttctg tgtagttttt aattgttaaa aaaaaaaagt 2040
tttaaacaga agcacatgac atatgaaagc ctgcaggact ggtcgttttt ttggcaattc 2100
ttccacgtgg gacttgtcca caagaatgaa agtagtggtt tttaaagagt taagttacat 2160
atttattttc tcacttaagt tatttatgca aaagtttttc ttgtagagaa tgacaatgtt 2220
aatattgctt tatgaattaa cagtctgttc ttccagagtc cagagacatt gttaataaag 2280
acaatgaatc atgaccgaaa g 2301
<210>8
<211>213
<212>PRT
<213>Homo sapien
<400>8
Met Gln Leu Pro Leu Ala Leu Cys Leu Val Cys Leu Leu Val His Thr
1 5 10 15
Ala Phe Arg Val Val Glu Gly Gln Gly Trp Gln Ala Phe Lys Asn Asp
20 25 30
Ala Thr Glu Ile Ile Arg Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro
35 40 45
Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg
50 55 60
Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser Cys
65 70 75 80
Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg Ser
85 90 95
Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala
100 105 110
Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser
115 120 125
Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val
130 135 140
Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg
145 150 155 160
Leu Val A1a Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn G1n
165 170 175
Ser Glu Leu Lys Asp Phe Gly Thr Glu Ala Ala Arg Pro Gln Lys Gly
180 185 190
Arg Lys Pro Arg Pro Arg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu
195 200 205
Leu Glu Asn Ala Tyr
210
<210>9
<211>642
<212>DNA
<213>Cercopithecus pygerythrus
<400>9
atgcagctcc cactggccct gtgtcttgtc tgcctgctgg tacacgcagc cttccgtgta 60
gtggagggcc aggggtggca ggccttcaag aatgatgcca cggaaatcat ccccgagctc 120
ggagagtacc ccgagcctcc accggagctg gagaacaaca agaccatgaa ccgggcggag 180
aatggagggc ggcctcccca ccaccccttt gagaccaaag acgtgtccga gtacagctgc 240
cgagagctgc acttcacccg ctacgtgacc gatgggccgt gccgcagcgc caagccagtc 300
accgagttgg tgtgctccgg ccagtgcggc ccggcacgcc tgctgcccaa cgccatcggc 360
cgcggcaagt ggtggcgccc gagtgggccc gacttccgct gcatccccga ccgctaccgc 420
gcgcagcgtg tgcagctgct gtgtcccggt ggtgccgcgc cgcgcgcgcg caaggtgcgc 480
ctggtggcct cgtgcaagtg caagcgcctc acccgcttcc acaaccagtc ggagctcaag 540
gacttcggtc ccgaggccgc tcggccgcag aagggccgga agccgcggcc ccgcgcccgg 600
ggggccaaag ccaatcaggc cgagctggag aacgcctact ag 642
<210>10
<211>213
<212>PRT
<213>Cercopithecus pygerythrus
<400>10
Met Gln Leu Pro Leu Ala Leu Cys Leu Val Cys Leu Leu Val His Ala
1 5 10 15
Ala phe Arg Val Val Glu Gly Gln Gly Trp Gln Ala Phe Lys Asn Asp
20 25 30
Ala Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro
35 40 45
Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg
50 55 60
Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser Cys
65 70 75 80
Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg Ser
85 90 95
Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala
100 105 110
Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser
115 120 125
Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val
130 135 140
Gln Leu Leu Cys Pro Gly Gly Ala Ala Pro Arg Ala Arg Lys Val Arg
145 150 155 160
Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln
165 170 175
Ser Glu Leu Lys Asp Phe Gly Pro Glu Ala Ala Arg Pro Gln Lys Gly
180 185 190
Arg Lys Pro Arg Pro Arg Ala Arg Gly Ala Lys Ala Asn Gln Ala Glu
195 200 205
Leu Glu Asn Ala Tyr
210
<210>11
<211>638
<212>DNA
<213>Mus musculus
<400>11
atgcagccct cactagcccc gtgcctcatc tgcctacttg tgcacgctgc cttctgtgct 60
gtggagggcc aggggtggca agccttcagg aatgatgcca cagaggtcat cccagggctt 120
ggagagtacc ccgagcctcc tcctgagaac aaccagacca tgaaccgggc ggagaatgga 180
ggcagacctc cccaccatcc ctatgacgcc aaaggtgtgt ccgagtacag ctgccgcgag 240
ctgcactaca cccgcttcct gacagacggc ccatgccgca gcgccaagcc ggtcaccgag 300
ttggtgtgct ccggccagtg cggccccgcg cggctgctgc ccaacgccat cgggcgcgtg 360
aagtggtggc gcccgaacgg accggatttc cgctgcatcc cggatcgcta ccgcgcgcag 420
cgggtgcagc tgctgtgccc cgggggcgcg gcgccgcgct cgcgcaaggt gcgtctggtg 480
gcctcgtgca agtgcaagcg cctcacccgc ttccacaacc agtcggagct caaggacttc 540
gggccggaga ccgcgcggcc gcagaagggt cgcaagccgc ggcccggcgc ccggggagcc 600
aaagccaacc aggcggagct ggagaacgcc tactagag 638
<210>12
<211>211
<212>PRT
<213>Mus musculus
<400>12
Met Gln Pro Ser Leu Ala Pro Cys Leu Ile Cys Leu Leu Val His Ala
1 5 10 15
Ala Phe Cys Ala Val Glu Gly Gln Gly Trp Gln Ala Phe Arg Asn Asp
20 25 30
Ala Thr Glu Val Ile Pro Gly Leu Gly Glu Tyr Pro Glu Pro Pro Pro
35 40 45
Glu Asn Asn Gln Thr Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro
50 55 60
His His Pro Tyr Asp Ala Lys Asp Val Ser Glu Tyr Ser Cys Arg Glu
65 70 75 80
Leu His Tyr Thr Arg Phe Leu Thr Asp Gly Pro Cys Arg Ser Ala Lys
85 90 95
Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala Arg Leu
100 105 110
Leu Pro Asn Ala Ile Gly Arg Val Lys Trp Trp Arg Pro Asn Gly Pro
115 120 125
Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu
130 135 140
Leu Cys Pro Gly Gly Ala Ala Pro Arg Ser Arg Lys Val Arg Leu Val
145 150 155 160
Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu
165 170 175
Leu Lys Asp Phe Gly Pro Glu Thr Ala Arg Pro Gln Lys Gly Arg Lys
180 185 190
Pro Arg Pro Gly Ala Arg Gly Ala Lys Ala Asn Gln Ala Glu Leu Glu
195 200 205
Asn Ala Tyr
210
<210>13
<211>674
<212>DNA
<213>Rattus norvegicus
<400>13
gaggaccgag tgcccttcct ccttctggca ccatgcagct ctcactagcc ccttgccttg 60
cctgcctgct tgtacatgca gccttcgttg ctgtggagag ccaggggtgg caagccttca 120
agaatgatgc cacagaaatc atcccgggac tcagagagta cccagagcct cctcaggaac 180
tagagaacaa ccagaccatg aaccgggccg agaacggagg cagacccccc caccatcctt 240
atgacaccaa agacgtgtcc gagtacagct gccgcgagct gcactacacc cgcttcgtga 300
ccgacggccc gtgccgcagt gccaagccgg tcaccgagtt ggtgtgctcg ggccagtgcg 360
gccccgcgcg gctgctgccc aacgccatcg ggcgcgtgaa gtggtggcgc ccgaacggac 420
ccgacttccg ctgcatcccg gatcgctacc gcgcgcagcg ggtgcagctg ctgtgccccg 480
gcggcgcggc gccgcgctcg cgcaaggtgc gtctggtggc ctcgtgcaag tgcaagcgcc 540
tcacccgctt ccacaaccag tcggagctca aggacttcgg acctgagacc gcgcggccgc 600
agaagggtcg caagccgcgg ccccgcgccc ggggagccaa agccaaccag gcggagctgg 660
agaacgccta ctag 674
<210>14
<211>213
<212>PRT
<213>Rattus norvegicus
<400>14
Met Gln Leu Ser Leu Ala Pro Cys Leu Ala Cys Leu Leu Val His Ala
1 5 10 15
Ala Phe Val Ala Val Glu Ser Gln Gly Trp Gln Ala Phe Lys Asn Asp
20 25 30
Ala Thr Glu Ile Ile Pro Gly Leu Arg Glu Tyr Pro Glu Pro Pro Gln
35 40 45
Glu Leu Glu Asn Asn Gln Thr Met Asn Arg Ala Glu Asn Gly Gly Arg
50 55 60
Pro Pro His His Pro Tyr Asp Thr Lys Asp Val Ser Glu Tyr Ser Cys
65 70 75 80
Arg Glu Leu His Tyr Thr Arg Phe Val Thr Asp Gly Pro Cys Arg Ser
85 90 95
Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala
100 105 110
Arg Leu Leu Pro Asn Ala Ile Gly Arg Val Lys Trp Trp Arg Pro Asn
115 120 125
Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val
130 135 140
Gln Leu Leu Cys Pro Gly Gly Ala Ala Pro Arg Ser Arg Lys Val Arg
145 150 155 160
Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln
165 170 175
Ser Glu Leu Lys Asp Phe Gly Pro Glu Thr Ala Arg Pro Gln Lys Gly
180 185 190
Arg Lys Pro Arg Pro Arg Ala Arg Gly Ala Lys Ala Asn Gln Ala Glu
195 200 205
Leu Glu Asn Ala Tyr
210
<210>15
<211>532
<212>DNA
<213>Bos torus
<400>15
agaatgatgc cacagaaatc atccccgagc tgggcgagta ccccgagcct ctgccagagc 60
tgaacaacaa gaccatgaac cgggcggaga acggagggag acctccccac cacccctttg 120
agaccaaaga cgcctccgag tacagctgcc gggagctgca cttcacccgc tacgtgaccg 180
atgggccgtg ccgcagcgcc aagccggtca ccgagctggt gtgctcgggc cagtgcggcc 240
cggcgcgcct gctgcccaac gccatcggcc gcggcaagtg gtggcgccca agcgggcccg 300
acttccgctg catccccgac cgctaccgcg cgcagcgggt gcagctgttg tgtcctggcg 360
gcgcggcgcc gcgcgcgcgc aaggtgcgcc tggtggcctc gtgcaagtgc aagcgcctca 420
ctcgcttcca caaccagtcc gagctcaagg acttcgggcc cgaggccgcg cggccgcaaa 480
cgggccggaa gctgcggccc cgcgcccggg gcaccaaagc cagccgggcc ga 532
<210>16
<211>176
<212>PRT
<213>Bos torus
<400>16
Asn Asp Ala Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu Pro
1 5 10 15
Leu Pro Glu Leu Asn Asn Lys Thr Met Asn Arg Ala Glu Asn Gly Gly
20 25 30
Arg Pro Pro His His Pro Phe Glu Thr Lys Asp Ala Ser Glu Tyr Ser
35 40 45
Cys Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg
50 55 60
Ser Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro
65 70 75 80
Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro
85 90 95
Ser Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg
100 105 110
Val Gln Leu Leu Cys Pro Gly Gly Ala Ala Pro Arg Ala Arg Lys Val
115 120 125
Arg Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn
130 135 140
Gln Ser Glu Leu Lys Asp Phe Gly Pro Glu Ala Ala Arg Pro Gln Thr
145 150 155 160
Gly Arg Lys Leu Arg Pro Arg Ala Arg Gly Thr Lys Ala Ser Arg Ala
165 170 175
<210>17
<211>35828
<212>DNA
<213>Mus musculus
<220>
<221>misc_feature
<222>(1)..(35828)
<223>n=A,T,C或G
<400>17
cgcgttttgg tgagcagcaa tattgcgctt cgatgagcct tggcgttgag attgatacct 60
ctgctgcaca aaaggcaatc gaccgagctg gaccagcgca ttcgtgacac cgtctccttc 120
gaacttattc gcaatggagtgtcattcatc aaggacngcc tgatcgcaaa tggtgctatc 180
cacgcagcgg caatcgaaaa ccctcagccg gtgaccaata tctacaacat cagccttggt 240
atcctgcgtg atgagccagc gcagaacaag gtaaccgtca gtgccgataa gttcaaagtt 300
aaacctggtg ttgataccaa cattgaaacg ttgatcgaaa acgcgctgaa aaacgctgct 360
gaatgtgcgg cgctggatgt cacaaagcaa atggcagcag acaagaaagc gatggatgaa 420
ctggcttcct atgtccgcac ggccatcatg atggaatgtt tccccggtgg tgttatctgg 480
cagcagtgcc gtcgatagta tgcaattgat aattattatc atttgcgggt cctttccggc 540
gatccgcctt gttacggggc ggcgacctcg cgggttttcg ctatttatga aaattttccg 600
gtttaaggcg tttccgttct tcttcgtcat aacttaatgt ttttatttaa aataccctct 660
gaaaagaaag gaaacgacag gtgctgaaag cgagcttttt ggcctctgtc gtttcctttc 720
tctgtttttg tccgtggaat gaacaatgga agtcaacaaa aagcagagct tatcgatgat 780
aagcggtcaa acatgagaat tcgcggccgc ataatacgac tcactatagg gatcgacgcc 840
tactccccgc gcatgaagcg gaggagctgg actccgcatg cccagagacg ccccccaacc 900
cccaaagtgc ctgacctcag cctctaccag ctctggcttg ggcttgggcg gggtcaaggc 960
taccacgttc tcttaacagg tggctgggct gtctcttggc cgcgcgtcat gtgacagctg 1020
cctagttctg cagtgaggtc accgtggaat gtctgccttc gttgccatgg caacgggatg 1080
acgttacaat ctgggtgtgg agcttttcct gtccgtgtca ggaaatccaa ataccctaaa 1140
ataccctaga agaggaagta gctgagccaa ggctttcctg gcttctccag ataaagtttg 1200
acttagatgg aaaaaaacaa aatgataaag acccgagcca tctgaaaatt cctcctaatt 1260
gcaccactag gaaatgtgta tattattgag ctcgtatgtg ttcttatttt aaaaagaaaa 1320
ctttagtcat gttattaata agaatttctc agcagtggga gagaaccaat attaacacca 1380
agataaaagt tggcatgatc cacattgcag gaagatccac gttgggtttt catgaatgtg 1440
aagaccccat ttattaaagt cctaagctct gtttttgcac actaggaagc gatggccggg 1500
atggctgagg ggctgtaagg atctttcaat gtcttacatg tgtgtttcct gtcctgcacc 1560
taggacctgc tgcctagcct gcagcagagc cagaggggtt tcacatgatt agtctcagac 1620
acttgggggc aggttgcatg tactgcatcg cttatttcca tacggagcac ctactatgtg 1680
tcaaacacca tatggtgttc actcttcaga acggtggtgg tcatcatggt gcatttgctg 1740
acggttggat tggtggtaga gagctgagat atatggacgc actcttcagc attctgtcaa 1800
cgtggctgtg cattcttgct cctgagcaag tggctaaaca gactcacagg gtcagcctcc 1860
agctcagtcg ctgcatagtc ttagggaacc tctcccagtc ctccctacct caactatcca 1920
agaagccagg gggcttggcg gtctcaggag cctgcttgct gggggacagg ttgttgagtt 1980
ttatctgcag taggttgcct aggcatagtg tcaggactga tggctgcctt ggagaacaca 2040
tcctttgccc tctatgcaaa tctgaccttg acatgggggc gctgctcagc tgggaggatc 2100
aactgcatac ctaaagccaa gcctaaagct tcttcgtcca cctgaaactc ctggaccaag 2160
gggcttccgg cacatcctct caggccagtg agggagtctg tgtgagctgc actttccaat 2220
ctcagggcgt gagaggcaga gggaggtggg ggcagagcct tgcagctctt tcctcccatc 2280
tggacagcgc tctggctcag cagcccatat gagcacaggc acatccccac cccaccccca 2340
cctttcctgt cctgcagaat ttaggctctg ttcacggggg gggggggggg ggggcagtcc 2400
tatcctctct taggtagaca ggactctgca ggagacactg ctttgtaaga tactgcagtt 2460
taaatttgga tgttgtgagg ggaaagcgaa gggcctcttt gaccattcag tcaaggtacc 2520
ttctaactcc catcgtattg gggggctact ctagtgctag acattgcaga gagcctcaga 2580
actgtagtta ccagtgtggt aggattgatc cttcagggag cctgacatgt gacagttcca 2640
ttcttcaccc agtcaccgaa catttattca gtacctaccc cgtaacaggc accgtagcag 2700
gtactgaggg acggaccact caaagaactg acagaccgaa gccttggaat ataaacacca 2760
aagcatcagg ctctgccaac agaacactct ttaacactca ggccctttaa cactcaggac 2820
ccccaccccc accccaagca gttggcactg ctatccacat tttacagaga ggaaaaacta 2880
ggcacaggac gatataagtg gcttgcttaa gcttgtctgc atggtaaatg gcagggctgg 2940
attgagaccc agacattcca actctagggt ctatttttct tttttctcgt tgttcgaatc 3000
tgggtcttac tgggtaaact caggctagcc tcacactcat atccttctcc catggcttac 3060
gagtgctagg attccaggtg tgtgctacca tgtctgactc cctgtagctt gtctatacca 3120
tcctcacaac ataggaattg tgatagcagc acacacaccg gaaggagctg gggaaatccc 3180
acagagggct ccgcaggatg acaggcgaat gcctacacag aaggtgggga agggaagcag 3240
agggaacagc atgggcgtgg gaccacaagt ctatttgggg aagctgccgg taaccgtata 3300
tggctggggt gaggggagag gtcatgagat gaggcaggaa gagccacagc aggcagcggg 3360
tacgggctcc ttattgccaa gaggctcgga tcttcctcct cttcctcctt ccggggctgc 3420
ctgttcattt tccaccactg cctcccatcc aggtctgtgg ctcaggacat cacccagctg 3480
cagaaactgg gcatcaccca cgtcctgaat gctgccgagg gcaggtcctt catgcacgtc 3540
aacaccagtg ctagcttcta cgaggattct ggcatcacct acttgggcat caaggccaat 3600
gatacgcagg agttcaacct cagtgcttac tttgaaaggg ccacagattt cattgaccag 3660
gcgctggccc ataaaaatgg taaggaacgt acattccggc acccatggag cgtaagccct 3720
ctgggacctg cttcctccaa agaggccccc acttgaaaaa ggttccagaa agatcccaaa 3780
atatgccacc aactagggat taagtgtcct acatgtgagc cgatgggggc cactgcatat 3840
agtctgtgcc atagacatga caatggataa taatatttca gacagagagc aggagttagg 3900
tagctgtgct cctttccctt taattgagtg tgcccatttt tttattcatg tatgtgtata 3960
catgtgtgtg cacacatgcc ataggttgat actgaacacc gtcttcaatc gttccccacc 4020
ccaccttatt ttttgaggca gggtctcttc cctgatcctg gggctcattg gtttatctag 4080
gctgctggcc agtgagctct ggagttctgc ttttctctac ctccctagcc ctgggactgc 4140
aggggcatgt gctgggccag gcttttatgt cgcgttgggg atctgaactt aggtccctag 4200
gcctgagcac cgtaaagact ctgccacatc cccagcctgt ttgagcaagt gaaccattcc 4260
ccagaattcc cccagtgggg ctttcctacc cttttattgg ctaggcattc atgagtggtc 4320
acctcgccag aggaatgagt ggccacgact ggctcagggt cagcagccta gagatactgg 4380
gttaagtctt cctgccgctc gctccctgca gccgcagaca gaaagtagga ctgaatgaga 4440
gctggctagt ggtcagacag gacagaaggc tgagagggtc acagggcaga tgtcagcaga 4500
gcagacaggt tctccctctg tgggggaggg gtggcccact gcaggtgtaa ttggccttct 4560
ttgtgctcca tagaggcttc ctgggtacac agcagcttcc ctgtcctggt gattcccaaa 4620
gagaactccc taccactgga cttacagaag ttctattgac tggtgtaacg gttcaacagc 4680
tttggctctt ggtggacggt gcatactgct gtatcagctc aagagctcat tcacgaatga 4740
acacacacac acacacacac acacacacac acacaagcta attttgatat gccttaacta 4800
gctcagtgac tgggcatttc tgaacatccc tgaagttagc acacatttcc ctctggtgtt 4860
cctggcttaa caccttctaa atctatattt tatctttgct gccctgttac cttctgagaa 4920
gcccctaggg ccacttccct tcgcacctac attgctggat ggtttctctc ctgcagctct 4980
taaatctgat ccctctgcct ctgagccatg ggaacagccc aataactgag ttagacataa 5040
aaacgtctct agccaaaact tcagctaaatttagacaata aatcttactg gttgtggaat 5100
ccttaagatt cttcatgacc tccttcacat ggcacgagta tgaagcttta ttacaattgt 5160
ttattgatca aactaactca taaaaagcca gttgtctttc acctgctcaa ggaaggaaca 5220
aaattcatcc ttaactgatc tgtgcacctt gcacaatcca tacgaatatc ttaagagtac 5280
taagattttg gttgtgagag tcacatgtta cagaatgtac agctttgaca aggtgcatcc 5340
ttgggatgcc gaagtgacct gctgttccag ccccctacct tctgaggctg ttttggaagc 5400
aatgctctgg aagcaacttt aggaggtagg atgctggaac agcgggtcac ttcagcatcc 5460
cgatgacgaa tcccgtcaaa gctgtacatt ctgtaacaga ctgggaaagc tgcagacttt 5520
aaggccaggg ccctatggtc cctcttaatc cctgtcacac ccaacccgag cccttctcct 5580
ccagccgttc tgtgcttctc actctggata gatggagaac acggccttgc tagttaaagg 5640
agtgaggctt cacccttctc acatggcagt ggttggtcat cctcattcag ggaactctgg 5700
ggcattctgc ctttacttcc tctttttgga ctacagggaa tatatgctga cttgttttga 5760
ccttgtgtat ggggagactg gatctttggt ctggaatgtt tcctgctagt ttttccccat 5820
cctttggcaa accctatcta tatcttacca ctaggcatag tggccctcgt tctggagcct 5880
gccttcaggc tggttctcgg ggaccatgtc cctggtttct ccccagcata tggtgttcac 5940
agtgttcact gcgggtggtt gctgaacaaa gcggggattg catcccagag ctccggtgcc 6000
ttgtgggtac actgctaaga taaaatggat actggcctct ctctgaccac ttgcagagct 6060
ctggtgcctt gtgggtacac tgctaagata aaatggatac tggcctctct ctatccactt 6120
gcaggactct agggaacagg aatccattac tgagaaaacc aggggctagg agcagggagg 6180
tagctgggca gctgaagtgc ttggcgacta accaatgaat accagagttt ggatctctag 6240
aatactctta aaatctgggt gggcagagtg gcctgcctgt aatcccagaa ctcgggaggc 6300
ggagacaggg aatcatcaga gcaaactggc taaccagaat agcaaaacac tgagctctgg 6360
gctctgtgag agatcctgcc ttaacatata agagagagaa taaaacattg aagaagacag 6420
tagatgccaa ttttaagccc ccacatgcac atggacaagt gtgcgtttga acacacatat 6480
gcactcatgt gaaccaggca tgcacactcg ggcttatcac acacataatt tgaaagagag 6540
agtgagagag gagagtgcac attagagttc acaggaaagt gtgagtgagc acacccatgc 6600
acacagacat gtgtgccagg gagtaggaaa ggagcctggg tttgtgtata agagggagcc 6660
atcatgtgtt tctaaggagg gcgtgtgaag gaggcgttgt gtgggctggg actggagcat 6720
ggttgtaact gagcatgctc cctgtgggaa acaggagggt ggccaccctg cagagggtcc 6780
cactgtccag cgggatcagt aaaagcccct gctgagaact ttaggtaata gccagagaga 6840
gaaaggtagg aaagtggggg gactcccatc tctgatgtag gaggatctgg gcaagtagag 6900
gtgcgtttga ggtagaaaga ggggtgcaga ggagatgctc ttaattctgg gtcagcagtt 6960
tctttccaaa taatgcctgt gaggaggtgt aggtggtggc cattcactca ctcagcagag 7020
ggatgatgat gcccggtgga tgctggaaat ggccgagcat caaccctggc tctggaagaa 7080
ctccatcttt cagaaggaga gtggatctgt gtatggccag cggggtcaca ggtgcttggg 7140
gcccctgggg gactcctagc actgggtgat gtttatcgag tgctcttgtg tgccaggcac 7200
tggcctgggg ctttgtttct gtctctgttt tgtttcgttt tttgagacag actcttgcta 7260
tgtatccgtg tcaatcttgg aatctcactg catagcccag gctgcggaga gaggggaggg 7320
caataggcct tgtaagcaag ccacacttca gagactagac tccaccctgc gaatgatgac 7380
aggtcagagc tgagttccgg aagatttttt ttccagctgc caggtggagt gtggagtggc 7440
agctagcggc aagggtagag ggcgagctcc ctgtgcagga gaaatgcaag caagagatgg 7500
caagccagtg agttaagcat tctgtgtggg gagcaggtgg atgaagagag aggctgggct 7560
ttcgcctctg gggggggggt gaggggtggg gatgaggtga gaggagggca gctccctgca 7620
gtgtgatgag atttttcctg acagtgacct ttggcctctc cctcccccac ttcccttctt 7680
tcctttcttc ccaccattgc tttccttgtc cttgagaaat tctgagtttc cacttcactg 7740
gtgatgcaga cggaaacaga agccgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 7800
gtgtgtgtgt ttgtgtgtat gtgtgtgtgt gtgtttgtgt gtatgtgtgt cagtgggaat 7860
ggctcatagt ctgcaggaag gtgggcagga aggaataagc tgtaggctga ggcagtgtgg 7920
gatgcaggga gagaggagag gagggatacc agagaaggaa attaagggag ctacaagagg 7980
gcattgttgg ggtgtgtgtg tgtgtgtgtt gtttatattt gtattggaaa tacattcttt 8040
taaaaaatac ttatccattt atttattttt atgtgcacgt gtgtgtgcct gcatgagttc 8100
atgtgtgcca cgtgtgtgcg ggaacccttg gaggccacaa gggggcatct gatcccctgg 8160
aactggagtt ggaggaggtt gtgagtcccc tgacatgttt gctgggaact gaaccccggt 8220
cctatgcaag agcaggaagt gcagttatct gctgagccat ctctccagtc ctgaaatcca 8280
ttctcttaaa atacacgtgg cagagacatg atgggattta cgtatggatt taatgtggcg 8340
gtcattaagt tccggcacag gcaagcacct gtaaagccat caccacaacc gcaacagtga 8400
atgtgaccat cacccccatg ttcttcatgt cccctgtccc ctccatcctc cattctcaag 8460
cacctcttgc tctgcctctg tcgctggaga acagtgtgca tctgcacact cttatgtcag 8520
tgaagtcaca cagcctgcac cccttcctgg tctgagtatt tgggttctga ctctgctatc 8580
acacactact gtactgcatt ctctcgctct ctttttttaa acatattttt atttgtttgt 8640
gtgtatgcac atgtgccaca tgtgtacaga tactatggag gccagaagag gccatggccg 8700
tccctggagc tggagttaca ggcagcgtgt gagctgcctg gtgtgggtgc tgggaaccaa 8760
acttgaatct aaagcaagca cttttaactg ctgaggcagc tctcagtacc cttcttcatt 8820
tctccgcctg ggttccattg tatggacaca tgtagctaga atatcttgct tatctaatta 8880
tgtacattgt tttgtgctaa gagagagtaa tgctctatag cctgagctgg cctcaacctt 8940
gccatcctcc tgcctcagcc tcctcctcct gagtgctagg atgacaggcg agtggtaact 9000
tacatggttt catgttttgt tcaagactga aggataacat tcatacagag aaggtctggg 9060
tcacaaagtg tgcagttcac tgaatggcac aacccgtgat caagaaacaa aactcagggg 9120
ctggagagat ggcactgact gctcttccag aggtccggag ttcaattccc agcaaccaca 9180
tggtggctca cagccatcta taacgagatc tgacgccctc ttctggtgtg tctgaagaca 9240
gctacagtgt actcacataa aataaataaa tctttaaaac acacacacac acacaattac 9300
caccccagaa agcccactcc atgttccctc ccacgtctct gcctacagta ctcccaggtt 9360
accactgttc aggcttctaa caacctggtt tacttgggcc tcttttctgc tctgtggagc 9420
cacacatttg tgtgcctcat acacgttctt tctagtaagt tgcatattac tctgcgtttt 9480
tacatgtatt tatttattgt agttgtgtgt gcgtgtgggc ccatgcatgg cacagtgtgt 9540
ggggatgtca gagtattgtg aacaggggac agttcttttc ttcaatcatg tgggttccag 9600
aggttgaact caggtcatca tgtgtggcag caaatgcctt tacccactga gacatctcca 9660
tattcttttt ttttcccctg aggtgggggc ttgttccata gcccaaactg gctttgcact 9720
tgcagttcaa agtgactccc tgtctccacc tcttagagta ttggaattac gatgtgtact 9780
accacacctg actggatcat taattctttg atgggggcgg ggaagcgcac atgctgcagg 9840
tgaagggatg actggactgg acatgagcgt ggaagccaga gaacagcttc agtctaatgc 9900
tctcccaact gagctatttc ggtttgccag agaacaactt acagaaagtt ctcagtgcca 9960
tgtggattcg gggttggagt tcaactcatc agcttgacat tggctcctct acccactgag 10020
ccttctcact actctctacc tagatcatta attctttttt aaaaagactt attagggggc 10080
tggagagatg gctcagccgt taagagcacc gaatgccctt ccagaggtcc tgagttcaat 10140
tcccagcatg ccattgctgg gcagtagggg gcgcaggtgt tcaacgtgag tagctgttgc 10200
cagttttccg cggtggagaa cctcttgaca ccctgctgtc cctggtcatt ctgggtgggt 10260
gcatggtgat atgcttgttg tatggaagac tttgactgtt acagtgaagt tgggcttcca 10320
cagttaccac gtctcccctg tttcttgcag gccgggtgct tgtccattgc cgcgagggct 10380
acagccgctc cccaacgcta gttatcgcct acctcatgat gcggcagaag atggacgtca 10440
agtctgctct gagtactgtg aggcagaatc gtgagatcgg ccccaacgat ggcttcctgg 10500
cccaactctg ccagctcaat gacagactag ccaaggaggg caaggtgaaa ctctagggtg 10560
cccacagcct cttttgcaga ggtctgactg ggagggccct ggcagccatg tttaggaaac 10620
acagtatacc cactccctgc accaccagac acgtgcccac atctgtccca ctctggtcct 10680
cgggggccac tccaccctta gggagcacat gaagaagctc cctaagaagt tctgctcctt 10740
agccatcctt tcctgtaatt tatgtctctc cctgaggtga ggttcaggtt tatgtccctg 10800
tctgtggcat agatacatct cagtgaccca gggtgggagg gctatcaggg tgcatggccc 10860
gggacacggg cactcttcat gacccctccc ccacctgggt tcttcctgtg tggtccagaa 10920
ccacgagcct ggtaaaggaa ctatgcaaac acaggccctg acctccccat gtctgttcct 10980
ggtcctcaca gcccgacacg ccctgctgag gcagacgaat gacattaagt tctgaagcag 11040
agtggagata gattagtgac tagatttcca aaaagaagga aaaaaaaggc tgcattttaa 11100
aattatttcc ttagaattaa agatactaca taggggccct tgggtaagca aatccatttt 11160
tcccagaggc tatcttgatt ctttggaatg tttaaagtgt gccttgccag agagcttacg 11220
atctatatct gctgcttcag agccttccct gaggatggct ctgttccttt gcttgttaga 11280
agagcgatgc cttgggcagg gtttccccct tttcagaata cagggtgtaa agtccagcct 11340
attacaaaca aacaaacaaa caaacaaaca aaggacctcc atttggagaa ttgcaaggat 11400
tttatcctga attatagtgt tggtgagttc aagtcatcac gccaagtgct tgccatcctg 11460
gttgctattc taagaataat taggaggagg aacctagcca attgcagctc atgtccgtgg 11520
gtgtgtgcac gggtgcatat gttggaaggg gtgcctgtcc ccttggggac agaaggaaaa 11580
tgaaaggccc ctctgctcac cctggccatt tacgggaggc tctgctggtt ccacggtgtc 11640
tgtgcaggat cctgaaactg actcgctgga cagaaacgag acttggcggc accatgagaa 11700
tggagagaga gagagcaaag aaagaaacag cctttaaaag aactttctaa gggtggtttt 11760
tgaacctcgc tggaccttgt atgtgtgcac atttgccaga gattgaacat aatcctcttg 11820
ggacttcacg ttctcattat ttgtatgtct ccggggtcac gcagagccgt cagccaccac 11880
cccagcaccc ggcacatagg cgtctcataa aagcccattt tatgagaacc agagctgttt 11940
gagtaccccg tgtatagaga gagttgttgt cgtggggcac ccggatccca gcagcctggt 12000
tgcctgcctg taggatgtct tacaggagtt tgcagagaaa ccttccttgg agggaaagaa 12060
atatcaggga tttttgttga atatttcaaa ttcagcttta agtgtaagac tcagcagtgt 12120
tcatggttaa ggtaaggaac atgccttttc cagagctgct gcaagaggca ggagaagcag 12180
acctgtctta ggatgtcact cccagggtaa agacctctga tcacagcagg agcagagctg 12240
tgcagcctgg atggtcattg tcccctattc tgtgtgacca cagcaaccct ggtcacatag 12300
ggctggtcat cctttttttt tttttttttt tttttttttg gcccagaatg aagtgaccat 12360
agccaagttg tgtacctcag tctttagttt ccaagcggct ctcttgctca atacaatgtg 12420
catttcaaaa taacactgta gagttgacag aactggttca tgtgttatga gagaggaaaa 12480
gagaggaaag aacaaaacaa aacaaaacac cacaaaccaa aaacatctgg gctagccagg 12540
catgattgca atgtctacag gcccagttca tgagaggcag agacaggaag accgccgaaa 12600
ggtcaaggat agcatggtct acgtatcgag actccagcca gggctacggt cccaagatcc 12660
taggttttgg attttgggct ttggtttttg agacagggtt tctctgtgta gccctggctg 12720
tcctggaact cgctctgtag accaggctgg cctcaaactt agagatctgc ctgactctgc 12780
ctttgagggc tgggacgaat gccaccactg cccaactaag attccattaa aaaaaaaaaa 12840
agttcaagat aattaagagt tgccagctcg ttaaagctaa gtagaagcag tctcaggcct 12900
gctgcttgag gctgttcttg gcttggacct gaaatctgcc cccaacagtg tccaagtgca 12960
catgactttg agccatctcc agagaaggaa gtgaaaattg tggctcccca gtcgattggg 13020
acacagtctc tctttgtcta ggtaacacat ggtgacacat agcattgaac tctccactct 13080
gagggtgggt ttccctcccc ctgcctcttc tgggttggtc accccatagg acagccacag 13140
gacagtcact agcacctact ggaaacctct ttgtgggaac atgaagaaag agcctttggg 13200
agattcctgg ctttccatta gggctgaaag tacaacggtt cttggttggc tttgcctcgt 13260
gtttataaaa ctagctacta ttcttcaggt aaaataccga tgttgtggaa aagccaaccc 13320
cgtggctgcc cgtgagtagg gggtggggtt gggaatcctg gatagtgttc tatccatgga 13380
aagtggtgga ataggaatta agggtgttcc cccccccccc aacctcttcc tcagacccag 13440
ccactttcta tgacttataa acatccaggt aaaaattaca aacataaaaa tggtttctct 13500
tctcaatctt ctaaagtctg cctgcctttt ccaggggtag gtctgtttct ttgctgttct 13560
attgtcttga gagcacagac taacacttac caaatgaggg aactcttggc ccatactaag 13620
gctcttctgg gctccagcac tcttaagtta ttttaagaat tctcacttgg cctttagcac 13680
acccgccacc cccaagtggg tgtggataat gccatggcca gcagggggca ctgttgaggc 13740
gggtgccttt ccaccttaag ttgcttatag tatttaagat gctaaatgtt ttaatcaaga 13800
gaagcactga tcttataata cgaggataag agattttctc acaggaaatt gtctttttca 13860
taattctttt acaggctttg tcctgatcgt agcatagaga gaatagctgg atatttaact 13920
tgtattccat tttcctctgc cagcgttagg ttaactccgt aaaaagtgat tcagtggacc 13980
gaagaggctc agagggcagg ggatggtggg gtgaggcaga gcactgtcac ctgccaggca 14040
tgggaggtcc tgccatccgg gaggaaaagg aaagtttagc ctctagtcta ccaccagtgt 14100
taacgcactc taaagttgta accaaaataa atgtcttaca ttacaaagac gtctgttttg 14160
tgtttccttt tgtgtgtttg ggctttttat gtgtgcttta taactgctgt ggtggtgctg 14220
ttgttagttt tgaggtagga tctcaggctg gccttgaact tctgatcgcc tgcccctgcc 14280
cctgcccctg cccctgtccc tgcctccaag tgctaggact aaaagcacat gccaccacac 14340
cagtacagca tttttctaac atttaaaaat aatcacctag gggctggaga gagggttcca 14400
gctaagagtg cacactgctc ttgggtagga cctgagttta gttcccagaa cctatactgg 14460
gtggctccag gtccagagga tccaggacct ctggcctcca tgggcatctg ctcttagcac 14520
atacccacat acagatacac acataaaaat aaaatgaagc ctttaaaaac ctcctaaaac 14580
ctagcccttg gaggtacgac tctggaaagc tggcatactg tgtaagtcca tctcatggtg 14640
ttctggctaa cgtaagactt acagagacag aaaagaactc agggtgtgct gggggttggg 14700
atggaggaag agggatgagt agggggagca cggggaactt gggcagtgaa aattctttgc 14760
aggacactag aggaggataa ataccagtca ttgcacccac tactggacaa ctccagggaa 14820
ttatgctggg tgaaaagaga aggccccagg tattggctgc attggctgca tttgcgtaac 14880
atttttttaa attgaaaaga aaaagatgta aatcaaggtt agatgagtgg ttgctgtgag 14940
ctgagagctg gggtgagtga gacatgtgga caactccatc aaaaagcgac agaaagaacg 15000
ggctgtggtg acagctacct ctaatctcca cctccgggag gtgatcaagg ttagccctca 15060
gctagcctgt ggtgcatgag accctgtttc aaaaacttta ataaagaaat aatgaaaaaa 15120
gacatcaggg cagatccttg gggccaaagg cggacaggcg agtctcgtgg taaggtcgtg 15180
tagaagcgga tgcatgagca cgtgccgcag gcatcatgag agagccctag gtaagtaagg 15240
atggatgtga gtgtgtcggc gtcggcgcac tgcacgtcct ggctgtggtg ctggactggc 15300
atctttggtg agctgtggag gggaaatggg tagggagatc ataaaatccc tccgaattat 15360
ttcaagaact gtctattaca attatctcaa aatattaaaa aaaaagaaga attaaaaaac 15420
aaaaaaccta tccaggtgtg gtggtgtgca cctatagcca cgggcacttg gaaagctgga 15480
gcaagaggat ggcgagtttg aaggtatctg gggctgtaca gcaagaccgt cgtccccaaa 15540
ccaaaccaaa cagcaaaccc attatgtcac acaagagtgt ttatagtgag cggcctcgct 15600
gagagcatgg ggtgggggtg ggggtggggg acagaaatat ctaaactgca gtcaataggg 15660
atccactgag accctggggc ttgactgcag cttaaccttg ggaaatgata agggttttgt 15720
gttgagtaaa agcatcgatt actgacttaa cctcaaatga agaaaaagaa aaaaagaaaa 15780
caacaaaagc caaaccaagg ggctggtgag atggctcagt gggtaagagc acccgactgc 15840
tcttccgaag gtccagagtt caaatcccag caaccacatg gtggctcaca accatctgta 15900
acgagatatg atgccctctt ctggtgtgtc tgaagacagc tacagtgtac ttacatataa 15960
taaataaatc ttaaaaaaaa aaaaaaaaaa aaaagccaaa ccgagcaaac caggccccca 16020
aacagaaggc aggcacgacg gcaggcacca cgagccatcc tgtgaaaagg cagggctacc 16080
catgggccga ggagggtcca gagagatagg ctggtaagct cagtttctct gtataccctt 16140
tttcttgttg acactacttc aattacagat aaaataacaa ataaacaaaa tctagagcct 16200
ggccactctc tgctcgcttg atttttcctg ttacgtccag caggtggcgg aagtgttcca 16260
aggacagatc gcatcattaa ggtggccagc ataatctccc atcagcaggt ggtgctgtga 16320
gaaccattat ggtgctcaca gaatcccggg cccaggagct gccctctccc aagtctggag 16380
caataggaaa gctttctggc ccagacaggg ttaacagtcc acattccaga gcaggggaaa 16440
aggagactgg aggtcacaga caaaagggcc agcttctaac aacttcacag ctctggtagg 16500
agagatagat cacccccaac aatggccaca gctggttttg tctgccccga aggaaactga 16560
cttaggaagc aggtatcaga gtccccttcc tgaggggact tctgtctgcc ttgtaaagct 16620
gtcagagcag ctgcattgat gtgtgggtga cagaagatga aaaggaggac ccaggcagat 16680
cgccacagat ggaccggcca cttacaagtc gaggcaggtg gcagagcctt gcagaagctc 16740
tgcaggtgga cgacactgat tcattaccca gttagcatac cacagcgggc taggcggacc 16800
acagcctcct tcccagtctt cctccagggc tggggagtcc tccaaccttc tgtctcagtg 16860
cagcttccgc cagcccctcc tccttttgca cctcaggtgt gaaccctccc tcctctcctt 16920
ctccctgtgg catggccctc ctgctactgc aggctgagca ttggatttct ttgtgcttag 16980
atagacctga gatggctttc tgatttatat atatatatcc atcccttgga tcttacatct 17040
aggacccaga gctgtttgtg ataccataag aggctgggga gatgatatgg taagagtgct 17100
tgctgtacaa gcatgaagac atgagttcga atccccagca accatgtgga aaaataacct 17160
tctaacctca gagttgaggg gaaaggcagg tggattctgg gggcttactg gccagctagc 17220
cagcctaacc taaatgtctc agtcagagat cctgtctcag ggaataactt gggagaatga 17280
ctgagaaaga cacctcctca ggtctcccat gcacccacac agacacacgg ggggggggta 17340
atgtaataag ctaagaaata atgagggaaa tgattttttg ctaagaaatg aaattctgtg 17400
ttggccgcaa gaagcctggc cagggaagga actgcctttg gcacaccagc ctataagtca 17460
ccatgagttc cctggctaag aatcacatgt aatggagccc aggtccctct tgcctggtgg 17520
ttgcctctcc cactggtttt gaagagaaat tcaagagaga tctccttggt cagaattgta 17580
ggtgctgagc aatgtggagc tggggtcaat gggattcctt taaaggcatc cttcccaggg 17640
ctgggtcata cttcaatagt agggtgcttg cacagcaagc gtgagaccct aggttagagt 17700
ccccagaatc tgcccccaac cccccaaaaa ggcatccttc tgcctctggg tgggtggggg 17760
gagcaaacac ctttaactaa gaccattagc tggcaggggt aacaaatgac cttggctaga 17820
ggaatttggt caagctggat tccgccttct gtagaagccc cacttgtttc ctttgttaag 17880
ctggcccaca gtttgttttg agaatgcctg aggggcccag ggagccagac aattaaaagc 17940
caagctcatt ttgatatctg aaaaccacag cctgactgcc ctgcccgtgg gaggtactgg 18000
gagagctggc tgtgtccctg cctcaccaac gccccccccc ccaacacaca ctcctcgggt 18060
cacctgggag gtgccagcag caatttggaa gtttactgag cttgagaagt cttgggaggg 18120
ctgacgctaa gcacacccct tctccacccc cccccacccc acccccgtga ggaggagggt 18180
gaggaaacat gggaccagcc ctgctccagc ccgtccttat tggctggcat gaggcagagg 18240
gggctttaaa aaggcaaccg tatctaggct ggacactgga gcctgtgcta ccgagtgccc 18300
tcctccacct ggcagcatgc agccctcact agccccgtgc ctcatctgcc tacttgtgca 18360
cgctgccttc tgtgctgtgg agggccaggg gtggcaagcc ttcaggaatg atgccacaga 18420
ggtcatccca gggcttggag agtaccccga gcctcctcct gagaacaacc agaccatgaa 18480
ccgggcggag aatggaggca gacctcccca ccatccctat gacgccaaag gtacgggatg 18540
aagaagcaca ttagtggggg ggggggtcct gggaggtgac tggggtggtt ttagcatctt 18600
cttcagaggt ttgtgtgggt ggctagcctc tgctacatca gggcagggac acatttgcct 18660
ggaagaatac tagcacagca ttagaacctg gagggcagca ttggggggct ggtagagagc 18720
acccaaggca gggtggaggc tgaggtcagc cgaagctggc attaacacgg gcatgggctt 18780
gtatgatggt ccagagaatc tcctcctaag gatgaggaca caggtcagat ctagctgctg 18840
accagtgggg aagtgatatg gtgaggctgg atgccagatg ccatccatgg ctgtactata 18900
tcccacatga ccaccacatg aggtaaagaa ggccccagct tgaagatgga gaaaccgaga 18960
ggctcctgag ataaagtcac ctgggagtaa gaagagctga gactggaagc tggtttgatc 19020
cagatgcaag gcaaccctag attgggtttg ggtgggaacc tgaagccagg aggaatccct 19080
ttagttcccc cttgcccagg gtctgctcaa tgagcccaga gggttagcat taaaagaaca 19140
gggtttgtag gtggcatgtg acatgagggg cagctgagtg aaatgtcccc tgtatgagca 19200
caggtggcac cacttgccct gagcttgcac cctgacccca gctttgcctc attcctgagg 19260
acagcagaaa ctgtggaggc agagccagca cagagagatg cctggggtgg gggtgggggt 19320
atcacgcacg gaactagcag caatgaatgg ggtggggtgg cagctggagg gacactccag 19380
agaaatgacc ttgctggtca ccatttgtgt gggaggagag ctcattttcc agcttgccac 19440
cacatgctgt ccctcctgtc tcctagccag taagggatgt ggaggaaagg gccaccccaa 19500
aggagcatgc aatgcagtca cgtttttgca gaggaagtgc ttgacctaag ggcactattc 19560
ttggaaagcc ccaaaactag tccttccctg ggcaaacagg cctcccccac ataccacctc 19620
tgcaggggtg agtaaattaa gccagccaca gaagggtggc aaggcctaca cctcccccct 19680
gttgtgcccc cccccccccc gtgaaggtgc atcctggcct ctgcccctct ggctttggta 19740
ctgggatttt ttttttcctt ttatgtcata ttgatcctga caccatggaa cttttggagg 19800
tagacaggac ccacacatgg attagttaaa agcctcccat ccatctaagc tcatggtagg 19860
agatagagca tgtccaagag aggagggcag gcatcagacc tagaagatat ggctgggcat 19920
ccaacccaat ctccttcccc ggagaacaga ctctaagtca gatccagcca cccttgagta 19980
accagctcaa ggtacacaga acaagagagt ctggtataca gcaggtgcta aacaaatgct 20040
tgtggtagca aaagctatag gttttgggtc agaactccga cccaagtcgc gagtgaagag 20100
cgaaaggccc tctactcgcc accgccccgc ccccacctgg ggtcctataa cagatcactt 20160
tcacccttgc gggagccaga gagccctggc atcctaggta gccccccccg cccccccccc 20220
gcaagcagcc cagccctgcc tttggggcaa gttcttttct cagcctggac ctgtgataat 20280
gagggggttg gacgcgccgc ctttggtcgc tttcaagtct aatgaattct tatccctacc 20340
acctgccctt ctaccccgct cctccacagc agctgtcctg atttattacc ttcaattaac 20400
ctccactcct ttctccatct cctgggatac cgcccctgtc ccagtggctg gtaaaggagc 20460
ttaggaagga ccagagccag gtgtggctag aggctaccag gcagggctgg ggatgaggag 20520
ctaaactgga agagtgtttg gttagtaggc acaaagcctt gggtgggatc cctagtaccg 20580
gagaagtgga gatgggcgct gagaagttca agaccatcca tccttaacta cacagccagt 20640
ttgaggccag cctgggctac ataaaaaccc aatctcaaaa gctgccaatt ctgattctgt 20700
gccacgt agt gcccgatgta atagtggatgaagtcgttga atcctggggc aacctatttt 20760
acagatgtgg ggaaaagcaa ctttaagtac cctgcccaca gatcacaaag aaagtaagtg 20820
acagagctcc agtgtttcat ccctgggttc caaggacagg gagagagaag ccagggtggg 20880
atctcactgc tccccggtgc ctccttccta taatccatac agattcgaaa gcgcagggca 20940
ggtttggaaa aagagagaag ggtggaagga gcagaccagt ctggcctagg ctgcagcccc 21000
tcacgcatcc ctctctccgc agatgtgtcc gagtacagct gccgcgagct gcactacacc 21060
cgcttcctga cagacggccc atgccgcagc gccaagccgg tcaccgagtt ggtgtgctcc 21120
ggccagtgcg gccccgcgcg gctgctgccc aacgccatcg ggcgcgtgaa gtggtggcgc 21180
ccgaacggac cggatttccg ctgcatcccg gatcgctacc gcgcgcagcg ggtgcagctg 21240
ctgtgccccg ggggcgcggc gccgcgctcg cgcaaggtgc gtctggtggc ctcgtgcaag 21300
tgcaagcgcc tcacccgctt ccacaaccag tcggagctca aggacttcgg gccggagacc 21360
gcgcggccgc agaagggtcg caagccgcgg cccggcgccc ggggagccaa agccaaccag 21420
gcggagctgg agaacgccta ctagagcgag cccgcgccta tgcagccccc gcgcgatccg 21480
attcgttttc agtgtaaagc ctgcagccca ggccaggggt gccaaacttt ccagaccgtg 21540
tggagttccc agcccagtag agaccgcagg tccttctgcc cgctgcgggg gatggggagg 21600
gggtggggtt cccgcgggcc aggagaggaa gcttgagtcc cagactctgc ctagccccgg 21660
gtgggatggg ggtctttcta ccctcgccgg acctatacag gacaaggcag tgtttccacc 21720
ttaaagggaa gggagtgtgg aacgaaagac ctgggactgg ttatggacgt acagtaagat 21780
ctactccttc cacccaaatg taaagcctgc gtgggctaga tagggtttct gaccctgacc 21840
tggccactga gtgtgatgtt gggctacgtg gttctctttt ggtacggtct tctttgtaaa 21900
atagggaccg gaactctgct gagattccaa ggattggggt accccgtgta gactggtgag 21960
agagaggaga acaggggagg ggttagggga gagattgtgg tgggcaaccg cctagaagaa 22020
gctgtttgtt ggctcccagc ctcgccgcct cagaggtttg gcttccccca ctccttcctc 22080
tcaaatctgc cttcaaatcc atatctggga tagggaaggc cagggtccga gagatggtgg 22140
aagggccaga aatcacactc ctggcccccc gaagagcagt gtcccgcccc caactgcctt 22200
gtcatattgt aaagggattt tctacacaac agtttaaggt cgttggagga aactgggctt 22260
gccagtcacc tcccatcctt gtcccttgcc aggacaccac ctcctgcctg ccacccacgg 22320
acacatttct gtctagaaac agagcgtcgt cgtgctgtcc tctgagacag catatcttac 22380
attaaaaaga ataatacggg gggggggggc ggagggcgca agtgttatac atatgctgag 22440
aagctgtcag gcgccacagc accacccaca atctttttgt aaatcatttc cagacacctc 22500
ttactttctg tgtagatttt aattgttaaa aggggaggag agagagcgtt tgtaacagaa 22560
gcacatggag gggggggtag gggggttggg gctggtgagt ttggcgaact ttccatgtga 22620
gactcatcca caaagactga aagccgcgtt ttttttttta agagttcagt gacatattta 22680
ttttctcatt taagttattt atgccaacat ttttttcttg tagagaaagg cagtgttaat 22740
atcgctttgt gaagcacaag tgtgtgtggt tttttgtttt ttgttttttc cccgaccaga 22800
ggcattgtta ataaagacaa tgaatctcga gcaggaggct gtggtcttgt tttgtcaacc 22860
acacacaatg tctcgccact gtcatctcac tcccttccct tggtcacaag acccaaacct 22920
tgacaacacc tccgactgct ctctggtagc ccttgtggca atacgtgttt cctttgaaaa 22980
gtcacattca tcctttcctt tgcaaacctg gctctcattc cccagctggg tcatcgtcat 23040
accctcaccc cagcctccct ttagctgacc actctccaca ctgtcttcca aaagtgcacg 23100
tttcaccgag ccagttccct ggtccaggtc atcccattgc tcctccttgc tccagaccct 23160
tctcccacaa agatgttcat ctcccactcc atcaagcccc agtggccctg cggctatccc 23220
tgtctcttca gttagctgaa tctacttgct gacaccacat gaattccttc ccctgtctta 23280
aggttcatgg aactcttgcc tgcccctgaa ccttccagga ctgtcccagc gtctgatgtg 23340
tcctctctct tgtaaagccc caccccacta tttgattccc aattctagat cttcccttgt 23400
tcattccttc acgggatagt gtctcatctg gccaagtcct gcttgatatt gggataaatg 23460
caaagccaag tacaattgag gaccagttca tcattgggcc aagctttttc aaaatgtgaa 23520
ttttacacct atagaagtgt aaaagccttc caaagcagag gcaatgcctg gctcttcctt 23580
caacatcagg gctcctgctt tatgggtctg gtggggtagt acattcataa acccaacact 23640
aggggtgtga aagcaagatg attgggagtt cgaggccaat cttggctatg aggccctgtc 23700
tcaacctctc ctccctccct ccagggtttt gttttgtttt gtttttttga tttgaaactg 23760
caacacttta aatccagtca agtgcatctt tgcgtgaggg gaactctatc cctaatataa 23820
gcttccatct tgatttgtgt atgtgcacac tgggggttga acctgggcct ttgtacctgc 23880
cgggcaagct ctctactgct ctaaacccag ccctcactgg ctttctgttt caactcccaa 23940
tgaattcccc taaatgaatt atcaatatca tgtctttgaa aaataccatt gagtgctgct 24000
ggtgtccctg tggttccaga ttccaggaag gacttttcag ggaatccagg catcctgaag 24060
aatgtcttag agcaggaggc catggagacc ttggccagcc ccacaaggca gtgtggtgca 24120
gagggtgagg atggaggcag gcttgcaatt gaagctgaga cagggtactc aggattaaaa 24180
agcttccccc aaaacaattc caagatcagt tcctggtact tgcacctgtt cagctatgca 24240
gagcccagtg ggcataggtg aagacaccgg ttgtactgtc atgtactaac tgtgcttcag 24300
agccggcaga gacaaataat gttatggtga ccccagggga cagtgattcc agaaggaaca 24360
cagaagagag tgctgctaga ggctgcctga aggagaaggg gtcccagact ctctaagcaa 24420
agactccact cacataaaga cacaggctga gcagagctgg ccgtggatgc agggagccca 24480
tccaccatcc tttagcatgc ccttgtattc ccatcacatg ccagggatga ggggcatcag 24540
agagtccaag tgatgcccaa acccaaacac acctaggact tgctttctgg gacagacaga 24600
tgcaggagag actaggttgg gctgtgatcc cattaccaca aagagggaaa aaacaaaaaa 24660
caaacaaaca aacaaaaaaa aacaaaacaa aacaaaaaaa aacccaaggt ccaaattgta 24720
ggtcaggtta gagtttattt atggaaagtt atattctacc tccatggggt ctacaaggct 24780
ggcgcccatc agaaagaaca aacaacaggc tgatctggga ggggtggtac tctatggcag 24840
ggagcacgtg tgcttggggt acagccagac acggggcttg tattaatcac agggcttgta 24900
ttaataggct gagagtcaag cagacagaga gacagaagga aacacacaca cacacacaca 24960
cacacacaca cacacacaca catgcacaca ccactcactt ctcactcgaa gagcccctac 25020
ttacattcta agaacaaacc attcctcctc ataaaggaga caaagttgca gaaacccaaa 25080
agagccacag ggtccccact ctctttgaaa tgacttggac ttgttgcagg gaagacagag 25140
gggtctgcag aggcttcctg ggtgacccag agccacagac actgaaatct ggtgctgaga 25200
cctgtataaa ccctcttcca caggttccct gaaaggagcc cacattcccc aaccctgtct 25260
cctgaccact gaggatgaga gcacttgggc cttccccatt cttggagtgc accctggttt 25320
ccccatctga gggcacatga ggtctcaggt cttgggaaag ttccacaagt attgaaagtg 25380
ttcttgtttt gtttgtgatt taatttaggt gtatgagtgc ttttgcttga atatatgcct 25440
gtgtagcatt tacaagcctg gtgcctgagg agatcagaag atggcatcag ataccctgga 25500
actggacttg cagacagtta tgagccactg tgtgggtgct aggaacagaa cctggatcct 25560
ccggaagagc agacagccag cgctcttagc cactaagcca tcactgaggt tctttctgtg 25620
gctaaagaga caggagacaa aggagagttt cttttagtca ataggaccat gaatgttcct 25680
cgtaacgtga gactagggca gggtgatccc ccagtgacac cgatggccct gtgtagttat 25740
tagcagctct agtcttattc cttaataagt cccagtttgg ggcaggagat atgtattccc 25800
tgctttgaag tggctgaggt ccagttatct acttccaagt acttgtttct ctttctggag 25860
ttggggaagc tccctgcctg cctgtaaatg tgtccattct tcaaccttag acaagatcac 25920
tttccctgag cagtcaggcc agtccaaagc ccttcaattt agctttcata aggaacaccc 25980
cttttgttgg gtggaggtag cacttgcctt gaatcccagc attaagaagg cagagacagt 26040
cggatctctg tgagttcaca gccagcctgg tctacggagt gagttccaag acagccaggc 26100
ctacacagag aaaccctgtc tcgaaaaaaa caaaaacaaa agaaataaag aaaaagaaaa 26160
caaaaacgaa caaacagaaa aacaagccag agtgtttgtc cccgtatttt attaatcata 26220
tttttgtccc tttgccattt tagactaaaa gactcgggaa agcaggtctc tctctgtttc 26280
tcatccggac acacccagaa ccagatgtat ggaagatggc taatgtgctg cagttgcaca 26340
tctggggctg ggtggattgg ttagatggca tgggctgggt gtggttacga tgactgcagg 26400
agcaaggagt atgtggtgca tagcaaacga ggaagtttgc acagaacaac actgtgtgta 26460
ctgatgtgca ggtatgggca catgcaagca gaagccaagg gacagcctta gggtagtgtt 26520
tccacagacc cctcccccct tttaacatgg gcatctctca ttggcctgga gcttgccaac 26580
tgggctgggc tggctagctt gtaggtccca gggatctgca tatctctgcc tccctagtgc 26640
tgggattaca gtcatatatg agcacacctg gcttttttat gtgggttctg ggctttgaac 26700
ccagatctga gtgcttgcaa ggcaatcggt tgaatgactg cttcatctcc ccagaccctg 26760
ggattctact ttctattaaa gtatttctat taaatcaatg agcccctgcc cctgcactca 26820
gcagttctta ggcctgctga gagtcaagtg gggagtgaga gcaagcctcg agaccccatc 26880
agcgaagcag aggacaaaga aatgaaaact tgggattcga ggctcgggat atggagatac 26940
agaaagggtc agggaaggaa atgaaccaga tgaatagagg caggaagggt agggccctgc 27000
atacatggaa cctggtgtac atgttatctg catggggttt gcattgcaat ggctcttcag 27060
caggttcacc acactgggaa acagaagcca aaaagaagag taggtggtgt tggagtcaga 27120
tactgtcagt catgcctgaa gaaatggaag caattaacga tgcgccgcaa ttaggatatt 27180
agctccctga agaaaggcaa gaagctgggc tgtgggcact gaagggagct ttgaatgatg 27240
tcacattctc tgtatgccta gcagggcagt attggagact gagacttgac ttgtgtgtcc 27300
atatgattcc tccttttcct acagtcatct ggggctcctg agcttcgtcc ttgtccaaga 27360
acctggagct ggcagtgggc agctgcagtg atagatgtct gcaagaaaga tctgaaaaga 27420
gggaggaaga tgaaggaccc agaggaccac cgacctctgc tgcctgacaa agctgcagga 27480
ccagtctctc ctacagatgg gagacagagg cgagagatga atggtcaggg gaggagtcag 27540
agaaaggaga gggtgaggca gagaccaaag gagggaaaca cttgtgctct acagctactg 27600
actgagtacc agctgcgtgg cagacagcca atgccaaggc tcggctgatc atggcacctc 27660
gtgggactcc tagcccagtg ctggcagagg ggagtgctga atggtgcatg gtttggatat 27720
gatctgaatg tggtccagcc ctagtttcct tccagttgct gggataaagc accctgacca 27780
aagctacttt tttgtttgtt tgttttggtt tggttttgtt tggtttttcg aggcagggtt 27840
tctctgtatc accctagctg tcctggaact cactctgtag accaggctgg cctcgaactc 27900
agaaatcccc ctgcctctgc ctcctaagtg ctggaattaa aggcctgcgc caccactgcc 27960
ggcccaaagc tactttaaga gagagagagg aatgtataag tattataatt ccaggttata 28020
gttcattgct gtagaattgg agtcttcata ttccaggtaa tctcccacag acatgccaca 28080
aaacaacctg ttctacgaaa tctctcatgg actcccttcc ccagtaattc taaactgtgt 28140
caaatctaca agaaatagtg acagtcacag tctctaacgt tttgggcatg agtctgaagt 28200
ctcattgcta agtactggga agatgaaaac tttacctagt gtcagcattt ggagcagagc 28260
ctttgggatt tgagatggtc ttttgcagag ctcctaatgg ctacatggag agagggggcc 28320
tgggagagac ccatacacct tttgctgcct tatgtcacct gacctgctcc ttgggaagct 28380
ctagcaagaa ggccttccct ggatcaccca ccaccttgca cctccagaac tcagagccaa 28440
attaaacttt cttgttactg tcgtcaaagc acagtcggtc tgggttgtat cactgtcaat 28500
gggaaacaga cttgcctgga tggataactt gtacattgca taatgtctag aaatgaaaag 28560
tcctatagag aaaaagaaaa ttagctggca cacagataga ggccctggag gaggctggct 28620
ttgtcctccc cgaggaggtg gcgagtaagg tgtaaatgtt catggatgta aatgggccca 28680
tatatgaggg tctggggtaa caagaaggcc tgtgaatata aagcactgaa ggtatgtcta 28740
gtctggagaa ggtcactaca gagagttctc caactcagtg cccatacaca cacacacaca 28800
cacacacaca cacacacaca cacacacaca ccacaaagaa aaaaaggaag aaaaatctga 28860
gagcaagtac agtacttaaa attgtgtgat tgtgtgtgtg actctgatgt cacatgctca 28920
tcttgcccta tgagttgaaa accaaatggc ccctgagagg cataacaacc acactgttgg 28980
ctgtgtgctc acgtttttct taaagcgtct gtctggtttg ctgctagcat caggcagact 29040
tgcagcagac tacatatgct cagccctgaa gtccttctag ggtgcatgtc tcttcagaat 29100
ttcagaaagt catctgtggc tccaggaccg cctgcactct ccctctgccg cgaggctgca 29160
gactctaggc tggggtggaa gcaacgctta cctctgggac aagtataaca tgttggcttt 29220
tctttccctc tgtggctcca acctggacat aaaatagatg caagctgtgt aataaatatt 29280
tcctcccgtc cacttagttc tcaacaataa ctactctgag agcacttatt aataggtggc 29340
ttagacataa gctttggctc attcccccac tagctcttac ttctttaact ctttcaaacc 29400
attctgtgtc ttccacatgg ttagttacct ctccttccat cctggttcgc ttcttccttc 29460
gagtcgccct cagtgtctct aggtgatgct tgtaagatat tctttctaca aagctgagag 29520
tggtggcact ctgggagttc aaagccagcc tgatctacac agcaagctcc aggatatcca 29580
gggcaatgtt gggaaaacct ttctcaaaca aaaagagggg ttcagttgtc aggaggagac 29640
ccatgggtta agaagtctag acgagccatg gtgatgcata cctttcatcc aagcacttag 29700
gaggcaaaga aaggtgaaac tctttgactt tgaggccagc taggttacat agtgataccc 29760
tgcttagtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtaatt taaaagtcta 29820
aaaatgcatt cttttaaaaa tatgtataag tatttgcctg cacatatgta tgtatgtatg 29880
tataccatgt gtgtgtctgg tgctgaagga ctaggcatag actccctaga actagagtca 29940
tagacagttg tgacactccc caacccccca ccatgtgggt gcttgaagct aaactcctgt 30000
cctttgtaaa gcagcaggtg tctatgaacc ctgaaccatc tctccagtct ccagatgtgc 30060
attctcaaag aggagtcctt catatttccc taaactgaac atccttatca gtgagcatcc 30120
tcgagtcacc aaagctactg caaaccctct tagggaacat tcactattca cttctacttg 30180
gctcatgaaa cttaagtaca cacacacaaa cacacacaca cacacagagt catgcactca 30240
caaaagcatg catgtacacc attcttatta gactatgctt tgctaaaaga ctttcctaga 30300
tactttaaaa catcacttct gccttttggt gggcaggttc caagattggt actggcgtac 30360
tggaaactga acaaggtaga gatctagaaa tcacagcagg tcagaagggc cagcctgtac 30420
aagagagagt tccacacctt ccaggaacac tgagcagggg gctgggacct tgcctctcag 30480
cccaagaaac tagtgcgttt cctgtatgca tgcctctcag agattccata agatctgcct 30540
tctgccataa gatctcctgc atccagacaa gcctagggga agttgagagg ctgcctgagt 30600
ctctcccaca ggccccttct tgcctggcag tattttttta tctggaggag aggaatcagg 30660
gtgggaatga tcaaatacaa ttatcaagga aaaagtaaaa aacatatata tatatatatt 30720
aactgatcta gggagctggc tcagcagtta agagttctgg ctgcccttgc ttcagatctt 30780
gctttgattc ccagcaccca catgatggct ttcaactgta tctctgcttc caggggatcc 30840
aacagcctct tctgacctcc atagacaaga cctagtcctc tgcaagagca ccaaatgctc 30900
ttatctgttg atccatctct ctagcctcat gccagatcat ttaaaactac tggacactgt 30960
cccattttac gaagatgtca ctgcccagtc atttgccatg agtggatatt tcgattcttt 31020
ctatgttctc acccttgcaa tttataagaa agatatctgc atttgtctcc tgagagaaca 31080
aagggtggag ggctactgag atggctctag gggtaaaggt gcttgccaca aaatctgaca 31140
acttaagttt ggtcttggaa tccacatggt ggagagagag aagagattcc cgtaagttgt 31200
cctcaaactt cccacacatg tgctgtggct tatgtgtaac cccaataagt aaagatagtt 31260
ttaaacacta cataaggtag ggtttcttca tgaccccaag gaatgatgcc cctgatagag 31320
cttatgctga aaccccatct ccattgtgcc atctggaaag agacaattgc atcccggaaa 31380
cagaatcttc atgaatggat taatgagcta ttaagaaagt ggcttggtta ttgcacatgc 31440
tggcggcgta atgacctcca ccatgatgtt atccagcatg aaggtcctca ccagaagtca 31500
tacaaatctt cttaggcttc cagagtcgtg agcaaaaaaa gcacacctct aaataaatta 31560
actagcctca ggtagttaac caccgaaaat gaaccaaggc agttctaata caaaaccact 31620
tcccttccct gttcaaacca cagtgcccta ttatctaaaa gataaacttc aagccaagct 31680
tttaggttgc cagtatttat gtaacaacaa ggcccgttga cacacatctg taactcctag 31740
tactgggcct caggggcaga gacaggtgga gccctggagt ttgaattcca ggttctgtga 31800
gaaactctgt ctgaaaagac aatatggtga gtgacccggg aggatatctg atattgactt 31860
ctggccaaca cacagccatc tctgcacatc tgtagttgca agccttttgc actaagtttg 31920
gccagagtca gagtttgcaa gtgtttgtgg actgaatgca cgtgttgctg gtgatctaca 31980
aagtcaccct ccttctcaag ctagcagcac tggcttcggc cagctgctca ttcaagcctc 32040
tttgcagagt catcacgggg atgggggagc agggcccctc cctagaacac caagcctgtg 32100
gttgtttatt caggacatta ttgagggcca agatgacaga taactctatc acttggccaa 32160
cagtcgggtg ttgcggtgtt aggttatttc tgtgtctgca gaaaacagtg caacctggac 32220
aaaagaaata aatgatatca tttttcattc aggcaactag attccgtggt acaaaaggct 32280
ccctggggaa cgaggccggg acagcgcggc tcctgagtcg ctatttccgt ctgtcaactt 32340
ctctaatctc ttgatttcct ccctctgtct gtttccttcc tcttgctggg gcccagtgga 32400
gtctgtgtac tcacagggag gagggtggca aagccctggt cctctacggg ctgggggaag 32460
gggggaagct gtcggcccag tgactttttc ccctttctct ttttcttaga aaccagtctc 32520
aatttaagat aatgagtctc ctcattcacg tgtgctcact attcataggg acttatccac 32580
ccccgccctg tcaatctggc taagtaagac aagtcaaatt taaaagggaa cgtttttcta 32640
aaaatgtggc tggaccgtgt gccggcacga aaccagggat ggcggtctaa gttacatgct 32700
ctctgccagc cccggtgcct tttcctttcg gaaaggagac ccggaggtaa aacgaagttg 32760
ccaacttttg atgatggtgt gcgccgggtg actctttaaa atgtcatcca tacctgggat 32820
agggaaggct cttcagggag tcatctagcc ctcccttcag gaaaagattc cacttccggt 32880
ttagttagct tccacctggt cccttatccg ctgtctctgc ccactagtcc tcatccatcc 32940
ggtttccgcc ctcatccacc ttgccctttt agttcctaga aagcagcacc gtagtcttgg 33000
caggtgggcc attggtcact ccgctaccac tgttaccatg gccaccaagg tgtcatttaa 33060
atatgagctc actgagtcct gcgggatggc ttggttggta atatgcttgc tgcaaaatcg 33120
tgagaactgg agttcaattc ccagcacatg gatgtatttc cagcacctgg aaggcaggga 33180
gcagagatct taaagctcct ggccagacag cccagcctaa ttagtaatca gtgagagacc 33240
ctgtctcaag aaacaagatg gaacatcaaa ggtcaacctc ttgtctccac acacacaaat 33300
acacacatgc acatacatcc acacacaggc aaacacatgc acacacctga acaccctcca 33360
caaatacata cataaaaaaa taaatacata cacacataca tacatacacc aacattccct 33420
ctccttagtc tcctggctac gctcttgtca cccccactaa ggcttcaact tcttctattt 33480
cttcatcttg actcctctgt actttgcatg ccttttccag caaaggcttt tctttaaatc 33540
tccgtcattc ataaactccc tctaaatttc ttcccctgcc cttttctttc tctctaggga 33600
gataaagaca cacactacaa agtcaccgtg ggaccagttt attcacccac ccacccctgc 33660
ttctgttcat ccggccagct aagtagtcca acctctctgg tgctgtaccc tggaccctgg 33720
cttcaccaca gctcctccat gctacccagc cctgcaaacc ttcagcctag cctctggttc 33780
tccaaccagc acaggcccag tctggcttct atgtcctaga aatctccttc attctctcca 33840
tttccctcct gaatctacca ccttctttct cccttctcct gacctctaat gtcttggtca 33900
aacgattaca aggaagccaa tgaaattagc agtttggggt acctcagagt cagcagggga 33960
gctgggatga attcacattt ccaggccttt gctttgctcc ccggattctg acaggcagtt 34020
ccgaagctga gtccaggaag ctgaatttaa aatcacactc cagctgggtt ctgaggcagc 34080
cctaccacat cagctggccc tgactgagct gtgtctgggt ggcagtggtg ctggtggtgc 34140
tggtggtgct ggtggtggtg gtggtggtgg tggtggtggt ggtggtggtg tgtgtgtgtg 34200
ttttctgctt ttacaaaact tttctaattc ttatacaaag gacaaatctg cctcatatag 34260
gcagaaagat gacttatgcc tatataagat ataaagatga ctttatgcca cttattagca 34320
atagttactg tcaaaagtaa ttctatttat acacccttat acatggtatt gcttttgttg 34380
gagactctaa aatccagatt atgtatttaa aaaaaaattc cccagtcctt aaaaggtgaa 34440
gaatggaccc agatagaagg tcacggcaca agtatggagt cggagtgtgg agtcctgcca 34500
atggtctgga cagaagcatc cagagagggt ccaagacaaa tgcctcgcct cctaaggaac 34560
actggcagcc ctgatgaggt accagagatt gctaagtgga ggaatacagg atcagaccca 34620
tggaggggct taaagcgtga ctgtagcagc cctccgctga ggggctccag gtgggcgccc 34680
aaggtgctgc agtgggagcc acatgagagg tgatgtcttg gagtcacctc gggtaccatt 34740
gtttagggag gtggggattt gtggtgtgga gacaggcagc ctcaaggatg cttttcaaca 34800
atggttgatg agttggaact aaaacagggg ccatcacact ggctcccata gctctgggct 34860
tgccagcttc cacatctgcc ccccaccccc tgtctggcac cagctcaagc tctgtgattc 34920
tacacatcca aaagaggaag agtagcctac tgggcatgcc acctcttctg gaccatcagg 34980
tgagagtgtg gcaagcccta ggctcctgtc caggatgcag ggctgccaga taggatgctc 35040
agctatctcc tgagctggaa ctattttagg aataaggatt atgcccgccc ggggttggcc 35100
agcaccccag cagcctgtgc ttgcgtaaaa gcaagtgctg ttgatttatc taaaaacaga 35160
gccgtggacc cacccacagg acaagtatgt atgcatctgt ttcatgtatc tgaaaagcga 35220
cacaaccatt tttcacatca tggcatcttc ctaaccccca ttcttttttg ttttgttttt 35280
ttgagacagg gtttctctgt gtagtcctgg ctgtcctgga actcactttg tagaccaggc 35340
tggcctcgaa ctcagaaatc ctgggattaa aggtgtgtgc caccacgccc ggccctaacc 35400
cccattctta atggtgatcc agtggttgaa atttcgggcc acacacatgt ccattaggga 35460
ttagctgctg tcttctgagc tacctggtac aatctttatc ccctggggcc tgggctcctg 35520
atccctgact cgggcccgat caagtccagt tcctgggccc gatcaagtcc agttcctggg 35580
cccgaacaag tccagtccct agctcgatta gctcatcctg gctccctggc ctgttcttac 35640
ttacactctt ccccttgctc tggacttgtt gctttcttta ctcaagttgt ctgccacagt 35700
ccctaagcca cctctgtaag acaactaaga taatacttcc ctcaagcacg gaaagtcctg 35760
agtcaccaca ccctctggag gtgtgtggac acatgttcat gcgtgtggtt gcgcttacgt 35820
acgtgtgc 35828
<210>18
<211>9301
<212>DNA
<213>Homo sapien
<400>18
tagaggagaa gtctttgggg agggtttgct ctgagcacac ccctttccct ccctccgggg 60
ctgagggaaa catgggacca gccctgcccc agcctgtcct cattggctgg catgaagcag 120
agaggggctt taaaaaggcg accgtgtctc ggctggagac cagagcctgt gctactggaa 180
ggtggcgtgc cctcctctgg ctggtaccat gcagctccca ctggccctgt gtctcgtctg 240
cctgctggta cacacagcct tccgtgtagt ggagggccag gggtggcagg cgttcaagaa 300
tgatgccacg gaaatcatcc ccgagctcgg agagtacccc gagcctccac cggagctgga 360
gaacaacaag accatgaacc gggcggagaa cggagggcgg cctccccacc acccctttga 420
gaccaaaggt atggggtgga ggagagaatt cttagtaaaa gatcctgggg aggttttaga 480
aacttctctt tgggaggctt ggaagactgg ggtagaccca gtgaagattg ctggcctctg 540
ccagcactgg tcgaggaaca gtcttgcctg gaggtggggg aagaatggct cgctggtgca 600
gccttcaaat tcaggtgcag aggcatgagg caacagacgc tggtgagagc ccagggcagg 660
gaggacgctg gggtggtgag ggtatggcat cagggcatca gaacaggctc aggggctcag 720
aaaagaaaag gtttcaaaga atctcctcct gggaatatag gagccacgtc cagctgctgg 780
taccactggg aagggaacaa ggtaagggag cctcccatcc acagaacagc acctgtgggg 840
caccggacac tctatgctgg tggtggctgt ccccaccaca cagacccaca tcatggaatc 900
cccaggaggt gaacccccag ctcgaagggg aagaaacagg ttccaggcac tcagtaactt 960
ggtagtgaga agagctgagg tgtgaacctg gtttgatcca actgcaagat agccctggtg 1020
tgtggggggg tgtgggggac agatctccac aaagcagtgg ggaggaaggc cagagaggca 1080
cccctgcagt gtgcattgcc catggcctgc ccagggagct ggcacttgaa ggaatgggag 1140
ttttcggcac agttttagcc cctgacatgg gtgcagctga gtccaggccc tggaggggag 1200
agcagcatcc tctgtgcagg agtagggaca tctgtcctca gcagccaccc cagtcccaac 1260
cttgcctcat tccaggggag ggagaaggaa gaggaaccct gggttcctgg tcaggcctgc 1320
acagagaagc ccaggtgaca gtgtgcatct ggctctataa ttggcaggaa tcctgaggcc 1380
atgggggcgt ctgaaatgac acttcagact aagagcttcc ctgtcctctg gccattatcc 1440
aggtggcaga gaagtccact gcccaggctc ctggacccca gccctccccg cctcacaacc 1500
tgttgggact atggggtgct aaaaagggca actgcatggg aggccagcca ggaccctccg 1560
tcttcaaaat ggaggacaag ggcgcctccc cccacagctc cccttctagg caaggtcagc 1620
tgggctccag cgactgcctg aagggctgta aggaacccaa acacaaaatg tccaccttgc 1680
tggactccca cgagaggcca cagcccctga ggaagccaca tgctcaaaac aaagtcatga 1740
tctgcagagg aagtgcctgg cctaggggcg ctattctcga aaagccgcaa aatgccccct 1800
tccctgggca aatgcccccc tgaccacaca cacattccag ccctgcagag gtgaggatgc 1860
aaaccagccc acagaccaga aagcagcccc agacgatggc agtggccaca tctcccctgc 1920
tgtgcttgct cttcagagtg ggggtggggg gtggccttct ctgtcccctc tctggtttgg 1980
tcttaagact atttttcatt ctttcttgtc acattggaac tatccccatg aaacctttgg 2040
gggtggactg gtactcacac gacgaccagc tatttaaaaa gctcccaccc atctaagtcc 2100
accataggag acatggtcaa ggtgtgtgca ggggatcagg ccaggcctcg gagcccaatc 2160
tctgcctgcc cagggagtat caccatgagg cgcccattca gataacacag aacaagaaat 2220
gtgcccagca gagagccagg tcaatgtttg tggcagctga acctgtaggt tttgggtcag 2280
agctcagggc ccctatggta ggaaagtaac gacagtaaaa agcagccctc agctccatcc 2340
cccagcccag cctcccatgg atgctcgaac gcagagcctc cactcttgcc ggagccaaaa 2400
ggtgctggga ccccagggaa gtggagtccg gagatgcagc ccagcctttt gggcaagttc 2460
ttttctctgg ctgggcctca gtattctcat tgataatgag ggggttggac acactgcctt 2520
tgattccttt caagtctaat gaattcctgt cctgatcacc tccccttcag tccctcgcct 2580
ccacagcagc tgccctgatt tattaccttc aattaacctc tactcctttc tccatcccct 2640
gtccacccct cccaagtggc tggaaaagga atttgggaga agccagagcc aggcagaagg 2700
tgtgctgagt acttaccctg cccaggccag ggaccctgcg gcacaagtgt ggcttaaatc 2760
ataagaagac cccagaagag aaatgataat aataatacat aacagccgac gctttcagct 2820
atatgtgcca aatggtattt tctgcattgc gtgtgtaatg gattaactcg caatgcttgg 2880
ggcggcccat tttgcagaca ggaagaagag agaggttaag gaacttgccc aagatgacac 2940
ctgcagtgag cgatggagcc ctggtgtttg aaccccagca gtcatttggc tccgagggga 3000
cagggtgcgc aggagagctt tccaccagct ctagagcatc tgggaccttc ctgcaataga 3060
tgttcagggg caaaagcctc tggagacagg cttggcaaaa gcagggctgg ggtggagaga 3120
gacgggccgg tccagggcag gggtggccag gcgggcggcc accctcacgc gcgcctctct 3180
ccacagacgt gtccgagtac agctgccgcg agctgcactt cacccgctac gtgaccgatg 3240
ggccgtgccg cagcgccaag ccggtcaccg agctggtgtg ctccggccag tgcggcccgg 3300
cgcgcctgctgcccaacgcc atcggccgcg gcaagtggtg gcgac ctagt gggcccgact 3360
tccgctgcat ccccgaccgc taccgcgcgc agcgcgtgca gctgctgtgt cccggtggtg 3420
aggcgccgcg cgcgcgcaag gtgcgcctgg tggcctcgtg caagtgcaag cgcctcaccc 3480
gcttccacaa ccagtcggag ctcaaggact tcgggaccga ggccgctcgg ccgcagaagg 3540
gccggaagcc gcggccccgc gcccggagcg ccaaagccaa ccaggccgag ctggagaacg 3600
cctactagag cccgcccgcg cccctcccca ccggcgggcg ccccggccct gaacccgcgc 3660
cccacatttc tgtcctctgc gcgtggtttg attgtttata tttcattgta aatgcctgca 3720
acccagggca gggggctgag accttccagg ccctgaggaa tcccgggcgc cggcaaggcc 3780
cccctcagcc cgccagctga ggggtcccac ggggcagggg agggaattga gagtcacaga 3840
cactgagcca cgcagccccg cctctggggc cgcctacctt tgctggtccc acttcagagg 3900
aggcagaaat ggaagcattt tcaccgccct ggggttttaa gggagcggtg tgggagtggg 3960
aaagtccagg gactggttaa gaaagttgga taagattccc ccttgcacct cgctgcccat 4020
cagaaagcct gaggcgtgcc cagagcacaa gactgggggc aactgtagat gtggtttcta 4080
gtcctggctc tgccactaac ttgctgtgta accttgaact acacaattct ccttcgggac 4140
ctcaatttcc actttgtaaa atgagggtgg aggtgggaat aggatctcga ggagactatt 4200
ggcatatgat tccaaggact ccagtgcctt ttgaatgggc agaggtgaga gagagagaga 4260
gaaagagaga gaatgaatgc agttgcattg attcagtgcc aaggtcactt ccagaattca 4320
gagttgtgat gctctcttct gacagccaaa gatgaaaaac aaacagaaaa aaaaaagtaa 4380
agagtctatt tatggctgac atatttacgg ctgacaaact cctggaagaa gctatgctgc 4440
ttcccagcct ggcttccccg gatgtttggc tacctccacc cctccatctc aaagaaataa 4500
catcatccat tggggtagaa aaggagaggg tccgagggtg gtgggaggga tagaaatcac 4560
atccgcccca acttcccaaa gagcagcatc cctcccccga cccatagcca tgttttaaag 4620
tcaccttccg aagagaagtg aaaggttcaa ggacactggc cttgcaggcc cgagggagca 4680
gccatcacaa actcacagac cagcacatcc cttttgagac accgccttct gcccaccact 4740
cacggacaca tttctgccta gaaaacagct tcttactgct cttacatgtg atggcatatc 4800
ttacactaaa agaatattat tgggggaaaa actacaagtg ctgtacatat gctgagaaac 4860
tgcagagcat aatagctgcc acccaaaaat ctttttgaaa atcatttcca gacaacctct 4920
tactttctgt gtagttttta attgttaaaa aaaaaaagtt ttaaaeagaa gcacatgaca 4980
tatgaaagcc tgcaggactg gtcgtttttt tggcaattct tccacgtggg acttgtccac 5040
aagaatgaaa gtagtggttt ttaaagagtt aagttacata tttattttct cacttaagtt 5100
atttatgcaa aagtttttct tgtagagaat gacaatgtta atattgcttt atgaattaac 5160
agtctgttct tccagagtcc agagacattg ttaataaaga caatgaatca tgaccgaaag 5220
gatgtggtct cattttgtca accacacatg acgtcatttc tgtcaaagtt gacacccttc 5280
tcttggtcac tagagctcca accttggaca cacctttgac tgctctctgg tggcccttgt 5340
ggcaattatg tcttcctttg aaaagtcatg tttatccctt cctttccaaa cccagaccgc 5400
atttcttcac ccagggcatg gtaataacct cagccttgta tccttttagc agcctcccct 5460
ccatgctggc ttccaaaatg ctgttctcat tgtatcactc ccctgctcaa aagccttcca 5520
tagctccccc ttgcccagga tcaagtgcag tttccctatc tgacatggga ggccttctct 5580
gcttgactcc cacctcccac tccaccaagc ttcctactga ctccaaatgg tcatgcagat 5640
ccctgcttcc ttagtttgcc atccacactt agcaccccca ataactaatc ctctttcttt 5700
aggattcaca ttacttgtca tctcttcccc taaccttcca gagatgttcc aatctcccat 5760
gatccctctc tcctctgagg ttccagcccc ttttgtctac accactactt tggttcctaa 5820
ttctgttttc catttgacag tcattcatgg aggaccagcc tggccaagtc ctgcttagta 5880
ctggcataga caacacaaag ccaagtacaa ttcaggacca gctcacagga aacttcatct 5940
tcttcgaagt gtggatttga tgcctcctgg gtagaaatgt aggatcttca aaagtgggcc 6000
agcctcctgc acttctctca aagtctcgcc tccccaaggt gtcttaatag tgctggatgc 6060
tagctgagtt agcatcttca gatgaagagt aaccctaaag ttactcttca gttgccctaa 6120
ggtgggatgg tcaactggaa agctttaaat taagtccagc ctaccttggg ggaacccacc 6180
cccacaaaga aagctgaggt ccctcctgat gacttgtcag tttaactacc aataacccac 6240
ttgaattaat catcatcatc aagtctttga taggtgtgag tgggtatcag tggccggtcc 6300
cttcctgggg ctccagcccc cgaggaggcc tcagtgagcc cctgcagaaa atccatgcat 6360
catgagtgtc tcagggccca gaatatgaga gcaggtagga aacagagaca tcttccatcc 6420
ctgagaggca gtgcggtcca gtgggtgggg acacgggctc tgggtcaggt ttgtgttgtt 6480
tgtttgtttg ttttgagaca gagtctcgct ctattgccca ggctggagtg cagtgtcaca 6540
atctcggctt actgcaactt ctgccttccc ggattcaagt gattctcctg cctcagcctc 6600
cagagtagct gggattacag gtgcgtgcca ccacgcctgg ctaatttttg tatttttgat 6660
agagacgggg tttcaccatg ttggccaggc tagtctcgaa ctcttgacct caagtgatct 6720
gcctgcctcg gcctcccaaa gtgctgggat tacaggcgtg agccaccaca cccagcccca 6780
ggttggtgtt tgaatctgag gagactgaag caccaagggg ttaaatgttt tgcccacagc 6840
catacttggg ctcagttcct tgccctaccc ctcacttgag ctgcttagaa cctggtgggc 6900
acatgggcaa taaccaggtc acactgtttt gtaccaagtg ttatgggaat ccaagatagg 6960
agtaatttgc tctgtggagg ggatgaggga tagtggttag ggaaagcttc acaaagtggg 7020
tgttgcttag agattttcca ggtggagaag ggggcttcta ggcagaaggc atagcccaag 7080
caaagactgc aagtgcatgg ctgctcatgg gtagaagaga atccaccatt cctcaacatg 7140
taccgagtcc ttgccatgtg caaggcaaca tgggggtacc aggaattcca agcaatgtcc 7200
aaacctaggg tctgctttct gggacctgaa gatacaggat ggatcagccc aggctgcaat 7260
cccattacca cgagggggaa aaaaacctga aggctaaatt gtaggtcggg ttagaggtta 7320
tttatggaaa gttatattct acctacatgg ggtctataag cctggcgcca atcagaaaag 7380
gaacaaacaa cagacctagc tgggaggggc agcattttgt tgtagggggc ggggcacatg 7440
ttctgggggt acagccagac tcagggcttg tattaatagt ctgagagtaa gacagacaga 7500
gggatagaag gaaataggtc cctttctctc tctctctctc tctctctctc actctctctc 7560
tctctcacac acacacacag acacacacac acgctctgta ggggtctact tatgctccaa 7620
gtacaaatca ggccacattt acacaaggag gtaaaggaaa agaacgttgg aggagccaca 7680
ggaccccaaa attccctgtt ttccttgaat caggcaggac ttacgcagct gggagggtgg 7740
agagcctgca gaagccacct gcgagtaagc caagttcaga gtcacagaca ccaaaagctg 7800
gtgccatgtc ccacacccgc ccacctccca cctgctcctt gacacagccc tgtgctccac 7860
aacccggctc ccagatcatt gattatagct ctggggcctg caccgtcctt cctgccacat 7920
ccccacccca ttcttggaac ctgccctctg tcttctccct tgtccaaggg caggcaaggg 7980
ctcagctatt gggcagcttt gaccaacagc tgaggctcct tttgtggctg gagatgcagg 8040
aggcagggga atattcctct tagtcaatgc gaccatgtgc ctggtttgcc cagggtggtc 8100
tcgtttacac ctgtaggcca agcgtaatta ttaacagctc ccacttctac tctaaaaaat 8160
gacccaatct gggcagtaaa ttatatggtg cccatgctat taagagctgc aacttgctgg 8220
gcgtggtggc tcacacctgt aatcccagta ctttgggacg tcaaggcggg tggatcacct 8280
gaggtcacga gttagagact ggcctggcca gcatggcaaa accccatctt tactaaaaat 8340
acaaaaatta gcaaggcatg gtggcatgca cctgtaatcc caggtactcg ggaggctgag 8400
acaggagaat ggcttgaacc caggaggcag aggttgcagt gagccaagat tgtgccactg 8460
ccctccagcc ctggcaacag agcaagactt catctcaaaa gaaaaaggat actgtcaatc 8520
actgcaggaa gaacccaggt aatgaatgag gagaagagag gggctgagtc accatagtgg 8580
cagcaccgac tcctgcagga aaggcgagac actgggtcat gggtactgaa gggtgccctg 8640
aatgacgttc tgctttagag accgaacctg agccctgaaa gtgcatgcct gttcatgggt 8700
gagagactaa attcatcatt ccttggcagg tactgaatcc tttcttacgg ctgccctcca 8760
atgcccaatt tccctacaat tgtctggggt gcctaagctt ctgcccacca agagggccag 8820
agctggcagc gagcagctgc aggtaggaga gataggtacc cataagggag gtgggaaaga 8880
gagatggaag gagaggggtg cagagcacac acctcccctg cctgacaact tcctgagggc 8940
tggtcatgcc agcagattta aggcggaggc aggggagatg gggcgggaga ggaagtgaaa 9000
aaggagaggg tggggatgga gaggaagaga gggtgatcat tcattcattc cattgctact 9060
gactggatgc cagctgtgag ccaggcacca ccctagctct gggcatgtgg ttgtaatctt 9120
ggagcctcat ggagctcaca gggagtgctg gcaaggagat ggataatgga cggataacaa 9180
ataaacattt agtacaatgt ccgggaatgg aaagttctcg aaagaaaaat aaagctggtg 9240
agcatataga cagccctgaa ggcggccagg ccaggcattt ctgaggaggt ggcatttgag 9300
c 9301
<210>19
<211>21
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>19
ccggagctgg agaacaacaa g 21
<210>20
<211>19
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>20
gcactggccg gagcacacc 19
<210>21
<211>23
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>21
aggccaaccg cgagaagatg acc 23
<210>22
<211>21
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>22
gaagtccagg gcgacgtagc a 21
<210>23
<211>25
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>23
aagcttggta ccatgcagct cccac 25
<210>24
<211>50
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>24
aagcttctac ttgtcatcgtcgtccttgta gtcgtaggcg ttctccagct 50
<210>25
<211>19
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>25
gcactggccg gagcacacc 19
<210>26
<211>39
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>26
gtcgtcggat ccatggggtg gcaggcgttc aagaatgat 39
<210>27
<211>57
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>27
gtcgtcaagc ttctacttgt catcgtcctt gtagtcgtag gcgttct cca gctcggc 57
<210>28
<211>29
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>28
gacttggatc ccaggggtgg caggcgttc 29
<210>29
<211>29
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>29
agcataagct tctagtaggc gttctccag 29
<210>30
<211>29
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>30
gacttggatc cgaagggaaa aagaaaggg 29
<210>31
<211>29
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>31
agcataagct tttaatccaa atcgatgga 29
<210>32
<211>33
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>32
actacgagct cggccccacc acccatcaac aag 33
<210>33
<211>34
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>33
acttagaagc tttcagtcct cagccccctc ttcc 34
<210>34
<211>66
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>34
aatctggatc cataacttcg tatagcatac attatacgaa gttatctgca ggattcgagg 60
gcccct 66
<210>35
<211>82
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>35
aatctgaatt ccaccggtgt taattaaata acttcgtata atgtatgcta tacgaagtta 60
tagatctaga gtcagcttct ga 82
<210>36
<211>62
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>36
atttaggtga cactatagaa ctcgagcagc tgaagcttaa ccacatggtg gctcacaacc 60
at 62
<210>37
<211>54
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>37
aacgacggcc agtgaatccgtaatcatggt catgctgcca ggtggaggag ggca 54
<210>38
<211>31
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>38
attaccaccg gtgacacccg cttcctgaca g 31
<210>39
<211>61
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>39
attacttaat taaacatggc gcgccatatg gccggcccct aattgcggcg catcgttaat 60
t 61
<210>40
<211>34
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>40
attacggccg gccgcaaagg aattcaagat ctga 34
<210>41
<211>34
<212>DNA
<213>人工序列
<220>
<223>用于PCR的引物
<400>41
attacggcgc gcccctcaca ggccgcaccc agct 34
<210>42
<211>184
<212>PRT
<213>Homo sapiens
<400>42
Met Ser Arg Thr Ala Tyr Thr Val Gly Ala Leu Leu Leu Leu Leu Gly
1 5 10 15
Thr Leu Leu Pro Ala Ala Glu Gly Lys Lys Lyg Gly Ser Gln Gly Ala
20 25 30
Ile Pro Pro Pro Asp Lys Ala Gln His Asn Asp Ser Glu Gln Thr Gln
35 40 45
Ser Pro Gln Gln Pro Gly Ser Arg Asn Arg Gly Arg Gly Gln Gly Arg
50 55 60
Gly Thr Ala Met Pro Gly Glu Glu Val Leu Glu Ser Ser Gln Glu Ala
65 70 75 80
Leu His Val Thr Glu Arg Lys Tyr Leu Lys Arg Asp Trp Cys Lys Thr
85 90 95
Gln Pro Leu Lys Gln Thr Ile His Glu Glu Gly Cys Asn Ser Arg Thr
100 105 110
Ile Ile Asn Arg Phe Cys Tyr Gly Gln Cys Asn Ser Phe Tyr Ile Pro
115 120 125
Arg His Ile Arg Lys Glu Glu Gly Ser Phe Gln Ser Cys Ser Phe Cys
130 135 140
Lys Pro Lys Lys Phe Thr Thr Met Met Val Thr Leu Asn Cys Pro Glu
145 150 155 160
Leu Gln Pro Pro Thr Lys Lys Lys Arg Val Thr Arg Val Lys Gln Cys
165 170 175
Arg Cys Ile Ser Ile Asp Leu Asp
180
<210>43
<211>267
<212>PRT
<213>Homo sapiens
<400>43
Met His Leu Leu Leu Phe Gln Leu Leu Val Leu Leu Pro Leu Gly Lys
1 5 10 15
Thr Thr Arg His Gln Asp Gly Arg Gln Asn Gln Ser Ser Leu Ser Pro
20 25 30
Val Leu Leu Pro Arg Asn Gln Arg Glu Leu Pro Thr Gly Asn His Glu
35 40 45
Glu Ala Glu Glu Lys Pro Asp Leu Phe Val Ala Val Pro His Leu Val
50 55 60
Ala Thr Ser Pro Ala Gly Glu Gly Gln Arg Gln Arg Glu Lys Met Leu
65 70 75 80
Ser Arg Phe Gly Arg Phe Trp Lys Lys Pro Glu Arg Glu Met His Pro
85 90 95
Ser Arg Asp Ser Asp Ser Glu Pro Phe Pro Pro Gly Thr Gln Ser Leu
100 105 110
Ile Gln Pro Ile Asp Gly Met Lys Met Glu Lys Ser Pro Leu Arg Glu
115 120 125
Glu Ala Lys Lys Phe Trp His His Phe Met Phe Arg Lys Thr Pro Ala
130 135 140
Ser Gln Gly Val Ile Leu Pro Ile Lys Ser His Glu Val His Trp Glu
145 150 155 160
Thr Cys Arg Thr Val Pro Phe Ser Gln Thr Ile Thr His Glu Gly Cys
165 170 175
Glu Lys Val Val Val Gln Asn Asn Leu Cys Phe Gly Lys Cys Gly Ser
180 185 190
Val His Phe Pro Gly Ala Ala Gln His Ser His Thr Ser Cys Ser His
195 200 205
Cys Leu Pro Ala Lys Phe Thr Thr Met His Leu Pro Leu Asn Cys Thr
210 215 220
Glu Leu Ser Ser Val Ile Lys Val Val Met Leu Val Glu Glu Cys Gln
225 230 235 240
Cys Lys Val Lys Thr Glu His Glu Asp Gly His Ile Leu His Ala Gly
245 250 255
Ser Gln Asp Ser Phe Ile Pro Gly Val Ser Ala
260 265
<210>44
<211>180
<212>PRT
<213>Homo sapiens
<400>44
Met Leu Arg Val Leu Val Gly Ala Val Leu Pro Ala Met Leu Leu Ala
1 5 10 15
Ala Pro Pro Pro Ile Asn Lys Leu Ala Leu Phe Pro Asp Lys Ser Ala
20 25 30
Trp Cys Glu Ala Lys Asn Ile Thr Gln Ile Val Gly His Ser Gly Cys
35 40 45
Glu Ala Lys Ser Ile Gln Asn Arg Ala Cys Leu Gly Gln Cys Phe Ser
50 55 60
Tyr Ser Val Pro Asn Thr Phe Pro Gln Ser Thr Glu Ser Leu Val His
65 70 75 80
Cys Asp Ser Cys Met Pro Ala Gln Ser Met Trp Glu Ile Val Thr Leu
85 90 95
Glu Cys Pro Gly His Glu Glu Val Pro Arg Val Asp Lys Leu Val Glu
100 105 110
Lys Ile Leu His Cys Ser Cys Gln Ala Cys Gly Lys Glu Pro Ser His
115 120 125
Glu Gly Leu Ser Val Tyr Val Gln Gly Glu Asp Gly Pro Gly Ser Gln
130 135 140
Pro Gly Thr His Pro His Pro His Pro His Pro His Pro Gly Gly Gln
145 150 155 160
Thr Pro Glu Pro Glu Asp Pro Pro Gly Ala Pro His Thr Glu Glu Glu
165 170 175
Gly Ala Glu Asp
180
<210>45
<211>642
<212>DNA
<213>Homo sapiens
<220>
<221>CDS
<222>(1)..(639)
<400>45
atg cag ctc cca ctg gcc ctg tgt ctc gtc tgc ctg ctg gta cac aca 48
Met Gln Leu Pro Leu Ala Leu Cys Leu Val Cys Leu Leu Val His Thr
1 5 10 15
gcc ttc cgt gta gtg gag ggc cag ggg tgg cag gcg ttc aag aat gat 96
Ala Phe Arg Val Val Glu Gly Gln Gly Trp Gln Ala Phe Lys Asn Asp
20 25 30
gcc acg gaa atc atc ccc gag ctc gga gag tac ccc gag cct cca ccg 144
Ala Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro
35 40 45
gag ctg gag aac aac aag acc atg aac cgg gcg gag aac gga ggg cgg 192
Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg
50 55 60
cct ccc cac cac ccc ttt gag acc aaa gac gtg tcc gag tac agc tgc 240
Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser Cys
65 70 75 80
cgc gag ctg cac ttc acc cgc tac gtg acc gat ggg ccg tgc cgc agc 288
Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg Ser
85 90 95
gcc aag ccg gtc acc gag ctg gtg tgc tcc ggc cag tgc ggc ccg gcg 336
Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala
100 105 110
cgc ctg ctg ccc aac gcc atc ggc cgc ggc aag tgg tgg cga cct agt 384
Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser
115 120 125
ggg ccc gac ttc cgc tgc atc ccc gac cgc tac cgc gcg cag cgc gtg 432
Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val
130 135 140
cag ctg ctg tgt ccc ggt ggt gag gcg ccg cgc gcg cgc aag gtg cgc 480
Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg
145 150 155 160
ctg gtg gcc tcg tgc aag tgc aag cgc ctc acc cgc ttc cac aac cag 528
Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln
165 170 175
tcg gag ctc aag gac ttc ggg acc gag gcc gct cgg ccg cag aag ggc 576
Ser Glu Leu Lys Asp Phe Gly Thr Glu Ala Ala Arg Pro Gln Lys Gly
180 185 190
cgg aag ccg cgg ccc cgc gcc cgg agc gcc aaa gcc aac cag gcc gag 624
Arg Lys Pro Arg Pro Arg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu
195 200 205
ctg gag aac gcc tac tag 642
Leu Glu Asn Ala Tyr
210
<210>46
<211>190
<212>PRT
<213>Homo sapiens
<400>46
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Glu
1 5 10 15
Leu Gly Glu Tyr Pro Glu Pro Pro Pro Glu Leu Glu Asn Asn Lys Thr
20 25 30
Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro Phe Glu
35 40 45
Thr Lys Asp Val Ser Glu Tyr Ser Cys Arg Glu Leu His Phe Thr Arg
50 55 60
Tyr Val Thr Asp Gly Pro Cys Arg Ser Ala Lys Pro Val Thr Glu Leu
65 70 75 80
Val Cys Ser Gly Gln Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile
85 90 95
Gly Arg Gly Lys Trp Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys Ile
100 105 110
Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly Gly
115 120 125
Glu Ala Pro Arg Ala Arg Lys Val Arg Leu Val Ala Ser Cys Lys Cys
130 135 140
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
145 150 155 160
Thr Glu Ala Ala Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Arg Ala
165 170 175
Arg Ser Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
180 185 190
<210>47
<211>20
<212>PRT
<213>Homo sapiens
<400>47
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Glu
1 5 10 15
Leu Gly Glu Tyr
20
<210>48
<211>20
<212>PRT
<213>Homo sapiens
<400>48
Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro Glu
1 5 10 15
Leu Glu Asn Asn
20
<210>49
<211>20
<212>PRT
<213>Homo sapiens
<400>49
Pro Glu Pro Pro Pro Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala
1 5 10 15
Glu Asn Gly Gly
20
<210>50
<211>20
<212>PRT
<213>Homo sapiens
<400>50
Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro
1 5 10 15
Phe Glu Thr Lys
20
<210>51
<211>16
<212>PRT
<213>Homo sapiens
<400>51
Arg Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser
1 5 10 15
<210>52
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>52
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Glu
1 5 10 15
Leu Gly Glu Tyr Cys
20
<210>53
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>53
Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro Glu
1 5 10 15
Leu Glu Asn Asn Cys
20
<210>54
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>54
Pro Glu Pro Pro Pro Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala
1 5 10 15
Glu Asn Gly Gly Cys
20
<210>55
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>55
Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro
34
1 5 10 15
Phe Glu Thr Lys Cys
20
<210>56
<211>17
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>56
Arg Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser
1 5 10 15
Cys
<210>57
<211>24
<212>PRT
<213>Rattus norvegicus
<400>57
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Gly
1 5 10 15
Leu Arg Glu Tyr Pro Glu Pro Pro
20
<210>58
<211>20
<212>PRT
<213>Rattus morvegicus
<400>58
Pro Glu Pro Pro Gln Glu Leu Glu Asn Asn Gln Thr Met Asn Arg Ala
1 5 10 15
Glu Asn Gly Gly
20
<210>59
<211>20
<212>PRT
<213>Rattus norvegicus
<400>59
Glu Asn Gly Gly Arg Pro Pro His His Pro Tyr Asp Thr Lys Asp Val
1 5 10 15
Ser Glu Tyr Ser
20
<210>60
<211>20
<212>PRT
<213>Rattus norvegicus
<400>60
Thr Glu Ile Ile Pro Gly Leu Arg Glu Tyr Pro Glu Pro Pro Gln Glu
1 5 10 15
Leu Glu Asn Asn
20
<210>61
<211>25
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>61
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Gly
1 5 10 15
Leu Arg Glu Tyr Pro Glu Pro Pro Cys
20 25
<210>62
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>62
Pro Glu Pro Pro Gln Glu Leu Glu Asn Asn Gln Thr Met Asn Arg Ala
1 5 10 15
Glu Asn Gly Gly Cys
20
<210>63
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>63
Glu Asn Gly Gly Arg Pro Pro His His Pro Tyr Asp Thr Lys Asp Val
1 5 10 15
Ser Glu Tyr Ser Cys
20
<210>64
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>64
Thr Glu Ile Ile Pro Gly Leu Arg Glu Tyr Pro Glu Pro Pro Gln Glu
1 5 10 15
Leu Glu Asn Asn Cys
20
<210>65
<211>190
<212>PRT
<213>Rattus norvegicus
<400>65
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Gly
1 5 10 15
Leu Arg Glu Tyr Pro Glu Pro Pro Gln Glu Leu Glu Asn Asn Gln Thr
20 25 30
Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro Tyr Asp
35 40 45
Thr Lys Asp Val Ser Glu Tyr Ser Cys Arg Glu Leu His Tyr Thr Arg
50 55 60
Phe Val Thr Asp Gly Pro Cys Arg Ser Ala Lys Pro Val Thr Glu Leu
65 70 75 80
Val Cys Ser Gly Gln Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile
85 90 95
Gly Arg Val Lys Trp Trp Arg Pro Asn Gly Pro Asp Phe Arg Cys Ile
100 105 110
Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly Gly
115 120 125
Ala Ala Pro Arg Ser Arg Lys Val Arg Leu Val Ala Ser Cys Lys Cys
130 135 140
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
145 150 155 160
Pro Glu Thr Ala Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Arg Ala
165 170 175
Arg Gly Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
180 185 190
<210>66
<211>20
<212>PRT
<213>Homo sapiens
<400>66
Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly
1 5 10 15
Gly Glu Ala Pro
20
<210>67
<211>20
<212>PRT
<213>Homo sapiens
<400>67
Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg
1 5 10 15
Leu Val Ala Ser
20
<210>68
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>68
Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly
1 5 10 15
Gly Glu Ala Pro Cys
20
<210>69
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>69
Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg
1 5 10 15
Leu Val Ala Ser Cys
20
<210>70
<211>17
<212>PRT
<213>Rattus Norvegicus
<400>70
Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly
1 5 10 15
Gly
<210>71
<211>16
<212>PRT
<213>Rattus norvegicus
<400>71
Pro Gly Gly Ala Ala Pro Arg Ser Arg Lys Val Arg Leu Val Ala Ser
1 5 10 15
<210>72
<211>18
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>72
Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Ser Pro Gly
1 5 10 15
Gly Cys
<210>73
<211>17
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>73
Pro Gly Gly Ala Ala Pro Arg Ser Arg Lys Val Arg Leu Val Ala Ser
1 5 10 15
Cys
<210>74
<211>20
<212>PRT
<213>Homo sapiens
<400>74
Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp
1 5 10 15
Trp Arg Pro Ser
20
<210>75
<211>16
<212>PRT
<213>Homo sapiens
<400>75
Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys
1 5 10 15
<210>76
<211>18
<212>PRT
<213>Rattus norvegicus
<400>76
Pro Asn Ala Ile Gly Arg Val Lys Trp Trp Arg Pro Asn Gly Pro Asp
1 5 10 15
Phe Arg
<210>77
<211>19
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>77
Pro Asn Ala Ile Gly Arg Val Lys Trp Trp Arg Pro Asn Gly Pro Asp
1 5 10 15
Phe Arg Cys
<210>78
<211>20
<212>PRT
<213>Homo sapiens
<400>78
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
1 5 10 15
Thr Glu Ala Ala
20
<210>79
<211>20
<212>PRT
<213>Homo sapiens
<400>79
Glu Leu Lys Asp Phe Gly Thr Glu Ala Ala Arg Pro Gln Lys Gly Arg
1 5 10 15
Lys Pro Arg Pro
20
<210>80
<211>20
<212>PRT
<213>Homo sapiens
<400>80
Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Arg Ala Arg Ser Ala Lys
1 5 10 15
Ala Asn Gln Ala
20
<210>81
<211>16
<212>PRT
<213>Homo sapiens
<400>81
Arg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
1 5 10 15
<210>82
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>82
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
1 5 10 15
Thr Glu Ala Ala Cys
20
<210>83
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>83
Glu Leu Lys Asp Phe Gly Thr Glu Ala Ala Arg Pro Gln Lys Gly Arg
1 5 10 15
Lys Pro Arg Pro Cys
20
<210>84
<211>21
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>84
Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Arg Ala Arg Ser Ala Lys
1 5 10 15
Ala Asn Gln Ala Cys
20
<210>85
<211>17
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的人SOST肽片段
<400>85
Arg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
1 5 10 15
Cys
<210>86
<211>23
<212>PRT
<213>Rattus norvegicus
<400>86
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
1 5 10 15
Pro Glu Thr Ala Arg Pro Gln
20
<210>87
<211>23
<212>PRT
<213>Rattus norvegicus
<400>87
Lys Gly Arg Lys Pro Arg Pro Arg Ala Arg Gly Ala Lys Ala Asn Gln
1 5 10 15
Ala Glu Leu Glu Asn Ala Tyr
20
<210>88
<211>24
<212>PRT
<213>Rattus norvegicus
<400>88
Ser Glu Leu Lys Asp Phe Gly Pro Glu Thr Ala Arg Pro Gln Lys Gly
1 5 10 15
Arg Lys Pro Arg Pro Arg Ala Arg
20
<210>89
<211>24
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>89
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
1 5 10 15
Pro Glu Thr Ala Arg Pro Gln Cys
20
<210>90
<211>24
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>90
Lys Gly Arg Lys Pro Arg Pro Arg Ala Arg Gly Ala Lys Ala Asn Gln
1 5 10 15
Ala Glu Leu Glu Asn Ala Tyr Cys
20
<210>91
<211>25
<212>PRT
<213>人工序列
<220>
<223>添加了额外半胱氨酸的大鼠SOST肽片段
<400>91
Ser Glu Leu Lys Asp Phe Gly Pro Glu Thr Ala Arg Pro Gln Lys Gly
1 5 10 15
Arg Lys Pro Arg Pro Arg Ala Arg Cys
20 25
<210>92
<211>56
<212>PRT
<213>Homo sapiens
<400>92
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Glu
1 5 10 15
Leu Gly Glu Tyr Pro Glu Pro Pro Pro Glu Leu Glu Asn Asn Lys Thr
20 25 30
Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro Phe Glu
35 40 45
Thr Lys Asp Val Ser Glu Tyr Ser
50 55
<210>93
<211>56
<212>PRT
<213>Rattus norvegicus
<400>93
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Gly
1 5 10 15
Leu Arg Glu Tyr Pro Glu Pro Pro Gln Glu Leu Glu Asn Asn Gln Thr
20 25 30
Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro Tyr Asp
35 40 45
Thr Lys Asp Val Ser Glu Tyr Ser
50 55
<210>94
<211>32
<212>PRT
<213>Homo sapiens
<400>94
Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro
1 5 10 15
Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg Leu Val Ala Ser Cys
20 25 30
<210>95
<211>32
<212>PRT
<213>Rattus norvegicus
<400>95
Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro
1 5 10 15
Gly Gly Ala Ala Pro Arg Ser Arg Lys Val Arg Leu Val Ala Ser Cys
20 25 30
<210>96
<211>44
<212>PRT
<213>Homo sapiens
<400>96
Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly Thr Glu
1 5 10 15
Ala Ala Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Arg Ala Arg Ser
20 25 30
Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
35 40
<210>97
<211>44
<212>PRT
<213>Rattus norvegicus
<400>97
Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly Pro Glu
1 5 10 15
Thr Ala Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Arg Ala Arg Gly
20 25 30
Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
35 40
<210>98
<211>26
<212>PRT
<213>Homo sapiens
<400>98
Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp
1 5 10 15
Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys
20 25
<210>99
<211>26
<212>PRT
<213>Rattus norvegicus
<400>99
Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Val Lys Trp
1 5 10 15
Trp Arg Pro Asn Gly Pro Asp Phe Arg Cys
20 25
<210>100
<211>570
<212>DNA
<213>Homo sapiens
<400>100
caggggtggc aggcgttcaa gaatgatgcc acggaaatca tccccgagct cggagagtac 60
cccgagcctc caccggagct ggagaacaac aagaccatga accgggcgga gaacggaggg 120
cggcctcccc accacccctt tgagaccaaa gacgtgtccg agtacagctg ccgcgagctg 180
cacttcaccc gctacgtgac cgatgggccg tgccgcagcg ccaagccggt caccgagctg 240
gtgtgctccg gccagtgcgg cccggcgcgc ctgctgccca acgccatcgg ccgcggcaag 300
tggtggcgac ctagtgggcc cgacttccgc tgcatccccg accgctaccg cgcgcagcgc 360
gtgcagctgc tgtgtcccgg tggtgaggcg ccgcgcgcgc gcaaggtgcg cctggtggcc 420
tcgtgcaagt gcaagcgcct cacccgcttc cacaaccagt cggagctcaa ggacttcggg 480
accgaggccg ctcggccgca gaagggccgg aagccgcggc cccgcgcccg gagcgccaaa 540
gccaaccagg ccgagctgga gaacgcctac 570
<210>101
<211>570
<212>DNA
<213>Rattus norvegicus
<400>101
caggggtggc aagccttcaa gaatgatgcc acagaaatca tcccgggact cagagagtac 60
ccagagcctc ctcaggaact agagaacaac cagaccatga accgggccga gaacggaggc 120
agaccccccc accatcctta tgacaccaaa gacgtgtccg agtacagctg ccgcgagctg 180
cactacaccc gcttcgtgac cgacggcccg tgccgcagtg ccaagccggt caccgagttg 240
gtgtgctcgg gccagtgcgg ccccgcgcgg ctgctgccca acgccatcgg gcgcgtgaag 300
tggtggcgcc cgaacggacc cgacttccgc tgcatcccgg atcgctaccg cgcgcagcgg 360
gtgcagctgc tgtgccccgg cggcgcggcg ccgcgctcgc gcaaggtgcg tctggtggcc 420
tcgtgcaagt gcaagcgcct cacccgcttc cacaaccagt cggagctcaa ggacttcgga 480
cctgagaccg cgcggccgca gaagggtcgc aagccgcggc cccgcgcccg gggagccaaa 540
gccaaccagg cggagctgga gaacgcctac 570
<210>102
<211>532
<212>PRT
<213>Homo sapiens
<400>102
Met Thr Gln Leu Tyr Ile Tyr Ile Arg Leu Leu Gly Ala Tyr Leu Phe
1 5 10 15
Ile Ile Ser Arg Val Gln Gly Gln Asn Leu Asp Ser Met Leu His Gly
20 25 30
Thr Gly Met Lys Ser Asp Ser Asp Gln Lys Lys Ser Glu Asn Gly Val
35 40 45
Thr Leu Ala Pro Glu Asp Thr Leu Pro Phe Leu Lys Cys Tyr Cys Ser
50 55 60
Gly His Cys Pro Asp Asp Ala Ile Asn Asn Thr Cys Ile Thr Asn Gly
65 70 75 80
His Cys Phe Ala Ile Ile Glu Glu Asp Asp Gln Gly Glu Thr Thr Leu
85 90 95
Ala Ser Gly Cys Met Lys Tyr Glu Gly Ser Asp Phe Gln Cys Lys Asp
100 105 110
Ser Pro Lys Ala Gln Leu Arg Arg Thr Ile Glu Cys Cys Arg Thr Asn
115 120 125
Leu Cys Asn Gln Tyr Leu Gln Pro Thr Leu Pro Pro Val Val Ile Gly
130 135 140
Pro Phe Phe Asp Gly Ser Ile Arg Trp Leu Val Leu Leu Ile Ser Met
145 150 155 160
Ala Val Cys Ile Ile Ala Met Ile Ile Phe Ser Ser Cys Phe Cys Tyr
165 170 175
Lys His Tyr Cys Lys Ser Ile Ser Ser Arg Arg Arg Tyr Asn Arg Asp
180 185 190
Leu Glu Gln Asp Glu Ala Phe Ile Pro Val Gly Glu Ser Leu Lys Asp
195 200 205
Leu Ile Asp Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu Pro Leu
210 215 220
Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Arg Gln Val
225 230 235 240
Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg Gly Glu
245 250 255
Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser Trp Phe
260 265 270
Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu Asn Ile
275 280 285
Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp Thr Gln
290 295 300
Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr Asp Phe
305 310 315 320
Leu Lys Cys Ala Thr Leu Asp Thr Arg Ala Leu Leu Lys Leu Ala Tyr
325 330 335
Ser Ala Ala Cys Gly Leu Cys His Leu His Thr Glu Ile Tyr Gly Thr
340 345 350
Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys Asn Ile
355 360 365
Leu Ile Lys Lys Asn Gly Ser Cys Cys Ile Ala Asp Leu Gly Leu Ala
370 375 380
Val Lys Phe Asn Ser Asp Thr Asn Glu Val Asp Val Pro Leu Asn Thr
385 390 395 400
Arg Val Gly Thr Lys Arg Tyr Met Ala Pro Glu Val Leu Asp Glu Ser
405 410 415
Leu Asn Lys Asn His Phe Gln Pro Tyr Ile Met Ala Asp Ile Tyr Ser
420 425 430
Phe Gly Leu Ile Ile Trp Glu Met Ala Arg Arg Cys Ile Thr Gly Gly
435 440 445
Ile Val Glu Glu Tyr Gln Leu Pro Tyr Tyr Asn Met Val Pro Ser Asp
450 455 460
Pro Ser Tyr Glu Asp Met Arg Glu Val Val Cys Val Lys Arg Leu Arg
465 470 475 480
Pro Ile Val Ser Asn Arg Trp Asn Ser Asp Glu Cys Leu Arg Ala Val
485 490 495
Leu Lys Leu Met Ser Glu Cys Trp Ala His Asn Pro Ala Ser Arg Leu
500 505 510
Thr Ala Leu Arg Ile Lys Lys Thr Leu Ala Lys Met Val Glu Ser Gln
515 520 525
Asp Val Lys Ile
530
<210>103
<211>502
<212>PRT
<213>Homo sapiens
<400>103
Met Leu Leu Arg Ser Ala Gly Lys Leu Asn Val Gly Thr Lys Lys Glu
1 5 10 15
Asp Gly Glu Ser Thr Ala Pro Thr Pro Arg Pro Lys Val Leu Arg Cys
20 25 30
Lys Cys His His His Cys Pro Glu Asp Ser Val Asn Asn Ile Cys Ser
35 40 45
Thr Asp Gly Tyr Cys Phe Thr Met Ile Glu Glu Asp Asp Ser Gly Leu
50 55 60
Pro Val Val Thr Ser Gly Cys Leu Gly Leu Glu Gly Ser Asp Phe Gln
65 70 75 80
Cys Arg Asp Thr Pro Ile Pro His Gln Arg Arg Ser Ile Glu Cys Cys
85 90 95
Thr Glu Arg Asn Glu Cys Asn Lys Asp Leu His Pro Thr Leu Pro Pro
100 105 110
Leu Lys Asn Arg Asp Phe Val Asp Gly Pro Ile His His Arg Ala Leu
115 120 125
Leu Ile Ser Val Thr Val Cys Ser Leu Leu Leu Val Leu Ile Ile Leu
130 135 140
Phe Cys Tyr Phe Arg Tyr Lys Arg Gln Glu Thr Arg Pro Arg Tyr Ser
145 150 155 160
Ile Gly Leu Glu Gln Asp Glu Thr Tyr Ile Pro Pro Gly Glu Ser Leu
165 170 175
Arg Asp Leu Ile Glu Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu
180 185 190
Pro Leu Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Lys
195 200 205
Gln Ile Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg
210 215 220
Gly Glu Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser
225 230 235 240
Trp Phe Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu
245 250 255
Asn Ile Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp
260 265 270
Thr Gln Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr
275 280 285
Asp Tyr Leu Lys Ser Thr Thr Leu Asp Ala Lys Ser Met Leu Lys Leu
290 295 300
Ala Tyr Ser Ser Val Ser Gly Leu Cys His Leu His Thr Glu Ile Phe
305 310 315 320
Ser Thr Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys
325 330 335
Asn Ile Leu Val Lys Lys Asn Gly Thr Cys Cys Ile Ala Asp Leu Gly
340 345 350
Leu Ala Val Lys Phe Ile Ser Asp Thr Asn Glu Val Asp Ile Pro Pro
355 360 365
Asn Thr Arg Val Gly Thr Lys Arg Tyr Met Pro Pro Glu Val Leu Asp
370 375 380
Glu Ser Leu Asn Arg Asn His Phe Gln Ser Tyr Ile Met Ala Asp Met
385 390 395 400
Tyr Ser Phe Gly Leu Ile Leu Trp Glu Val Ala Arg Arg Cys Val Ser
405 410 415
Gly Gly Ile Val Glu Glu Tyr Gln Leu Pro Tyr His Asp Leu Val Pro
420 425 430
Ser Asp Pro Ser Tyr Glu Asp Met Arg Glu Ile Val Cys Ile Lys Lys
435 440 445
Leu Arg Pro Ser Phe Pro Asn Arg Trp Ser Ser Asp Glu Cys Leu Arg
450 455 460
Gln Met Gly Lys Leu Met Thr Glu Cys Trp Ala His Asn Pro Ala Ser
465 470 475 480
Arg Leu Thr Ala Leu Arg Val Lys Lys Thr Leu Ala Lys Met Ser Glu
485 490 495
Ser Gln Asp Ile LysLeu
500
<210>104
<211>502
<212>PRT
<213>Homo sapiens
<400>104
Met Leu Leu Arg Ser Ala Gly Lys Leu Asn Val Gly Thr Lys Lys Glu
1 5 10 15
Asp Gly Glu Ser Thr Ala Pro Thr Pro Arg Pro Lys Val Leu Arg Cys
20 25 30
Lys Cys His His His Cys Pro Glu Asp Ser Val Asn Asn Ile Cys Ser
35 40 45
Thr Asp Gly Tyr Cys Phe Thr Met Ile Glu Glu Asp Asp Ser Gly Leu
50 55 60
Pro Val Val Thr Ser Gly Cys Leu Gly Leu Glu Gly Ser Asp Phe Gln
65 70 75 80
Cys Arg Asp Thr Pro Ile Pro His Gln Arg Arg Ser Ile Glu Cys Cys
85 90 95
Thr Glu Arg Asn Glu Cys Asn Lys Asp Leu His Pro Thr Leu Pro Pro
100 105 110
Leu Lys Asn Arg Asp Phe Val Asp Gly Pro Ile His His Arg Ala Leu
115 120 125
Leu Ile Ser Val Thr Val Cys Ser Leu Leu Leu Val Leu Ile Ile Leu
130 135 140
Phe Cys Tyr Phe Arg Tyr Lys Arg Gln Glu Thr Arg Pro Arg Tyr Ser
145 150 155 160
Ile Gly Leu Glu Gln Asp Glu Thr Tyr Ile Pro Pro Gly Glu Ser Leu
165 170 175
Arg Asp Leu Ile Glu Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu
180 185 190
Pro Leu Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Lys
195 200 205
Gln Ile Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg
210 215 220
Gly Glu Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser
225 230 235 240
Trp Phe Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu
245 250 255
Asn Ile Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp
260 265 270
Thr Gln Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr
275 280 285
Asp Tyr Leu Lys Ser Thr Thr Leu Asp Ala Lys Ser Met Leu Lys Leu
290 295 300
Ala Tyr Ser Ser Val Ser Gly Leu Cys His Leu His Thr Glu Ile Phe
305 310 315 320
Ser Thr Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys
325 330 335
Asn Ile Leu Val Lys Lys Asn Gly Thr Cys Cys Ile Ala Asp Leu Gly
340 345 350
Leu Ala Val Lys Phe Ile Ser Asp Thr Asn Glu Val Asp Ile Pro Pro
355 360 365
Asn Thr Arg Val Gly Thr Lys Arg Tyr Met Pro Pro Glu Val Leu Asp
370 375 380
Glu Ser Leu Asn Arg Asn His Phe Gln Ser Tyr Ile Met Ala Asp Met
385 390 395 400
Tyr Ser Phe Gly Leu Ile Leu Trp Glu Val Ala Arg Arg Cys Val Ser
405 410 415
Gly Gly Ile Val Glu Glu Tyr Gln Leu Pro Tyr His Asp Leu Val Pro
420 425 430
Ser Asp Pro Ser Tyr Glu Asp Met Arg Glu Ile Val Cys Ile Lys Lys
435 440 445
Leu Arg Pro Ser Phe Pro Asn Arg Trp Ser Ser Asp Glu Cys Leu Arg
450 455 460
Gln Met Gly Lys Leu Met Thr Glu Cys Trp Ala His Asn Pro Ala Ser
465 470 475 480
Arg Leu Thr Ala Leu Arg Val Lys Lys Thr Leu Ala Lys Met Ser Glu
485 490 495
Ser Gln Asp Ile Lys Leu
500
<210>105
<211>532
<212>PRT
<213>Rattus sp.
<400>105
Met Thr Gln Leu Tyr Thr Tyr Ile Arg Leu Leu Gly Ala Cys Leu Phe
1 5 10 15
Ile Ile Ser His Val Gln Gly Gln Asn Leu Asp Ser Met Leu His Gly
20 25 30
Thr Gly Met Lys Ser Asp Val Asp Gln Lys Lys Pro Glu Asn Gly Val
35 40 45
Thr Leu Ala Pro Glu Asp Thr Leu Pro Phe Leu Lys Cys Tyr Cys Ser
50 55 60
Gly His Cys Pro Asp Asp Ala Ile Asn Asn Thr Cys Ile Thr Asn Gly
65 70 75 80
His Cys Phe Ala Ile Ile Glu Glu Asp Asp Gln Gly Glu Thr Thr Leu
85 90 95
Thr Ser Gly Cys Met Lys Tyr Glu Gly Ser Asp Phe Gln Cys Lys Asp
100 105 110
Ser Pro Lys Ala Gln Leu Arg Arg Thr Ile Glu Cys Cys Arg Thr Asn
115 120 125
Leu Cys Asn Gln Tyr Leu Gln Pro Thr Leu Pro Pro Val Val Ile Gly
130 135 140
Pro Phe Phe Asp Gly Ser Val Arg Trp Leu Ala Val Leu Ile Ser Met
145 150 155 160
Ala Val Cys Ile Val Ala Met Ile Val Phe Ser Ser Cys Phe Cys Tyr
165 170 175
Lys His Tyr Cys Lys Ser Ile Ser Ser Arg Gly Arg Tyr Asn Arg Asp
180 185 190
Leu Glu Gln Asp Glu Ala Phe Ile Pro Val Gly Glu Ser Leu Lys Asp
195 200 205
Leu Ile Asp Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu Pro Leu
210 215 220
Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Arg Gln Val
225 230 235 240
Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg Gly Glu
245 250 255
Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser Trp Phe
260 265 270
Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu Asn Ile
275 280 285
Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp Thr Gln
290 295 300
Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr Asp Phe
305 310 315 320
Leu Lys Cys Ala Thr Leu Asp Thr Arg Ala Leu Leu Lys Leu Ala Tyr
325 330 335
Ser Ala Ala Cys Gly Leu Cys His Leu His Thr Glu Ile Tyr Gly Thr
340 345 350
Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys Asn Ile
355 360 365
Leu Ile Lys Lys Asn Gly Ser Cys Cys Ile Ala Asp Leu Gly Leu Ala
370 375 380
Val Lys Phe Asn Ser Asp Thr Asn Glu Val Asp Ile Pro Leu Asn Thr
385 390 395 400
Arg Val Gly Thr Arg Arg Tyr Met Ala Pro Glu Val Leu Asp Glu Ser
405 410 415
Leu Ser Lys Asn His Phe Gln Pro Tyr Ile Met Ala Asp Ile Tyr Ser
420 425 430
Phe Gly Leu Ile Ile Trp Glu Met Ala Arg Arg Cys Ile Thr Gly Gly
435 440 445
Ile Val Glu Glu Tyr Gln Leu Pro Tyr Tyr Asn Met Val Pro Ser Asp
450 455 460
Pro Ser Tyr Glu Asp Met Arg Glu Val Val Cys Val Lys Arg Leu Arg
465 470 475 480
Pro Ile Val Ser Asn Arg Trp Asn Ser Asp Glu Cys Leu Arg Ala Val
485 490 495
Leu Lys Leu Met Ser Glu Cys Trp Ala His Asn Pro Ala Ser Arg Leu
500 505 510
Thr Ala Leu Arg Ile Lys Lys Thr Leu Ala Lys Met Val Glu Ser Gln
515 520 525
Asp Val Lys Ile
530
<210>106
<211>532
<212>PRT
<213>Rattus norvegicus
<400>106
Met Thr Gln Leu Tyr Thr Tyr Ile Arg Leu Leu Gly Ala Cys Leu Phe
1 5 10 15
Ile Ile Ser His Val Gln Gly Gln Asn Leu Asp Ser Met Leu His Gly
20 25 30
Thr Gly Met Lys Ser Asp Val Asp Gln Lys Lys Pro Glu Asn Gly Val
35 40 45
Thr Leu Ala Pro Glu Asp Thr Leu Pro Phe Leu Lys Cys Tyr Cys Ser
50 55 60
Gly His Cys Pro Asp Asp Ala Ile Asn Asn Thr Cys Ile Thr Asn Gly
65 70 75 80
His Cys Phe Ala Ile Ile Glu Glu Asp Asp Gln Gly Glu Thr Thr Leu
85 90 95
Thr Ser Gly Cys Met Lys Tyr Glu Gly Ser Asp Phe Gln Cys Lys Asp
100 105 110
Ser Pro Lys Ala Gln Leu Arg Arg Thr Ile Glu Cys Cys Arg Thr Asn
115 120 125
Leu Cys Asn Gln Tyr Leu Gln Pro Thr Leu Pro Pro Val Val Ile Gly
130 135 140
Pro Phe Phe Asp Gly Ser Val Arg Trp Leu Ala Val Leu Ile Ser Met
145 150 155 160
Ala Val Cys Ile Val Ala Met Ile Val Phe Ser Ser Cys Phe Cys Tyr
165 170 175
Lys His Tyr Cys Lys Ser Ile Ser Ser Arg Gly Arg Tyr Asn Arg Asp
180 185 190
Leu Glu Gln Asp Glu Ala Phe Ile Pro Val Gly Glu Ser Leu Lys Asp
195 200 205
Leu Ile Asp Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu Pro Leu
210 215 220
Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Arg Gln Val
225 230 235 240
Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg Gly Glu
245 250 255
Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser Trp Phe
260 265 270
Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu Asn Ile
275 280 285
Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp Thr Gln
290 295 300
Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr Asp Phe
305 310 315 320
Leu Lys Cys Ala Thr Leu Asp Thr Arg Ala Leu Leu Lys Leu Ala Tyr
325 330 335
Ser Ala Ala Cys Gly Leu Cys His Leu His Thr Glu Ile Tyr Gly Thr
340 345 350
Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys Asn Ile
355 360 365
Leu Ile Lys Lys Asn Gly Ser Cys Cys Ile Ala Asp Leu Gly Leu Ala
370 375 380
Val Lys Phe Asn Ser Asp Thr Asn Glu Val Asp Ile Pro Leu Asn Thr
385 390 395 400
Arg Val Gly Thr Arg Arg Tyr Met Ala Pro Glu Val Leu Asp Glu Ser
405 410 415
Leu Ser Lys Asn His Phe Gln Pro Tyr Ile Met Ala Asp Ile Tyr Ser
420 425 430
Phe Gly Leu Ile Ile Trp Glu Met Ala Arg Arg Cys Ile Thr Gly Gly
435 440 445
Ile Val Glu Glu Tyr Gln Leu Pro Tyr Tyr Asn Met Val Pro Ser Asp
450 455 460
Pro Ser Tyr Glu Asp Met Arg Glu Val Val Cys Val Lys Arg Leu Arg
465 470 475 480
Pro Ile Val Ser Asn Arg Trp Asn Ser Asp Glu Cys Leu Arg Ala Val
485 490 495
Leu Lys Leu Met Ser Glu Cys Trp Ala His Asn Pro Ala Ser Arg Leu
500 505 510
Thr Ala Leu Arg Ile Lys Lys Thr Leu Ala Lys Met Val Glu Ser Gln
515 520 525
Asp Val Lys Ile
530
<210>107
<211>532
<212>PRT
<213>Rattus norvegicus
<400>107
Met Thr Gln Leu Tyr Thr Tyr Ile Arg Leu Leu Gly Ala Cys Leu Phe
1 5 10 15
Ile Ile Ser His Val Gln Gly Gln Asn Leu Asp Ser Met Leu His Gly
20 25 30
Thr Gly Met Lys Ser Asp Val Asp Gln Lys Lys Pro Glu Asn Gly Val
35 40 45
Thr Leu Ala Pro Glu Asp Thr Leu Pro Phe Leu Lys Cys Tyr Cys Ser
50 55 60
Gly His Cys Pro Asp Asp Ala Ile Asn Asn Thr Cys Ile Thr Asn Gly
65 70 75 80
His Cys Phe Ala Ile Ile Glu Glu Asp Asp Gln Gly Glu Thr Thr Leu
85 90 95
Thr Ser Gly Cys Met Lys Tyr Glu Gly Ser Asp Phe Gln Cys Lys Asp
100 105 110
Ser Pro Lys Ala Gln Leu Arg Arg Thr Ile Glu Cys Cys Arg Thr Asn
115 120 125
Leu Cys Asn Gln Tyr Leu Gln Pro Thr Leu Pro Pro Val Val Ile Gly
130 135 140
Pro Phe Phe Asp Gly Ser Val Arg Trp Leu Ala Val Leu Ile Ser Met
145 150 155 160
Ala Val Cys Ile Val Ala Met Ile Val Phe Ser Ser Cys Phe Cys Tyr
165 170 175
Lys His Tyr Cys Lys Ser Ile Ser Ser Arg Gly Arg Tyr Asn Arg Asp
180 185 190
Leu Glu Gln Asp Glu Ala Phe Ile Pro Val Gly Glu Ser Leu Lys Asp
195 200 205
Leu Ile Asp Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu Pro Leu
210 215 220
Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Arg Gln Val
225 230 235 240
Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg Gly Glu
245 250 255
Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser Trp Phe
260 265 270
Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu Asn Ile
275 280 285
Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp Thr Gln
290 295 300
Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr Asp Phe
305 310 315 320
Leu Lys Cys Ala Thr Leu Asp Thr Arg Ala Leu Leu Lys Leu Ala Tyr
325 330 335
Ser Ala Ala Cys Gly Leu Cys His Leu His Thr Glu Ile Tyr Gly Thr
340 345 350
Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys Asn Ile
355 360 365
Leu Ile Lys Lys Asn Gly Ser Cys Cys Ile Ala Asp Leu Gly Leu Ala
370 375 380
Val Lys Phe Asn Ser Asp Thr Asn Glu Val Asp Ile Pro Leu Asn Thr
385 390 395 400
Arg Val Gly Thr Arg Arg Tyr Met Ala Pro Glu Val Leu Asp Glu Ser
405 410 415
Leu Ser Lys Asn His Phe Gln Pro Tyr Ile Met Ala Asp Ile Tyr Ser
420 425 430
Phe Gly Leu Ile Ile Trp Glu Met Ala Arg Arg Cys Ile Thr Gly Gly
435 440 445
Ile Val Glu Glu Tyr Gln Leu Pro Tyr Tyr Asn Met Val Pro Ser Asp
450 455 460
Pro Ser Tyr Glu Asp Met Arg Glu Val Val Cys Val Lys Arg Leu Arg
465 470 475 480
Pro Ile Val Ser Asn Arg Trp Asn Ser Asp Glu Cys Leu Arg Ala Val
485 490 495
Leu Lys Leu Met Ser Glu Cys Trp Ala His Asn Pro Ala Ser Arg Leu
500 505 510
Thr Ala Leu Arg Ile Lys Lys Thr Leu Ala Lys Met Val Glu Ser Gln
515 520 525
Asp Val Lys Ile
530
<210>108
<211>502
<212>PRT
<213>Homo sapiens
<400>108
Met Leu Leu Arg Ser Ala Gly Lys Leu Asn Val Gly Thr Lys Lys Glu
1 5 10 15
Asp Gly Glu Ser Thr Ala Pro Thr Pro Arg Pro Lys Val Leu Arg Cys
20 25 30
Lys Cys His His His Cys Pro Glu Asp Ser Val Asn Asn Ile Cys Ser
35 40 45
Thr Asp Gly Tyr Cys Phe Thr Met Ile Glu Glu Asp Asp Ser Gly Leu
50 55 60
Pro Val Val Thr Ser Gly Cys Leu Gly Leu Glu Gly Ser Asp Phe Gln
65 70 75 80
Cys Arg Asp Thr Pro Ile Pro His Gln Arg Arg Ser Ile Glu Cys Cys
85 90 95
Thr Glu Arg Asn Glu Cys Asn Lys Asp Leu His Pro Thr Leu Pro Pro
100 105 110
Leu Lys Asn Arg Asp Phe Val Asp Gly Pro Ile His His Arg Ala Leu
115 120 125
Leu Ile Ser Val Thr Val Cys Ser Leu Leu Leu Val Leu Ile Ile Leu
130 135 140
Phe Cys Tyr Phe Arg Tyr Lys Arg Gln Glu Thr Arg Pro Arg Tyr Ser
145 150 155 160
Ile Gly Leu Glu Gln Asp Glu Thr Tyr Ile Pro Pro Gly Glu Ser Leu
165 170 175
Arg Asp Leu Ile Glu Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu
180 185 190
Pro Leu Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Lys
195 200 205
Gln Ile Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg
210 215 220
Gly Glu Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser
225 230 235 240
Trp Phe Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu
245 250 255
Asn Ile Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp
260 265 270
Thr Gln Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr
275 280 285
Asp Tyr Leu Lys Ser Thr Thr Leu Asp Ala Lys Ser Met Leu Lys Leu
290 295 300
Ala Tyr Ser Ser Val Ser Gly Leu Cys His Leu His Thr Glu Ile Phe
305 310 315 320
Ser Thr Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys
325 330 335
Asn Ile Leu Val Lys Lys Asn Gly Thr Cys Cys Ile Ala Asp Leu Gly
340 345 350
Leu Ala Val Lys Phe Ile Ser Asp Thr Asn Glu Val Asp Ile Pro Pro
355 360 365
Asn Thr Arg Val Gly Thr Lys Arg Tyr Met Pro Pro Glu Val Leu Asp
370 375 380
Glu Ser Leu Asn Arg Asn His Phe Gln Ser Tyr Ile Met Ala Asp Met
385 390 395 400
Tyr Ser Phe Gly Leu Ile Leu Trp Glu Val Ala Arg Arg Cys Val Ser
405 410 415
Gly Gly Ile Val Glu Glu Tyr Gln Leu Pro Tyr His Asp Leu Val Pro
420 425 430
Ser Asp Pro Ser Tyr Glu Asp Met Arg Glu Ile Val Cys Ile Lys Lys
435 440 445
Leu Arg Pro Ser Phe Pro Asn Arg Trp Ser Ser Asp Glu Cys Leu Arg
450 455 460
Gln Met Gly Lys Leu Met Thr Glu Cys Trp Ala His Asn Pro Ala Ser
465 470 475 480
Arg Leu Thr Ala Leu Arg Val Lys Lys Thr Leu Ala Lys Met Ser Glu
485 490 495
Ser Gln Asp Ile Lys Leu
500
<210>109
<211>502
<212>PRT
<213>Homo sapiens
<400>109
Met Leu Leu Arg Ser Ala Gly Lys Leu Asn Val Gly Thr Lys Lys Glu
1 5 10 15
Asp Gly Glu Ser Thr Ala Pro Thr Pro Arg Pro Lys Val Leu Arg Cys
20 25 30
Lys Cys His His His Cys Pro Glu Asp Ser Val Asn Asn Ile Cys Ser
35 40 45
Thr Asp Gly Tyr Cys Phe Thr Met Ile Glu Glu Asp Asp Ser Gly Leu
50 55 60
Pro Val Val Thr Ser Gly Cys Leu Gly Leu Glu Gly Ser Asp Phe Gln
65 70 75 80
Cys Arg Asp Thr Pro Ile Pro His Gln Arg Arg Ser Ile Glu Cys Cys
85 90 95
Thr Glu Arg Asn Glu Cys Asn Lys Asp Leu His Pro Thr Leu Pro Pro
100 105 110
Leu Lys Asn Arg Asp Phe Val Asp Gly Pro Ile His His Arg Ala Leu
115 120 125
Leu Ile Ser Val Thr Val Cys Ser Leu Leu Leu Val Leu Ile Ile Leu
130 135 140
Phe Cys Tyr Phe Arg Tyr Lys Arg Gln Glu Thr Arg Pro Arg Tyr Ser
145 150 155 160
Ile Gly Leu Glu Gln Asp Glu Thr Tyr Ile Pro Pro Gly Glu Ser Leu
165 170 175
Arg Asp Leu Ile Glu Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu
180 185 190
Pro Leu Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Lys
195 200 205
Gln Ile Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg
210 215 220
Gly Glu Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser
225 230 235 240
Trp Phe Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu
245 250 255
Asn Ile Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp
260 265 270
Thr Gln Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr
275 280 285
Asp Tyr Leu Lys Ser Thr Thr Leu Asp Ala Lys Ser Met Leu Lys Leu
290 295 300
Ala Tyr Ser Ser Val Ser Gly Leu Cys His Leu His Thr Glu Ile Phe
305 310 315 320
Ser Thr Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys
325 330 335
Asn Ile Leu Val Lys Lys Asn Gly Thr Cys Cys Ile Ala Asp Leu Gly
340 345 350
Leu Ala Val Lys Phe Ile Ser Asp Thr Asn Glu Val Asp Ile Pro Pro
355 360 365
Asn Thr Arg Val Gly Thr Lys Arg Tyr Met Pro Pro Glu Val Leu Asp
370 375 380
Glu Ser Leu Asn Arg Asn His Phe Gln Ser Tyr Ile Met Ala Asp Met
385 390 395 400
Tyr Ser Phe Gly Leu Ile Leu Trp Glu Val Ala Arg Arg Cys Val Ser
405 410 415
Gly Gly Ile Val Glu Glu Tyr Gln Leu Pro Tyr His Asp Leu Val Pro
420 425 430
Ser Asp Pro Ser Tyr Glu Asp Met Arg Glu Ile Val Cys Ile Lys Lys
435 440 445
Leu Arg Pro Ser Phe Pro Asn Arg Trp Ser Ser Asp Glu Cys Leu Arg
450 455 460
Gln Met Gly Lys Leu Met Thr Glu Cys Trp Ala His Asn Pro Ala Ser
465 470 475 480
Arg Leu Thr Ala Leu Arg Val Lys Lys Thr Leu Ala Lys Met Ser Glu
485 490 495
Ser Gln Asp Ile Lys Leu
500
<210>110
<211>532
<212>PRT
<213>Rattus sp.
<400>110
Met Thr Gln Leu Tyr Thr Tyr Ile Arg Leu Leu Gly Ala Cys Leu Phe
1 5 10 15
Ile Ile Ser His Val Gln Gly Gln Asn Leu Asp Ser Met Leu His Gly
20 25 30
Thr Gly Met Lys Ser Asp Val Asp Gln Lys Lys Pro Glu Asn Gly Val
35 40 45
Thr Leu Ala Pro Glu Asp Thr Leu Pro Phe Leu Lys Cys Tyr Cys Ser
50 55 60
Gly His Cys Pro Asp Asp Ala Ile Asn Asn Thr Cys Ile Thr Asn Gly
65 70 75 80
His Cys Phe Ala Ile Ile Glu Glu Asp Asp Gln Gly Glu Thr Thr Leu
85 90 95
Thr Ser Gly Cys Met Lys Tyr Glu Gly Ser Asp Phe Gln Cys Lys Asp
100 105 110
Ser Pro Lys Ala Gln Leu Arg Arg Thr Ile Glu Cys Cys Arg Thr Asn
115 120 125
Leu Cys Asn Gln Tyr Leu Gln Pro Thr Leu Pro Pro Val Val Ile Gly
130 135 140
Pro Phe Phe Asp Gly Ser Val Arg Trp Leu Ala Val Leu Ile Ser Met
145 150 155 160
Ala Val Cys Ile Val Ala Met Ile Val Phe Ser Ser Cys Phe Cys Tyr
165 170 175
Lys His Tyr Cys Lys Ser Ile Ser Ser Arg Gly Arg Tyr Asn Arg Asp
180 185 190
Leu Glu Gln Asp Glu Ala Phe Ile Pro Val Gly Glu Ser Leu Lys Asp
195 200 205
Leu Ile Asp Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly Leu Pro Leu
210 215 220
Leu Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met Val Arg Gln Val
225 230 235 240
Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly Lys Trp Arg Gly Glu
245 250 255
Lys Val Ala Val Lys Val Phe Phe Thr Thr Glu Glu Ala Ser Trp Phe
260 265 270
Arg Glu Thr Glu Ile Tyr Gln Thr Val Leu Met Arg His Glu Asn Ile
275 280 285
Leu Gly Phe Ile Ala Ala Asp Ile Lys Gly Thr Gly Ser Trp Thr Gln
290 295 300
Leu Tyr Leu Ile Thr Asp Tyr His Glu Asn Gly Ser Leu Tyr Asp Phe
305 310 315 320
Leu Lys Cys Ala Thr Leu Asp Thr Arg Ala Leu Leu Lys Leu Ala Tyr
325 330 335
Ser Ala Ala Cys Gly Leu Cys His Leu His Thr Glu Ile Tyr Gly Thr
340 345 350
Gln Gly Lys Pro Ala Ile Ala His Arg Asp Leu Lys Ser Lys Asn Ile
355 360 365
Leu Ile Lys Lys Asn Gly Ser Cys Cys Ile Ala Asp Leu Gly Leu Ala
370 375 380
Val Lys Phe Asn Ser Asp Thr Asn Glu Val Asp Ile Pro Leu Asn Thr
385 390 395 400
Arg Val Gly Thr Arg Arg Tyr Met Ala Pro Glu Val Leu Asp Glu Ser
405 410 415
Leu Ser Lys Asn His Phe Gln Pro Tyr Ile Met Ala Asp Ile Tyr Ser
420 425 430
Phe Gly Leu Ile Ile Trp Glu Met Ala Arg Arg Cys Ile Thr Gly Gly
435 440 445
Ile Val Glu Glu Tyr Gln Leu Pro Tyr Tyr Asn Met Val Pro Ser Asp
450 455 460
Pro Ser Tyr Glu Asp Met Arg Glu Val Val Cys Val Lys Arg Leu Arg
465 470 475 480
Pro Ile Val Ser Asn Arg Trp Asn Ser Asp Glu Cys Leu Arg Ala Val
485 490 495
Leu Lys Leu Met Ser Glu Cys Trp Ala His Asn Pro Ala Ser Arg Leu
500 505 510
Thr Ala Leu Arg Ile Lys Lys Thr Leu Ala Lys Met Val Glu Ser Gln
515 520 525
Asp Val Lys Ile
530
<210>111
<211>530
<212>PRT
<213>Homo sapiens
<400>111
Met Thr Ser Ser Leu Gln Arg Pro Trp Arg Val Pro Trp Leu Pro Trp
1 5 10 15
Thr Ile Leu Leu Val Ser Thr Ala Ala Ala Ser Gln Asn Gln Glu Arg
20 25 30
Leu Cys Ala Phe Lys Asp Pro Tyr Gln Gln Asp Leu Gly Ile Gly Glu
35 40 45
Ser Arg Ile Ser His Glu Asn Gly Thr Ile Leu Cys Ser Lys Gly Ser
50 55 60
Thr Cys Tyr Gly Leu Trp Glu Lys Ser Lys Gly Asp Ile Asn Leu Val
65 70 75 80
Lys Gln Gly Cys Trp Ser His Ile Gly Asp Pro Gln Glu Cys His Tyr
85 90 95
Glu Glu Cys Val Val Thr Thr Thr Pro Pro Ser Ile Gln Asn Gly Thr
100 105 110
Tyr Arg Phe Cys Cys Cys Ser Thr Asp Leu Cys Asn Val Asn Phe Thr
115 120 125
Glu Asn Phe Pro Pro Pro Asp Thr Thr Pro Leu Ser Pro Pro His Ser
130 135 140
Phe Asn Arg Asp Glu Thr Ile Ile Ile Ala Leu Ala Ser Val Ser Val
145 150 155 160
Leu Ala Val Leu Ile Val Ala Leu Cys Phe Gly Tyr Arg Met Leu Thr
165 170 175
Gly Asp Arg Lys Gln Gly Leu His Ser Met Asn Met Met Glu Ala Ala
180 185 190
Ala Ser Glu Pro Ser Leu Asp Leu Asp Asn Leu Lys Leu Leu Glu Leu
195 200 205
Ile Gly Arg Gly Arg Tyr Gly Ala Val Tyr Lys Gly Ser Leu Asp Glu
210 215 220
Arg Pro Val Ala Val Lys Val Phe Ser Phe Ala Asn Arg Gln Asn Phe
225 230 235 240
Ile Asn Glu Lys Asn Ile Tyr Arg Val Pro Leu Met Glu His Asp Asn
245 250 255
Ile Ala Arg Phe Ile Val Gly Asp Glu Arg Val Thr Ala Asp Gly Arg
260 265 270
Met Glu Tyr Leu Leu Val Met Glu Tyr Tyr Pro Asn Gly Ser Leu Cys
275 280 285
Lys Tyr Leu Ser Leu His Thr Ser Asp Trp Val Ser Ser Cys Arg Leu
290 295 300
Ala His Ser Val Thr Arg Gly Leu Ala Tyr Leu His Thr Glu Leu Pro
305 310 315 320
Arg Gly Asp His Tyr Lys Pro Ala Ile Ser His Arg Asp Leu Asn Ser
325 330 335
Arg Asn Val Leu Val Lys Asn Asp Gly Thr Cys Val Ile Ser Asp Phe
340 345 350
Gly Leu Ser Met Arg Leu Thr Gly Asn Arg Leu Val Arg Pro Gly Glu
355 360 365
Glu Asp Asn Ala Ala Ile Ser Glu Val Gly Thr Ile Arg Tyr Met Ala
370 375 380
Pro Glu Val Leu Glu Gly Ala Val Asn Leu Arg Asp Cys Glu Ser Ala
385 390 395 400
Leu Lys Gln Val Asp Met Tyr Ala Leu Gly Leu Ile Tyr Trp Glu Ile
405 410 415
Phe Met Arg Cys Thr Asp Leu Phe Pro Gly Glu Ser Val Pro Glu Tyr
420 425 430
Gln Met Ala Phe Gln Thr Glu Val Gly Asn His Pro Thr Phe Glu Asp
435 440 445
Met Gln Val Leu Val Ser Arg Glu Lys Gln Arg Pro Lys Phe Pro Glu
450 455 460
Ala Trp Lys Glu Asn Ser Leu Ala Val Arg Ser Leu Lys Glu Thr Ile
465 470 475 480
Glu Asp Cys Trp Asp Gln Asp Ala Glu Ala Arg Leu Thr Ala Gln Cys
485 490 495
Ala Glu Glu Arg Met Ala Glu Leu Met Met Ile Trp Glu Arg Asn Lys
500 505 510
Ser Val Ser Pro Thr Val Asn Pro Met Ser Thr Ala Met Gln Asn Glu
515 520 525
Arg Arg
530
<210>112
<211>530
<212>PRT
<213>Homo sapiens
<400>112
Met Thr Ser Ser Leu Gln Arg Pro Trp Arg Val Pro Trp Leu Pro Trp
1 5 10 15
Thr Ile Leu Leu Val Ser Thr Ala Ala Ala Ser Gln Asn Gln Glu Arg
20 25 30
Leu Cys Ala Phe Lys Asp Pro Tyr Gln Gln Asp Leu Gly Ile Gly Glu
35 40 45
Ser Arg Ile Ser His Glu Asn Gly Thr Ile Leu Cys Ser Lys Gly Ser
50 55 60
Thr Cys Tyr Gly Leu Trp Glu Lys Ser Lys Gly Asp Ile Asn Leu Val
65 70 75 80
Lys Gln Gly Cys Trp Ser His Ile Gly Asp Pro Gln Glu Cys His Tyr
85 90 95
Glu Glu Cys Val Val Thr Thr Thr Pro Pro Ser Ile Gln Asn Gly Thr
100 105 110
Tyr Arg Phe Cys Cys Cys Ser Thr Asp Leu Cys Asn Val Asn Phe Thr
115 120 125
Glu Asn Phe Pro Pro Pro Asp Thr Thr Pro Leu Ser Pro Pro His Ser
130 135 140
Phe Asn Arg Asp Glu Thr Ile Ile Ile Ala Leu Ala Ser Val Ser Val
145 150 155 160
Leu Ala Val Leu Ile Val Ala Leu Cys Phe Gly Tyr Arg Met Leu Thr
165 170 175
Gly Asp Arg Lys Gln Gly Leu His Ser Met Asn Met Met Glu Ala Ala
180 185 190
Ala Ser Glu Pro Ser Leu Asp Leu Asp Asn Leu Lys Leu Leu Glu Leu
195 200 205
Ile Gly Arg Gly Arg Tyr Gly Ala Val Tyr Lys Gly Ser Leu Asp Glu
210 215 220
Arg Pro Val Ala Val Lys Val Phe Ser Phe Ala Asn Arg Gln Asn Phe
225 230 235 240
Ile Asn Glu Lys Asn Ile Tyr Arg Val Pro Leu Met Glu His Asp Asn
245 250 255
Ile Ala Arg Phe Ile Val Gly Asp Glu Arg Val Thr Ala Asp Gly Arg
260 265 270
Met Glu Tyr Leu Leu Val Met Glu Tyr Tyr Pro Asn Gly Ser Leu Cys
275 280 285
Lys Tyr Leu Ser Leu His Thr Ser Asp Trp Val Ser Ser Cys Arg Leu
290 295 300
Ala His Ser Val Thr Arg Gly Leu Ala Tyr Leu His Thr Glu Leu Pro
305 310 315 320
Arg Gly Asp His Tyr Lys Pro Ala Ile Ser His Arg Asp Leu Asn Ser
325 330 335
Arg Asn Val Leu Val Lys Asn Asp Gly Thr Cys Val Ile Ser Asp Phe
340 345 350
Gly Leu Ser Met Arg Leu Thr Gly Asn Arg Leu Val Arg Pro Gly Glu
355 360 365
Glu Asp Asn Ala Ala Ile Ser Glu Val Gly Thr Ile Arg Tyr Met Ala
370 375 380
Pro Glu Val Leu Glu Gly Ala Val Asn Leu Arg Asp Cys Glu Ser Ala
385 390 395 400
Leu Lys Gln Val Asp Met Tyr Ala Leu Gly Leu Ile Tyr Trp Glu Ile
405 410 415
Phe Met Arg Cys Thr Asp Leu Phe Pro Gly Glu Ser Val Pro Glu Tyr
420 425 430
Gln Met Ala Phe Gln Thr Glu Val Gly Asn His Pro Thr Phe Glu Asp
435 440 445
Met Gln Val Leu Val Ser Arg Glu Lys Gln Arg Pro Lys Phe Pro Glu
450 455 460
Ala Trp Lys Glu Asn Ser Leu Ala Val Arg Ser Leu Lys Glu Thr Ile
465 470 475 480
Glu Asp Cys Trp Asp Gln Asp Ala Glu Ala Arg Leu Thr Ala Gln Cys
485 490 495
Ala Glu Glu Arg Met Ala Glu Leu Met Met Ile Trp Glu Arg Asn Lys
500 505 510
Ser Val Ser Pro Thr Val Asn Pro Met Ser Thr Ala Met Gln Asn Glu
515 520 525
Arg Arg
530
<210>113
<211>1038
<212>PRT
<213>Homo sapiens
<400>113
Met Thr Ser Ser Leu Gln Arg Pro Trp Arg Val Pro Trp Leu Pro Trp
1 5 10 15
Thr Ile Leu Leu Val Ser Thr Ala Ala Ala Ser Gln Asn Gln Glu Arg
20 25 30
Leu Cys Ala Phe Lys Asp Pro Tyr Gln Gln Asp Leu Gly Ile Gly Glu
35 40 45
Ser Arg Ile Ser His Glu Asn Gly Thr Ile Leu Cys Ser Lys Gly Ser
50 55 60
Thr Cys Tyr Gly Leu Trp Glu Lys Ser Lys Gly Asp Ile Asn Leu Val
65 70 75 80
Lys Gln Gly Cys Trp Ser His Ile Gly Asp Pro Gln Glu Cys His Tyr
85 90 95
Glu Glu Cys Val Val Thr Thr Thr Pro Pro Ser Ile Gln Asn Gly Thr
100 105 110
Tyr Arg Phe Cys Cys Cys Ser Thr Asp Leu Cys Asn Val Asn Phe Thr
115 120 125
Glu Asn Phe Pro Pro Pro Asp Thr Thr Pro Leu Ser Pro Pro His Ser
130 135 140
Phe Asn Arg Asp Glu Thr Ile Ile Ile Ala Leu Ala Ser Val Ser Val
145 150 155 160
Leu Ala Val Leu Ile Val Ala Leu Cys Phe Gly Tyr Arg Met Leu Thr
165 170 175
Gly Asp Arg Lys Gln Gly Leu His Ser Met Asn Met Met Glu Ala Ala
180 185 190
Ala Ser Glu Pro Ser Leu Asp Leu Asp Asn Leu Lys Leu Leu Glu Leu
195 200 205
Ile Gly Arg Gly Arg Tyr Gly Ala Val Tyr Lys Gly Ser Leu Asp Glu
210 215 220
Arg Pro Val Ala Val Lys Val Phe Ser Phe Ala Asn Arg Gln Asn Phe
225 230 235 240
Ile Asn Glu Lys Asn Ile Tyr Arg Val Pro Leu Met Glu His Asp Asn
245 250 255
Ile Ala Arg Phe Ile Val Gly Asp Glu Arg Val Thr Ala Asp Gly Arg
260 265 270
Met Glu Tyr Leu Leu Val Met Glu Tyr Tyr Pro Asn Gly Ser Leu Cys
275 280 285
Lys Tyr Leu Ser Leu His Thr Ser Asp Trp Val Ser Ser Cys Arg Leu
290 295 300
Ala His Ser Val Thr Arg Gly Leu Ala Tyr Leu His Thr Glu Leu Pro
305 310 315 320
Arg Gly Asp His Tyr Lys Pro Ala Ile Ser His Arg Asp Leu Asn Ser
325 330 335
Arg Asn Val Leu Val Lys Asn Asp Gly Thr Cys Val Ile Ser Asp Phe
340 345 350
Gly Leu Ser Met Arg Leu Thr Gly Asn Arg Leu Val Arg Pro Gly Glu
355 360 365
Glu Asp Asn Ala Ala Ile Ser Glu Val Gly Thr Ile Arg Tyr Met Ala
370 375 380
Pro Glu Val Leu Glu Gly Ala Val Asn Leu Arg Asp Cys Glu Ser Ala
385 390 395 400
Leu Lys Gln Val Asp Met Tyr Ala Leu Gly Leu Ile Tyr Trp Glu Ile
405 410 415
Phe Met Arg Cys Thr Asp Leu Phe Pro Gly Glu Ser Val Pro Glu Tyr
420 425 430
Gln Met Ala Phe Gln Thr Glu Val Gly Asn His Pro Thr Phe Glu Asp
435 440 445
Met Gln Val Leu Val Ser Arg Glu Lys Gln Arg Pro Lys Phe Pro Glu
450 455 460
Ala Trp Lys Glu Asn Ser Leu Ala Val Arg Ser Leu Lys Glu Thr Ile
465 470 475 480
Glu Asp Cys Trp Asp Gln Asp Ala Glu Ala Arg Leu Thr Ala Gln Cys
485 490 495
Ala Glu Glu Arg Met Ala Glu Leu Met Met Ile Trp Glu Arg Asn Lys
500 505 510
Ser Val Ser Pro Thr Val Asn Pro Met Ser Thr Ala Met Gln Asn Glu
515 520 525
Arg Asn Leu Ser His Asn Arg Arg Val Pro Lys Ile Gly Pro Tyr Pro
530 535 540
Asp Tyr Ser Ser Ser Ser Tyr Ile Glu Asp Ser Ile His His Thr Asp
545 550 555 560
Ser Ile Val Lys Asn Ile Ser Ser Glu His Ser Met Ser Ser Thr Pro
565 570 575
Leu Thr Ile Gly Glu Lys Asn Arg Asn Ser Ile Asn Tyr Glu Arg Gln
580 585 590
Gln Ala Gln Ala Arg Ile Pro Ser Pro Glu Thr Ser Val Thr Ser Leu
595 600 605
Ser Thr Asn Thr Thr Thr Thr Asn Thr Thr Gly Leu Thr Pro Ser Thr
610 615 620
Gly Met Thr Thr Ile Ser Glu Met Pro Tyr Pro Asp Glu Thr Asn Leu
625 630 635 640
His Thr Thr Asn Val Ala Gln Ser Ile Gly Pro Thr Pro Val Cys Leu
645 650 655
Gln Leu Thr Glu Glu Asp Leu Glu Thr Asn Lys Leu Asp Pro Lys Glu
660 665 670
Val Asp Lys Asn Leu Lys Glu Ser Ser Asp Glu Asn Leu Met Glu His
675 680 685
Ser Leu Lys Gln Phe Ser Gly Pro Asp Pro Leu Ser Ser Thr Ser Ser
690 695 700
Ser Leu Leu Tyr Pro Leu Ile Lys Leu Ala Val Glu Ala Thr Gly Gln
705 710 715 720
Gln Asp Phe Thr Gln Thr Ala Asn Gly Gln Ala Cys Leu Ile Pro Asp
725 730 735
Val Leu Pro Thr Gln Ile Tyr Pro Leu Pro Lys Gln Gln Asn Leu Pro
740 745 750
Lys Arg Pro Thr Ser Leu Pro Leu Asn Thr Lys Asn Ser Thr Lys Glu
755 760 765
Pro Arg Leu Lys Phe Gly Ser Lys His Lys Ser Asn Leu Lys Gln Val
770 775 780
Glu Thr Gly Val Ala Lys Met Asn Thr Ile Asn Ala Ala Glu Pro His
785 790 795 800
Val Val Thr Val Thr Met Asn Gly Val Ala Gly Arg Asn His Ser Val
805 810 815
Asn Ser His Ala Ala Thr Thr Gln Tyr Ala Asn Gly Thr Val Leu Ser
820 825 830
Gly Gln Thr Thr Asn Ile Val Thr His Arg Ala Gln Glu Met Leu Gln
835 840 845
Asn Gln Phe Ile Gly Glu Asp Thr Arg Leu Asn Ile Asn Ser Ser Pro
850 855 860
Asp Glu His Glu Pro Leu Leu Arg Arg Glu Gln Gln Ala Gly His Asp
865 870 875 880
Glu Gly Val Leu Asp Arg Leu Val Asp Arg Arg Glu Arg Pro Leu Glu
885 890 895
Gly Gly Arg Thr Asn Ser Asn Asn Asn Asn Ser Asn Pro Cys Ser Glu
900 905 910
Gln Asp Val Leu Ala Gln Gly Val Pro Ser Thr Ala Ala Asp Pro Gly
915 920 925
Pro Ser Lys Pro Arg Arg Ala Gln Arg Pro Asn Ser Leu Asp Leu Ser
930 935 940
Ala Thr Asn Val Leu Asp Gly Ser Ser Ile Gln Ile Gly Glu Ser Thr
945 950 955 960
Gln Asp Gly Lys Ser Gly Ser Gly Glu Lys Ile Lys Lys Arg Val Lys
965 970 975
Thr Pro Tyr Ser Leu Lys Arg Trp Arg Pro Ser Thr Trp Val Ile Ser
980 985 990
Thr Glu Ser Leu Asp Cys Glu Val Asn Asn Asn Gly Ser Asn Arg Ala
995 1000 1005
Val His Ser Lys Ser Ser Thr Ala Val Tyr Leu Ala Glu Gly Gly Thr
1010 1015 1020
Ala Thr Thr Met Val Ser Lys Asp Ile Gly Met Asn Cys Leu
1025 1030 1035
<210>114
<211>1038
<212>PRT
<213>Homo sapiens
<400>114
Met Thr Ser Ser Leu Gln Arg Pro Trp Arg Val Pro Trp Leu Pro Trp
1 5 10 15
Thr Ile Leu Leu Val Ser Thr Ala Ala Ala Ser Gln Asn Gln Glu Arg
20 25 30
Leu Cys Ala Phe Lys Asp Pro Tyr Gln Gln Asp Leu Gly Ile Gly Glu
35 40 45
Ser Arg Ile Ser His Glu Asn Gly Thr Ile Leu Cys Ser Lys Gly Ser
50 55 60
Thr Cys Tyr Gly Leu Trp Glu Lys Ser Lys Gly Asp Ile Asn Leu Val
65 70 75 80
Lys Gln Gly Cys Trp Ser His Ile Gly Asp Pro Gln Glu Cys His Tyr
85 90 95
Glu Glu Cys Val Val Thr Thr Thr Pro Pro Ser Ile Gln Asn Gly Thr
100 105 110
Tyr Arg Phe Cys Cys Cys Ser Thr Asp Leu Cys Asn Val Asn Phe Thr
115 120 125
Glu Asn Phe Pro Pro Pro Asp Thr Thr Pro Leu Ser Pro Pro His Ser
130 135 140
Phe Asn Arg Asp Glu Thr Ile Ile Ile Ala Leu Ala Ser Val Ser Val
145 150 155 160
Leu Ala Val Leu Ile Val Ala Leu Cys Phe Gly Tyr Arg Met Leu Thr
165 170 175
Gly Asp Arg Lys Gln Gly Leu His Ser Met Asn Met Met Glu Ala Ala
180 185 190
Ala Ser Glu Pro Ser Leu Asp Leu Asp Asn Leu Lys Leu Leu Glu Leu
195 200 205
Ile Gly Arg Gly Arg Tyr Gly Ala Val Tyr Lys Gly Ser Leu Asp Glu
210 215 220
Arg Pro Val Ala Val Lys Val Phe Ser Phe Ala Asn Arg Gln Asn Phe
225 230 235 240
Ile Asn Glu Lys Asn Ile Tyr Arg Val Pro Leu Met Glu His Asp Asn
245 250 255
Ile Ala Arg Phe Ile Val Gly Asp Glu Arg Val Thr Ala Asp Gly Arg
260 265 270
Met Glu Tyr Leu Leu Val Met Glu Tyr Tyr Pro Asn Gly Ser Leu Cys
275 280 285
Lys Tyr Leu Ser Leu His Thr Ser Asp Trp Val Ser Ser Cys Arg Leu
290 295 300
Ala His Ser Val Thr Arg Gly Leu Ala Tyr Leu His Thr Glu Leu Pro
305 310 315 320
Arg Gly Asp His Tyr Lys Pro Ala Ile Ser His Arg Asp Leu Asn Ser
325 330 335
Arg Asn Val Leu Val Lys Asn Asp Gly Thr Cys Val Ile Ser Asp Phe
340 345 350
Gly Leu Ser Met Arg Leu Thr Gly Asn Arg Leu Val Arg Pro Gly Glu
355 360 365
Glu Asp Asn Ala Ala Ile Ser Glu Val Gly Thr Ile Arg Tyr Met Ala
370 375 380
Pro Glu Val Leu Glu Gly Ala Val Asn Leu Arg Asp Cys Glu Ser Ala
385 390 395 400
Leu Lys Gln Val Asp Met Tyr Ala Leu Gly Leu Ile Tyr Trp Glu Ile
405 410 415
Phe Met Arg Cys Thr Asp Leu Phe Pro Gly Glu Ser Val Pro Glu Tyr
420 425 430
Gln Met Ala Phe Gln Thr Glu Val Gly Asn His Pro Thr Phe Glu Asp
435 440 445
Met Gln Val Leu Val Ser Arg Glu Lys Gln Arg Pro Lys Phe Pro Glu
450 455 460
Ala Trp Lys Glu Asn Ser Leu Ala Val Arg Ser Leu Lys Glu Thr Ile
465 470 475 480
Glu Asp Cys Trp Asp Gln Asp Ala Glu Ala Arg Leu Thr Ala Gln Cys
485 490 495
Ala Glu Glu Arg Met Ala Glu Leu Met Met Ile Trp Glu Arg Asn Lys
500 505 510
Ser Val Ser Pro Thr Val Asn Pro Met Ser Thr Ala Met Gln Asn Glu
515 520 525
Arg Asn Leu Ser His Asn Arg Arg Val Pro Lys Ile Gly Pro Tyr Pro
530 535 540
Asp Tyr Ser Ser Ser Ser Tyr Ile Glu Asp Ser Ile His His Thr Asp
545 550 555 560
Ser Ile Val Lys Asn Ile Ser Ser Glu His Ser Met Ser Ser Thr Pro
565 570 575
Leu Thr Ile Gly Glu Lys Asn Arg Asn Ser Ile Asn Tyr Glu Arg Gln
580 585 590
Gln Ala Gln Ala Arg Ile Pro Ser Pro Glu Thr Ser Val Thr Ser Leu
595 600 605
Ser Thr Asn Thr Thr Thr Thr Asn Thr Thr Gly Leu Thr Pro Ser Thr
610 615 620
Gly Met Thr Thr Ile Ser Glu Met Pro Tyr Pro Asp Glu Thr Asn Leu
625 630 635 640
His Thr Thr Asn Val Ala Gln Ser Ile Gly Pro Thr Pro Val Cys Leu
645 650 655
Gln Leu Thr Glu Glu Asp Leu Glu Thr Asn Lys Leu Asp Pro Lys Glu
660 665 670
Val Asp Lys Asn Leu Lys Glu Ser Ser Asp Glu Asn Leu Met Glu His
675 680 685
Ser Leu Lys Gln Phe Ser Gly Pro Asp Pro Leu Ser Ser Thr Ser Ser
690 695 700
Ser Leu Leu Tyr Pro Leu Ile Lys Leu Ala Val Glu Ala Thr Gly Gln
705 710 715 720
Gln Asp Phe Thr Gln Thr Ala Asn Gly Gln Ala Cys Leu Ile Pro Asp
725 730 735
Val Leu Pro Thr Gln Ile Tyr Pro Leu Pro Lys Gln Gln Asn Leu Pro
740 745 750
Lys Arg Pro Thr Ser Leu Pro Leu Asn Thr Lys Asn Ser Thr Lys Glu
755 760 765
pro Arg Leu Lys Phe Gly Ser Lys His Lys Ser Asn Leu Lys Gln Val
770 775 780
Glu Thr Gly Val Ala Lys Met Asn Thr Ile Asn Ala Ala Glu Pro His
785 790 795 800
Val Val Thr Val Thr Met Asn Gly Val Ala Gly Arg Asn His Ser Val
805 810 815
Asn Ser His Ala Ala Thr Thr Gln Tyr Ala Asn Arg Thr Val Leu Ser
820 825 830
Gly Gln Thr Thr Asn Ile Val Thr His Arg Ala Gln Glu Met Leu Gln
835 840 845
Asn Gln Phe Ile Gly Glu Asp Thr Arg Leu Asn Ile Asn Ser Ser Pro
850 855 860
Asp Glu His Glu Pro Leu Leu Arg Arg Glu Gln Gln Ala Gly His Asp
865 870 875 880
Glu Gly Val Leu Asp Arg Leu Val Asp Arg Arg Glu Arg Pro Leu Glu
885 890 895
Gly Gly Arg Thr Asn Ser Asn Asn Asn Asn Ser Asn Pro Cys Ser Glu
900 905 910
Gln Asp Val Leu Ala Gln Gly Val Pro Ser Thr Ala Ala Asp Pro Gly
915 920 925
Pro Ser Lys Pro Arg Arg Ala Gln Arg Pro Asn Ser Leu Asp Leu Ser
930 935 940
Ala Thr Asn Val Leu Asp Gly Ser Ser Ile Gln Ile Gly Glu Ser Thr
945 950 955 960
Gln Asp Gly Lys Ser Gly Ser Gly Glu Lys Ile Lys Lys Arg Val Lys
965 970 975
Thr Pro Tyr Ser Leu Lys Arg Trp Arg Pro Ser Thr Trp Val Ile Ser
980 985 990
Thr Glu Ser Leu Asp Cys Glu Val Asn Asn Asn Gly Ser Asn Arg Ala
995 1000 1005
Val His Ser Lys Ser Ser Thr Ala Val Tyr Leu Ala Glu Gly Gly Thr
1010 1015 1020
Ala Thr Thr Met Val Ser Lys Asp Ile Gly Met Asn Cys Leu
1025 1030 1035
<210>115
<211>1038
<212>PRT
<213>Homo sapiens
<400>115
Met Thr Ser Ser Leu Gln Arg Pro Trp Arg Val Pro Trp Leu Pro Trp
1 5 10 15
Thr Ile Leu Leu Val Ser Thr Ala Ala Ala Ser Gln Asn Gln Glu Arg
20 25 30
Leu Cys Ala Phe Lys Asp Pro Tyr Gln Gln Asp Leu Gly Ile Gly Glu
35 40 45
Ser Arg Ile Ser His Glu Asn Gly Thr Ile Leu Cys Ser Lys Gly Ser
50 55 60
Thr Cys Tyr Gly Leu Trp Glu Lys Ser Lys Gly Asp Ile Asn Leu Val
65 70 75 80
Lys Gln GLy Cys Trp Ser His Ile Gly Asp Pro Gln Glu Cys His Tyr
85 90 95
Glu Glu Cys Val Val Thr Thr Thr Pro Pro Ser Ile Gln Asn Gly Thr
100 105 110
Tyr Arg Phe Cys Cys Cys Ser Thr Asp Leu Cys Asn Val Asn Phe Thr
115 120 125
Glu Asn Phe Pro Pro Pro Asp Thr Thr Pro Leu Ser Pro Pro His Ser
130 135 140
Phe Asn Arg Asp Glu Thr Ile Ile Ile Ala Leu Ala Ser Val Ser Val
145 150 155 160
Leu Ala Val Leu Ile Val Ala Leu Cys Phe Gly Tyr Arg Met Leu Thr
165 170 175
Gly Asp Arg Lys Gln Gly Leu His Ser Met Asn Met Met Glu Ala Ala
180 185 190
Ala Ser Glu Pro Ser Leu Asp Leu Asp Asn Leu Lys Leu Leu Glu Leu
195 200 205
Ile Gly Arg Gly Arg Tyr Gly Ala Val Tyr Lys Gly Ser Leu Asp Glu
210 215 220
Arg Pro Val Ala Val Lys Val Phe Ser Phe Ala Asn Arg Gln Asn Phe
225 230 235 240
Ile Asn Glu Lys Asn Ile Tyr Arg Val Pro Leu Met Glu His Asp Asn
245 250 255
Ile Ala Arg Phe Ile Val Gly Asp Glu Arg Val Thr Ala Asp Gly Arg
260 265 270
Met Glu Tyr Leu Leu Val Met Glu Tyr Tyr Pro Asn Gly Ser Leu Cys
275 280 285
Lys Tyr Leu Ser Leu His Thr Ser Asp Trp Val Ser Ser Cys Arg Leu
290 295 300
Ala His Ser Val Thr Arg Gly Leu Ala Tyr Leu His Thr Glu Leu Pro
305 310 315 320
Arg Gly Asp His Tyr Lys Pro Ala Ile Ser His Arg Asp Leu Asn Ser
325 330 335
Arg Asn Val Leu Val Lys Asn Asp Gly Thr Cys Val Ile Ser Asp Phe
340 345 350
Gly Leu Ser Met Arg Leu Thr Gly Asn Arg Leu Val Arg Pro Gly Glu
355 360 365
Glu Asp Asn Ala Ala Ile Ser Glu Val Gly Thr Ile Arg Tyr Met Ala
370 375 380
Pro Glu Val Leu Glu Gly Ala Val Asn Leu Arg Asp Cys Glu Ser Ala
385 390 395 400
Leu Lys Gln Val Asp Met Tyr Ala Leu Gly Leu Ile Tyr Trp Glu Ile
405 410 415
Phe Met Arg Cys Thr Asp Leu Phe Pro Gly Glu Ser Val Pro Glu Tyr
420 425 430
Gln Met Ala Phe Gln Thr Glu Val Gly Asn His Pro Thr Phe Glu Asp
435 440 445
Met Gln Val Leu Val Ser Arg Glu Lys Gln Arg Pro Lys Phe Pro Glu
450 455 460
Ala Trp Lys Glu Asn Ser Leu Ala Val Arg Ser Leu Lys Glu Thr Ile
465 470 475 480
Glu Asp Cys Trp Asp Gln Asp Ala Glu Ala Arg Leu Thr Ala Gln Cys
485 490 495
Ala Glu Glu Arg Met Ala Glu Leu Met Met Ile Trp Glu Arg Asn Lys
500 505 510
Ser Val Ser Pro Thr Val Asn Pro Met Ser Thr Ala Met Gln Asn Glu
515 520 525
Arg Asn Leu Ser His Asn Arg Arg Val Pro Lys Ile Gly Pro Tyr Pro
530 535 540
Asp Tyr Ser Ser Ser Ser Tyr Ile Glu Asp Ser Ile His His Thr Asp
545 550 555 560
Ser Ile Val Lys Asn Ile Ser Ser Glu His Ser Met Ser Ser Thr Pro
565 570 575
Leu Thr Ile Gly Glu Lys Asn Arg Asn Ser Ile Asn Tyr Glu Arg Gln
580 585 590
Gln Ala Gln Ala Arg Ile Pro Ser Pro Glu Thr Ser Val Thr Ser Leu
595 600 605
Ser Thr Asn Thr Thr Thr Thr Asn Thr Thr Gly Leu Thr Pro Ser Thr
610 615 620
Gly Met Thr Thr Ile Ser Glu Met Pro Tyr Pro Asp Glu Thr Asn Leu
625 630 635 640
His Thr Thr Asn Val Ala Gln Ser Ile Gly Pro Thr Pro Val Cys Leu
645 650 655
Gln Leu Thr Glu Glu Asp Leu Glu Thr Asn Lys Leu Asp Pro Lys Glu
660 665 670
Val Asp Lys Asn Leu Lys Glu Ser Ser Asp Glu Asn Leu Met Glu His
675 680 685
Ser Leu Lys Gln Phe Ser Gly Pro Asp Pro Leu Ser Ser Thr Ser Ser
690 695 700
Ser Leu Leu Tyr Pro Leu Ile Lys Leu Ala Val Glu Ala Thr Gly Gln
705 710 715 720
Gln Asp Phe Thr Gln Thr Ala Asn Gly Gln Ala Cys Leu Ile Pro Asp
725 730 735
Val Leu Pro Thr Gln Ile Tyr Pro Leu Pro Lys Gln Gln Asn Leu Pro
740 745 750
Lys Arg Pro Thr Ser Leu Pro Leu Asn Thr Lys Asn Ser Thr Lys Glu
755 760 765
Pro Arg Leu Lys Phe Gly Ser Lys His Lys Ser Asn Leu Lys Gln Val
770 775 780
Glu Thr Gly Val Ala Lys Met Asn Thr Ile Asn Ala Ala Glu Pro His
785 790 795 800
Val Val Thr Val Thr Met Asn Gly Val Ala Gly Arg Asn His Ser Val
805 810 815
Asn Ser His Ala Ala Thr Thr Gln Tyr Ala Asn Arg Thr Val Leu Ser
820 825 830
Gly Gln Thr Thr Asn Ile Val Thr His Arg Ala Gln Glu Met Leu Gln
835 840 845
Asn Gln Phe Ile Gly Glu Asp Thr Arg Leu Asn Ile Asn Ser Ser Pro
850 855 860
Asp Glu His Glu Pro Leu Leu Arg Arg Glu Gln Gln Ala Gly His Asp
865 870 875 880
Glu Gly Val Leu Asp Arg Leu Val Asp Arg Arg Glu Arg Pro Leu Glu
885 890 895
Gly Gly Arg Thr Asn Ser Asn Asn Asn Asn Ser Asn Pro Cys Ser Glu
900 905 910
Gln Asp Val Leu Ala Gln Gly Val Pro Ser Thr Ala Ala Asp Pro Gly
915 920 925
Pro Ser Lys Pro Arg Arg Ala Gln Arg Pro Asn Ser Leu Asp Leu Ser
930 935 940
Ala Thr Asn Val Leu Asp Gly Ser Ser Ile Gln Ile Gly Glu Ser Thr
945 950 955 960
Gln Asp Gly Lys Ser Gly Ser Gly Glu Lys Ile Lys Lys Arg Val Lys
965 970 975
Thr Pro Tyr Ser Leu Lys Arg Trp Arg Pro Ser Thr Trp Val Ile Ser
980 985 990
Thr Glu Ser Leu Asp Cys Glu Val Asn Asn Asn Gly Ser Asn Arg Ala
995 1000 1005
Val His Ser Lys Ser Ser Thr Ala Val Tyr Leu Ala Glu Gly Gly Thr
1010 1015 1020
Ala Thr Thr Met Val Ser Lys Asp Ile Gly Met Asn Cys Leu
1025 1030 1035
<210>116
<211>2932
<212>DNA
<213>Homo sapiens
<400>116
gctccgcgcc gagggctgga ggatgcgttc cctggggtcc ggacttatga aaatatgcat 60
cagtttaata ctgtcttgga attcatgaga tggaagcata ggtcaaagct gtttggagaa 120
aatcagaagt acagttttat ctagccacat cttggaggag tcgtaagaaa gcagtgggag 180
ttgaagtcat tgtcaagtgc ttgcgatctt ttacaagaaa atctcactga atgatagtca 240
tttaaattgg tgaagtagca agaccaatta ttaaaggtga cagtacacag gaaacattac 300
aattgaacaa tgactcagct atacatttac atcagattat tgggagccta tttgttcatc 360
atttctcgtg ttcaaggaca gaatctggat agtatgcttc atggcactgg gatgaaatca 420
gactccgacc agaaaaagtc agaaaatgga gtaaccttag caccagagga taccttgcct 480
tttttaaagt gctattgctc agggcactgt ccagatgatg ctattaataa cacatgcata 540
actaatggac attgctttgc catcatagaa gaagatgacc agggagaaac cacattagct 600
tcagggtgta tgaaatatga aggatctgat tttcagtgca aagattctcc aaaagcccag 660
ctacgccgga caatagaatg ttgtcggacc aatttatgta accagtattt gcaacccaca 720
ctgccccctg ttgtcatagg tccgtttttt gatggcagca ttcgatggct ggttttgctc 780
atttctatgg ctgtctgcat aattgctatg atcatcttct ccagctgctt ttgttacaaa 840
cattattgca agagcatctc aagcagacgt cgttacaatc gtgatttgga acaggatgaa 900
gcatttattc cagttggaga atcactaaaa gaccttattg accagtcaca aagttctggt 960
agtgggtctg gactaccttt attggttcag cgaactattg ccaaacagat tcagatggtc 1020
cggcaagttg gtaaaggccg atatggagaa gtatggatgg gcaaatggcg tggcgaaaaa 1080
gtggcggtga aagtattctt taccactgaa gaagccagct ggtttcgaga aacagaaatc 1140
taccaaactg tgctaatgcg ccatgaaaac atacttggtt tcatagcggc agacattaaa 1200
ggtacaggtt cctggactca gctctatttg attactgatt accatgaaaa tggatctctc 1260
tatgacttcc tgaaatgtgc tacactggac accagagccc tgcttaaatt ggcttattca 1320
gctgcctgtg gtctgtgcca cctgcacaca gaaatttatg gcacccaagg aaagcccgca 1380
attgctcatc gagacctaaa gagcaaaaac atcctcatca agaaaaatgg gagttgctgc 1440
attgctgacc tgggccttgc tgttaaattc aacagtgaca caaatgaagt tgatgtgccc 1500
ttgaatacca gggtgggcac caaacgctac atggctcccg aagtgctgga cgaaagcctg 1560
aacaaaaacc acttccagcc ctacatcatg gctgacatct acagcttcgg cctaatcatt 1620
tgggagatgg ctcgtcgttg tatcacagga gggatcgtgg aagaatacca attgccatat 1680
tacaacatgg taccgagtga tccgtcatac gaagatatgc gtgaggttgt gtgtgtcaaa 1740
cgtttgcggc caattgtgtc taatcggtgg aacagtgatg aatgtctacg agcagttttg 1800
aagctaatgt cagaatgctg ggcccacaat ccagcctcca gactcacagc attgagaatt 1860
aagaagacgc ttgccaagat ggttgaatcc caagatgtaa aaatctgatg gttaaaccat 1920
cggaggagaa actctagact gcaagaactg tttttaccca tggcatgggt ggaattagag 1980
tggaataagg atgttaactt ggttctcaga ctctttcttc actacgtgtt cacaggctgc 2040
taatattaaa cctttcagta ctcttattag gatacaagct gggaacttct aaacacttca 2100
ttctttatat atggacagct ttattttaaa tgtggttttt gatgcctttt tttaagtggg 2160
tttttatgaa ctgcatcaag acttcaatcc tgattagtgt ctccagtcaa gctctgggta 2220
ctgaattgcc tgttcataaa acggtgcttt ctgtgaaagc cttaagaaga taaatgagcg 2280
cagcagagat ggagaaatag actttgcctt ttacctgaga cattcagttc gtttgtattc 2340
tacctttgta aaacagccta tagatgatga tgtgtttggg atactgctta ttttatgata 2400
gtttgtcctg tgtccttagt gatgtgtgtg tgtctccatg cacatgcacg ccgggattcc 2460
tctgctgcca tttgaattag aagaaaataa tttatatgca tgcacaggaa gatattggtg 2520
gccggtggtt ttgtgcttta aaaatgcaat atctgaccaa gattcgccaa tctcatacaa 2580
gccatttact ttgcaagtga gatagcttcc ccaccagctt tattttttaa catgaaagct 2640
gatgccaagg ccaaaagaag tttaaagcat ctgtaaattt ggactgtttt ccttcaacca 2700
ccattttttt tgtggttatt atttttgtca cggaaagcat cctctccaaa gttggagctt 2760
ctattgccat gaaccatgct tacaaagaaa gcacttctta ttgaagtgaa ttcctgcatt 2820
tgatagcaat gtaagtgcct ataaccatgt tctatattct ttattctcag taacttttaa 2880
aagggaagtt atttatattt tgtgtataat gtgctttatt tgcaaatcac cc 2932
<210>117
<211>1575
<212>DNA
<213>Homo sapiens
<400>117
gcaaacttcc ttgataacat gcttttgcga agtgcaggaa aattaaatgt gggcaccaag 60
aaagaggatg gtgagagtac agcccccacc ccccgtccaa aggtcttgcg ttgtaaatgc 120
caccaccatt gtccagaaga ctcagtcaac aatatttgca gcacagacgg atattgtttc 180
acgatgatag aagaggatga ctctgggttg cctgtggtca cttctggttg cctaggacta 240
gaaggctcag attttcagtg tcgggacact cccattcctc atcaaagaag atcaattgaa 300
tgctgcacag aaaggaacga atgtaataaa gacctacacc ctacactgcc tccattgaaa 360
aacagagatt ttgttgatgg acctatacac cacagggctt tacttatatc tgtgactgtc 420
tgtagtttgc tcttggtcct tatcatatta ttttgttact tccggtataa aagacaagaa 480
accagacctc gatacagcat tgggttagaa caggatgaaa cttacattcc tcctggagaa 540
tccctgagag acttaattga gcagtctcag agctcaggaa gtggatcagg cctccctctg 600
ctggtccaaa ggactatagc taagcagatt cagatggtga aacagattgg aaaaggtcgc 660
tatggggaag tttggatggg aaagtggcgt ggcgaaaagg tagctgtgaa agtgttcttc 720
accacagagg aagccagctg gttcagagag acagaaatat atcagacagt gttgatgagg 780
catgaaaaca ttttgggttt cattgctgca gatatcaaag ggacagggtc ctggacccag 840
ttgtacctaa tcacagacta tcatgaaaat ggttcccttt atgattatct gaagtccacc 900
accctagacg ctaaatcaat gctgaagtta gcctactctt ctgtcagtgg cttatgtcat 960
ttacacacag aaatctttag tactcaaggc aaaccagcaa ttgcccatcg agatctgaaa 1020
agtaaaaaca ttctggtgaa gaaaaatgga acttgctgta ttgctgacct gggcctggct 1080
gttaaattta ttagtgatac aaatgaagtt gacataccac ctaacactcg agttggcacc 1140
aaacgctata tgcctccaga agtgttggac gagagcttga acagaaatca cttccagtct 1200
tacatcatgg ctgacatgta tagttttggc ctcatccttt gggaggttgc taggagatgt 1260
gtatcaggag gtatagtgga agaataccag cttccttatc atgacctagt gcccagtgac 1320
ccctcttatg aggacatgag ggagattgtg tgcatcaaga agttacgccc ctcattccca 1380
aaccggtgga gcagtgatga gtgtctaagg cagatgggaa aactcatgac agaatgctgg 1440
gctcacaatc ctgcatcaag gctgacagcc ctgcgggtta agaaaacact tgccaaaatg 1500
tcagagtccc aggacattaa actctgatag gagaggaaaa gtaagcatct ctgcagaaag 1560
ccaacaggta ccctt 1575
<210>118
<211>2032
<212>DNA
<213>Homo sapiens
<400>118
cgcggggcgc ggagtcggcg gggcctcgcg ggacgcgggc agtgcggaga ccgcggcgct 60
gaggacgcgg gagccgggag cgcacgcgcg gggtggagtt cagcctactc tttcttagat 120
gtgaaaggaa aggaagatca tttcatgcct tgttgataaa ggttcagact tctgctgatt 180
cataaccatt tggctctgag ctatgacaag agaggaaaca aaaagttaaa cttacaagcc 240
tgccataagt gagaagcaaa cttccttgat aacatgcttt tgcgaagtgc aggaaaatta 300
aatgtgggca ccaagaaaga ggatggtgag agtacagccc ccaccccccg tccaaaggtc 360
ttgcgttgta aatgccacca ccattgtcca gaagactcag tcaacaatat ttgcagcaca 420
gacggatatt gtttcacgat gatagaagag gatgactctg ggttgcctgt ggtcacttct 480
ggttgcctag gactagaagg ctcagatttt cagtgtcggg acactcccat tcctcatcaa 540
agaagatcaa ttgaatgctg cacagaaagg aacgaatgta ataaagacct acaccctaca 600
ctgcctccat tgaaaaacag agattttgtt gatggaccta tacaccacag ggctttactt 660
atatctgtga ctgtctgtag tttgctcttg gtccttatca tattattttg ttacttccgg 720
tataaaagac aagaaaccag acctcgatac agcattgggt tagaacagga tgaaacttac 780
attcctcctg gagaatccct gagagactta attgagcagt ctcagagctc aggaagtgga 840
tcaggcctcc ctctgctggt ccaaaggact atagctaagc agattcagat ggtgaaacag 900
attggaaaag gtcgctatgg ggaagtttgg atgggaaagt ggcgtggcga aaaggtagct 960
gtgaaagtgt tcttcaccac agaggaagcc agctggttca gagagacaga aatatatcag 1020
acagtgttga tgaggcatga aaacattttg ggtttcattg ctgcagatat caaagggaca 1080
gggtcctgga cccagttgta cctaatcaca gactatcatg aaaatggttc cctttatgat 1140
tatctgaagt ccaccaccct agacgctaaa tcaatgctga agttagccta ctcttctgtc 1200
agtggcttat gtcatttaca cacagaaatc tttagtactc aaggcaaacc agcaattgcc 1260
catcgagatc tgaaaagtaa aaacattctg gtgaagaaaa atggaacttg ctgtattgct 1320
gacctgggcc tggctgttaa atttattagt gatacaaatg aagttgacat accacctaac 1380
actcgagttg gcaccaaacg ctatatgcct ccagaagtgt tggacgagag cttgaacaga 1440
aatcacttcc agtcttacat catggctgac atgtatagtt ttggcctcat cctttgggag 1500
gttgctagga gatgtgtatc aggaggtata gtggaagaat accagcttcc ttatcatgac 1560
ctagtgccca gtgacccctc ttatgaggac atgagggaga ttgtgtgcat caagaagtta 1620
cgcccctcat tcccaaaccg gtggagcagt gatgagtgtc taaggcagat gggaaaactc 1680
atgacagaat gctgggctca caatcctgca tcaaggctga cagccctgcg ggttaagaaa 1740
acacttgcca aaatgtcaga gtcccaggac attaaactct gataggagag gaaaagtaag 1800
catctctgca gaaagccaac aggtactctt ctgtttgtgg gcagagcaaa agacatcaaa 1860
taagcatcca cagtacaagc cttgaacatc gtcctgcttc ccagtgggtt cagacctcac 1920
ctttcaggga gcgacctggg caaagacaga gaagctccca gaaggagaga ttgatccgtg 1980
tctgtttgta ggcggagaaa ccgttgggta acttgttcaa gatatgatgc at 2032
<210>119
<211>3167
<212>DNA
<213>Rattus sp.
<400>119
gaattcatga gatggaaaca taggtcaaag ctgtttggag aaattggaac tacagtttta 60
tctagccaca tctctgagaa gtctgaagaa agcagcaggt gaaagtcatt gtcaagtgat 120
tttgttcttc tgtaaggaaa cctcgttcag taaggccgtt tacttcagtg aaacagcagg 180
accagtaatc aaggtggccc ggacaggaca cgtgcgaatt ggacaatgac tcagctatac 240
acttacatca gattactggg agcctgtctg ttcatcattt ctcatgttca agggcagaat 300
ctagatagta tgctccatgg tactggtatg aaatcagacg tggaccagaa gaagccggaa 360
aatggagtga cgttagcacc agaggacacc ttacctttct taaaatgcta ttgctcagga 420
cactgcccag atgacgctat taataacaca tgcataacta atggccattg ctttgccatt 480
atagaagaag atgatcaggg agaaaccacg ttaacttctg ggtgtatgaa gtatgaaggc 540
tctgattttc aatgcaagga ttcaccaaaa gcccagctac gcaggacaat agaatgttgt 600
cggaccaatt tgtgcaacca atatttgcag cctacactgc cccctgtcgt tataggccca 660
ttctttgatg gcagcgtccg atggctggct gtgctcatct ctatggctgt ctgtattgtc 720
gccatgatcg tcttctccag ctgcttctgt tacaaacatt actgtaagag tatctcaagc 780
agaggtcgtt acaaccgtga cttggaacag gatgaagcat ttattccagt aggagaatca 840
ctgaaagacc tgattgacca gtcacaaagc tctggtagtg gatctggatt acctttattg 900
gttcagcgaa ctattgccaa acagattcag atggttcggc aggttggtaa aggccggtat 960
ggagaagtat ggatgggtaa atggcgtggt gaaaaagtgg ctgtcaaagt attttttacc 1020
actgaagaag ctagctggtt tagagaaaca gaaatctacc agacggtgtt aatgcgtcat 1080
gaaaatatac ttggttttat agctgcagac attaaaggca ccggttcctg gactcagctg 1140
tatttgatta ctgattacca tgagaatggg tctctctatg acttcctgaa atgtgccacc 1200
ctggacacca gagccctact caagttagct tattctgctg cctgtggtct gtgccacctc 1260
cacacagaaa tttatggcac gcaaggcaag cctgcaattg ctcatcgaga cctgaagagc 1320
aaaaacatcc ttattaagaa aaatggtagt tgctgtattg ctgacctggg cctagctgtt 1380
aaattcaaca gtgacacaaa tgaagttgac atacccttga acaccagggt gggcaccagg 1440
cggtacatgg ctccagaagt gctggacgag agcctgagta aaaaccattt ccagccctac 1500
atcatggctg acatctacag ctttggtttg atcatttggg agatggcccg tcgctgtatt 1560
acaggaggaa tcgtggagga atatcaatta ccatattaca acatggtgcc tagtgaccca 1620
tcttatgaag acatgcgtga ggtcgtgtgt gtgaaacgct tgcggccaat cgtctctaac 1680
cgctggaaca gtgatgaatg tcttcgagcc gttttgaagc tgatgtcaga atgctgggcc 1740
cataatccag catccagact cacagctttg agaatcaaga agacgctcgc aaagatggtt 1800
gaatcccagg atgtaaagat ttgacaaaca gttttgagaa agaatttaga ctgcaagaaa 1860
ttcacccgag gaagggtgga gttagcatgg actaggatgt cggcttggtt tccagactct 1920
ctcctctaca tcttcacagg ctgctaacag taaactttca ggactctgca gaatgcaggg 1980
ttggagcttc agacatagga cttcagacat gctgttcttt gcgtatggac agctttgttt 2040
taaatgtggg cttttgatgc ctttttggtt tttatgaatt gcatcaagac tccaatcctg 2100
ataagaagtc tctggtcaaa ctctggttac tcactatcct gtccataaag tggtgctttc 2160
tgtgaaagcc ttaaggaaat tagtgagctc agcagagatg gagaaaggca tatttgccct 2220
ctacagagaa aatatctgtc tgtgttctgt ctctgtaaac agcctggact atgatctctt 2280
tgggatgctg cctggttgat gatggtgcat catgcctctg atatgcatac cagacttcct 2340
ctgctgccat gggcttacaa gacaagaatg tgaaggttgc acaggacggt atttgtggcc 2400
agtggtttaa atatgcaata tctaatcgac attcgccaat ctcataaaag ccatctacct 2460
tgtaactgaa gtaacttctc taccaacttt atttttagca taatagttgt aaaggccaaa 2520
ctatgtataa agtgtccata gactcgaact gttttcctcc agtcaccatt ttgttttcct 2580
tttggtaatt atttttgtta tataattcct cctatccaga attggcgctc actgtcttga 2640
accatacttt gaaagaaatg cctcttcctg gagtctgcct tactgcatct gatcaccatg 2700
tgcatacctc tgatcaaatt ctggagtctt tgttctcggt acctcttaaa aagggaaatt 2760
gtgtatcatg tgtagtgtgc ttttattttc aaaatcttca tagcctttat tctagccatt 2820
tttacctaca tactcattct gtacaaaaca gctcactcgg tctcacggct gatcctcagt 2880
ggaaatgatt taaagtagag ctgtgtacga atttcagaat tcatgtattt aaaaacttca 2940
cactaacact ttactaagat attgtctcat atcttttatg aggatgtcag ctgattttca 3000
atgactataa atgtatctta gctatctaaa tcttttgaaa tttggtttta taatttctgg 3060
tccctaactt gtgaagacaa agaggcagaa gtacccagtc taccacattt acactgtaca 3120
ttattaaata aaaaaatgta tattttaaaa aaaaaaaaaa aaaaaaa 3167
<210>120
<211>3167
<212>DNA
<213>Rattus noryegicus
<400>120
gaattcatga gatggaaaca taggtcaaag ctgtttggag aaattggaac tacagtttta 60
tctagccaca tctctgagaa gtctgaagaa agcagcaggt gaaagtcatt gtcaagtgat 120
tttgttcttc tgtaaggaaa cctcgttcag taaggccgtt tacttcagtg aaacagcagg 180
accagtaatc aaggtggccc ggacaggaca cgtgcgaatt ggacaatgac tcagctatac 240
acttacatca gattactggg agcctgtctg ttcatcattt ctcatgttca agggcagaat 300
ctagatagta tgctccatgg tactggtatg aaatcagacg tggaccagaa gaagccggaa 360
aatggagtga cgttagcacc agaggacacc ttacctttct taaaatgcta ttgctcagga 420
cactgcccag atgacgctat taataacaca tgcataacta atggccattg ctttgccatt 480
atagaagaag atgatcaggg agaaaccacg ttaacttctg ggtgtatgaa gtatgaaggc 540
tctgattttc aatgcaagga ttcaccaaaa gcccagctac gcaggacaat agaatgttgt 600
cggaccaatt tgtgcaacca atatttgcag cctacactgc cccctgtcgt tataggccca 660
ttctttgatg gcagcgtccg atggctggct gtgctcatct ctatggctgt ctgtattgtc 720
gccatgatcg tcttctccag ctgcttctgt tacaaacatt actgtaagag tatctcaagc 780
agaggtcgtt acaaccgtga cttggaacag gatgaagcat ttattccagt aggagaatca 840
ctgaaagacc tgattgacca gtcacaaagc tctggtagtg gatctggatt acctttattg 900
gttcagcgaa ctattgccaa acagattcag atggttcggc aggttggtaa aggccggtat 960
ggagaagtat ggatgggtaa atggcgtggt gaaaaagtgg ctgtcaaagt attttttacc 1020
actgaagaag ctagctggtt tagagaaaca gaaatctacc agacggtgtt aatgcgtcat 1080
gaaaatatac ttggttttat agctgcagac attaaaggca ccggttcctg gactcagctg 1140
tatttgatta ctgattacca tgagaatggg tctctctatg acttcctgaa atgtgccacc 1200
ctggacacca gagccctact caagttagct tattctgctg cctgtggtct gtgccacctc 1260
cacacagaaa tttatggcac gcaaggcaag cctgcaattg ctcatcgaga cctgaagagc 1320
aaaaacatcc ttattaagaa aaatggtagt tgctgtattg ctgacctggg cctagctgtt 1380
aaattcaaca gtgacacaaa tgaagttgac atacccttga acaccagggt gggcaccagg 1440
cggtacatgg ctccagaagt gctggacgag agcctgagta aaaaccattt ccagccctac 1500
atcatggctg acatctacag ctttggtttg atcatttggg agatggcccg tcgctgtatt 1560
acaggaggaa tcgtggagga atatcaatta ccatattaca acatggtgcc tagtgaccca 1620
tcttatgaag acatgcgtga ggtcgtgtgt gtgaaacgct tgcggccaat cgtctctaac 1680
cgctggaaca gtgatgaatg tcttcgagcc gttttgaagc tgatgtcaga atgctgggcc 1740
cataatccag catccagact cacagctttg agaatcaaga agacgctcgc aaagatggtt 1800
gaatcccagg atgtaaagat ttgacaaaca gttttgagaa agaatttaga ctgcaagaaa 1860
ttcacccgag gaagggtgga gttagcatgg actaggatgt cggcttggtt tccagactct 1920
ctcctctaca tcttcacagg ctgctaacag taaactttca ggactctgca gaatgcaggg 1980
ttggagcttc agacatagga cttcagacat gctgttcttt gcgtatggac agctttgttt 2040
taaatgtggg cttttgatgc ctttttggtt tttatgaatt gcatcaagac tccaatcctg 2100
ataagaagtc tctggtcaaa ctctggttac tcactatcct gtccataaag tggtgctttc 2160
tgtgaaagcc ttaaggaaat tagtgagctc agcagagatg gagaaaggca tatttgccct 2220
ctacagagaa aatatctgtc tgtgttctgt ctctgtaaac agcctggact atgatctctt 2280
tgggatgctg cctggttgat gatggtgcat catgcctctg atatgcatac cagacttcct 2340
ctgctgccat gggcttacaa gacaagaatg tgaaggttgc acaggacggt atttgtggcc 2400
agtggtttaa atatgcaata tctaatcgac attcgccaat ctcataaaag ccatctacct 2460
tgtaactgaa gtaacttctc taccaacttt atttttagca taatagttgt aaaggccaaa 2520
ctatgtataa agtgtccata gactcgaact gttttcctcc agtcaccatt ttgttttcct 2580
tttggtaatt atttttgtta tataattcct cctatccaga attggcgctc actgtcttga 2640
accatacttt gaaagaaatg cctcttcctg gagtctgcct tactgcatct gatcaccatg 2700
tgcatacctc tgatcaaatt ctggagtctt tgttctcggt acctcttaaa aagggaaatt 2760
gtgtatcatg tgtagtgtgc ttttattttc aaaatcttca tagcctttat tctagccatt 2820
tttacctaca tactcattct gtacaaaaca gctcactcgg tctcacggct gatcctcagt 2880
ggaaatgatt taaagtagag ctgtgtacga atttcagaat tcatgtattt aaaaacttca 2940
cactaacact ttactaagat attgtctcat atcttttatg aggatgtcag ctgattttca 3000
atgactataa atgtatctta gctatctaaa tcttttgaaa tttggtttta taatttctgg 3060
tccctaactt gtgaagacaa agaggcagaa gtacccagtc taccacattt acactgtaca 3120
ttattaaata aaaaaatgta tattttaaaa aaaaaaaaaa aaaaaaa 3167
<210>121
<211>3003
<212>DNA
<213>Rattus norvegicus
<400>121
cgttcagtaa ggccgtttac ttcagtgaaa cagcaggacc agtaatcaag gtggcccgga 60
caggacacgt gcgaattgga caatgactca gctatacact tacatcagat tactgggagc 120
ctgtctgttc atcatttctc atgttcaagg gcagaatcta gatagtatgc tccatggtac 180
tggtatgaaa tcagacgtgg accagaagaa gccggaaaat ggagtgacgt tagcaccaga 240
ggacacctta cctttcttaa aatgctattg ctcaggacac tgcccagatg acgctattaa 300
taacacatgc ataactaatg gccattgctt tgccattata gaagaagatg atcagggaga 360
aaccacgtta acttctgggt gtatgaagta tgaaggctct gattttcaat gcaaggattc 420
accaaaagcc cagctacgca ggacaataga atgttgtcgg accaatttgt gcaaccaata 480
tttgcagcct acactgcccc ctgtcgttat aggcccattc tttgatggca gcgtccgatg 540
gctggctgtg ctcatctcta tggctgtctg tattgtcgcc atgatcgtct tctccagctg 600
cttctgttac aaacattact gtaagagtat ctcaagcaga ggtcgttaca accgtgactt 660
ggaacaggat gaagcattta ttccagtagg agaatcactg aaagacctga ttgaccagtc 720
acaaagctct ggtagtggat ctggattacc tttattggtt cagcgaacta ttgccaaaca 780
gattcagatg gttcggcagg ttggtaaagg ccggtatgga gaagtatgga tgggtaaatg 840
gcgtggtgaa aaagtggctg tcaaagtatt ttttaccact gaagaagcta gctggtttag 900
agaaacagaa atctaccaga cggtgttaat gcgtcatgaa aatatacttg gttttatagc 960
tgcagacatt aaaggcaccg gttcctggac tcagctgtat ttgattactg attaccatga 1020
gaatgggtct ctctatgact tcctgaaatg tgccaccctg gacaccagag ccctactcaa 1080
gttagcttat tctgctgcct gtggtctgtg ccacctccac acagaaattt atggcacgca 1140
aggcaagcct gcaattgctc atcgagacct gaagagcaaa aacatcctta ttaagaaaaa 1200
tggtagttgc tgtattgctg acctgggcct agctgttaaa ttcaacagtg acacaaatga 1260
agttgacata cccttgaaca ccagggtggg caccaggcgg tacatggctc cagaagtgct 1320
ggacgagagc ctgagtaaaa accatttcca gccctacatc atggctgaca tctacagctt 1380
tggtttgatc atttgggaga tggcccgtcg ctgtattaca ggaggaatcg tggaggaata 1440
tcaattacca tattacaaca tggtgcctag tgacccatct tatgaagaca tgcgtgaggt 1500
cgtgtgtgtg aaacgcttgc ggccaatcgt ctctaaccgc tggaacagtg atgaatgtct 1560
tcgagccgtt ttgaagctga tgtcagaatg ctgggcccat aatccagcat ccagactcac 1620
agctttgaga atcaagaaga cgctcgcaaa gatggttgaa tcccaggatg taaagatttg 1680
acaaacagtt ttgagaaaga atttagactg caagaaattc acccgaggaa gggtggagtt 1740
agcatggact aggatgtcgg cttggtttcc agactctctc ctctacatct tcacaggctg 1800
ctaacagtaa actttcagga ctctgcagaa tgcagggttg gagcttcaga cataggactt 1860
cagacatgct gttctttgcg tatggacagc tttgttttaa atgtgggctt ttgatgcctt 1920
tttggttttt atgaattgca tcaagactcc aatcctgata agaagtctct ggtcaaactc 1980
tggttactca ctatcctgtc cataaagtgg tgctttctgt gaaagcctta aggaaattag 2040
tgagctcagc agagatggag aaaggcatat ttgccctcta cagagaaaat atctgtctgt 2100
gttctgtctc tgtaaacagc ctggactatg atctctttgg gatgctgcct ggttgatgat 2160
ggtgcatcat gcctctgata tgcataccag acttcctctg ctgccatggg cttacaagac 2220
aagaatgtga aggttgcaca ggacggtatt tgtggccagt ggtttaaata tgcaatatct 2280
aatcgacatt cgccaatctc ataaaagcca tctaccttgt aactgaagta acttctctac 2340
caactttatt tttagcataa tagttgtaaa ggccaaacta tgtataaagt gtccatagac 2400
tcgaactgtt ttcctccagt caccattttg ttttcctttt ggtaattatt tttgttatat 2460
aattcctcct atccagaatt ggcgctcact gtcttgaacc atactttgaa agaaatgcct 2520
cttcctggag tctgccttac tgcatctgat caccatgtgc atacctctga tcaaattctg 2580
gagtctttgt tctcggtacc tcttaaaaag ggaaattgtg tatcatgtgt agtgtgcttt 2640
tattttcaaa atcttcatag cctttattct agccattttt acctacatac tcattctgta 2700
caaaacagct cactcggtct cacggctgat cctcagtgga aatgatttaa agtagagctg 2760
tgtacgaatt tcagaattca tgtatttaaa aacttcacac taacacttta ctaagatatt 2820
gtctcatatc ttttatgagg atgtcagctg attttcaatg actataaatg tatcttagct 2880
atctaaatct tttgaaattt ggttttataa tttctggtcc ctaacttgtg aagacaaaga 2940
ggcagaagta cccagtctac cacatttaca ctgtacatta ttaaataaaa aaatgtatat 3000
ttt 3003
<210>122
<211>2063
<212>DNA
<213>Homo sapiens
<400>122
gaattccggt gatgatgatg gtgatggtga tgatggtgat gaggatgatg gtgatgatga 60
tgatggtgtt ggtgatggtt tttgcatctt ccattcatga actaagtact cttattagtg 120
aatttctttt ctttgccctc ctgattcttg gctggcccag ggatgacttc ctcgctgcag 180
cggccctggc gggtgccctg gctaccatgg accatcctgc tggtcagcac tgcggctgct 240
tcgcagaatc aagaacggct atgtgcgttt aaagatccgt atcagcaaga ccttgggata 300
ggtgagagta gaatctctca tgaaaatggg acaatattat gctcgaaagg tagcacctgc 360
tatggccttt gggagaaatc aaaaggggac ataaatcttg taaaacaagg atgttggtct 420
cacattggag atccccaaga gtgtcactat gaagaatgtg tagtaactac cactcctccc 480
tcaattcaga atggaacata ccgtttctgc tgttgtagca cagatttatg taatgtcaac 540
tttactgaga attttccacc tcctgacaca acaccactca gtccacctca ttcatttaac 600
cgagatgaga caataatcat tgctttggca tcagtctctg tattagctgt tttgatagtt 660
gccttatgct ttggatacag aatgttgaca ggagaccgta aacaaggtct tcacagtatg 720
aacatgatgg aggcagcagc atccgaaccc tctcttgatc tagataatct gaaactgttg 780
gagctgattg gccgaggtcg atatggagca gtatataaag gctccttgga tgagcgtcca 840
gttgctgtaa aagtgttttc ctttgcaaac cgtcagaatt ttatcaacga aaagaacatt 900
tacagagtgc ctttgatgga acatgacaac attgcccgct ttatagttgg agatgagaga 960
gtcactgcag atggacgcat ggaatatttg cttgtgatgg agtactatcc caatggatct 1020
ttatgcaagt atttaagtct ccacacaagt gactgggtaa gctcttgccg tcttgctcat 1080
tctgttacta gaggactggc ttatcttcac acagaattac cacgaggaga tcattataaa 1140
cctgcaattt cccatcgaga tttaaacagc agaaatgtcc tagtgaaaaa tgatggaacc 1200
tgtgttatta gtgactttgg actgtccatg aggctgactg gaaatagact ggtgcgccca 1260
ggggaggaag ataatgcagc cataagcgag gttggcacta tcagatatat ggcaccagaa 1320
gtgctagaag gagctgtgaa cttgagggac tgtgaatcag ctttgaaaca agtagacatg 1380
tatgctcttg gactaatcta ttgggagata tttatgagat gtacagacct cttcccaggg 1440
gaatccgtac cagagtacca gatggctttt cagacagagg ttggaaacca tcccactttt 1500
gaggatatgc aggttctcgt gtctagggaa aaacagagac ccaagttccc agaagcctgg 1560
aaagaaaata gcctggcagt gaggtcactc aaggagacaa tcgaagactg ttgggaccag 1620
gatgcagagg ctcggcttac tgcacagtgt gctgaggaaa ggatggctga acttatgatg 1680
atttgggaaa gaaacaaatc tgtgagccca acagtcaatc caatgtctac tgctatgcag 1740
aatgaacgta ggtgagtcaa cacaagatgg caaatcagga tcaggtgaaa agatcaagaa 1800
acgtgtgaaa actccctatt ctcttaagcg gtggcgcccc tccacctggg tcatctccac 1860
tgaatcgctg gactgtgaag tcaacaataa tggcagtaac agggcagttc attccaaatc 1920
cagcactgct gtttaccttg cagaaggagg cactgctaca accatggtgt ctaaagatat 1980
aggaatgaac tgtctgtgaa atgttttcaa gcctatggag tgaaattatt ttttgcatca 2040
tttaaacatg cagaagatgt tta 2063
<210>123
<211>1964
<212>DNA
<213>Homo sapiens
<400>123
atttcttttc tttgccctcc tgattcttgg ctggcccagg gatgacttcc tcgctgcagc 60
ggccctggcg ggtgccctgg ctaccatgga ccatcctgct ggtcagcact gcggctgctt 120
cgcagaatca agaacggcta tgtgcgttta aagatccgta tcagcaagac cttgggatag 180
gtgagagtag aatctctcat gaaaatggga caatattatg ctcgaaaggt agcacctgct 240
atggcctttg ggagaaatca aaaggggaca taaatcttgt aaaacaagga tgttggtctc 300
acattggaga tccccaagag tgtcactatg aagaatgtgt agtaactacc actcctccct 360
caattcagaa tggaacatac cgtttctgct gttgtagcac agatttatgt aatgtcaact 420
ttactgagaa ttttccacct cctgacacaa caccactcag tccacctcat tcatttaacc 480
gagatgagac aataatcatt gctttggcat cagtctctgt attagctgtt ttgatagttg 540
ccttatgctt tggatacaga atgttgacag gagaccgtaa acaaggtctt cacagtatga 600
acatgatgga ggcagcagca tccgaaccct ctcttgatct agataatctg aaactgttgg 660
agctgattgg ccgaggtcga tatggagcag tatataaagg ctccttggat gagcgtccag 720
ttgctgtaaa agtgttttcc tttgcaaacc gtcagaattt tatcaacgaa aagaacattt 780
acagagtgcc tttgatggaa catgacaaca ttgcccgctt tatagttgga gatgagagag 840
tcactgcaga tggacgcatg gaatatttgc ttgtgatgga gtactatccc aatggatctt 900
tatgcaagta tttaagtctc cacacaagtg actgggtaag ctcttgccgt cttgctcatt 960
ctgttactag aggactggct tatcttcaca cagaattacc acgaggagat cattataaac 1020
ctgcaatttc ccatcgagat ttaaacagca gaaatgtcct agtgaaaaat gatggaacct 1080
gtgttattag tgactttgga ctgtccatga ggctgactgg aaatagactg gtgcgcccag 1140
gggaggaaga taatgcagcc ataagcgagg ttggcactat cagatatatg gcaccagaag 1200
tgctagaagg agctgtgaac ttgagggact gtgaatcagc tttgaaacaa gtagacatgt 1260
atgctcttgg actaatctat tgggagatat ttatgagatg tacagacctc ttcccagggg 1320
aatccgtacc agagtaccag atggcttttc agacagaggt tggaaaccat cccacttttg 1380
aggatatgca ggttctcgtg tctagggaaa aacagagacc caagttccca gaagcctgga 1440
aagaaaatag cctggcagtg aggtcactca aggagacaat cgaagactgt tgggaccagg 1500
atgcagaggc tcggcttact gcacagtgtg ctgaggaaag gatggctgaa cttatgatga 1560
tttgggaaag aaacaaatct gtgagcccaa cagtcaatcc aatgtctact gctatgcaga 1620
atgaacgtag gtgagtcaac acaagatggc aaatcaggat caggtgaaaa gatcaagaaa 1680
cgtgtgaaaa ctccctattc tcttaagcgg tggcgcccct ccacctgggt catctccact 1740
gaatcgctgg actgtgaagt caacaataat ggcagtaaca gggcagttca ttccaaatcc 1800
agcactgctg tttaccttgc agaaggaggc actgctacaa ccatggtgtc taaagatata 1860
ggaatgaact gtctgtgaaa tgttttcaag cctatggagt gaaattattt tttgcatcat 1920
ttaaacatgc agaagatgtt taaaaataaa aaaaaaactg cttt 1964
<210>124
<211>3611
<212>DNA
<213>Homo sapiens
<400>124
cgccccccga ccccggatcg aatccccgcc ctccgcaccc tggatatgtt ttctcccaga 60
cctggatatt tttttgatat cgtgaaacta cgagggaaat aatttggggg atttcttctt 120
ggctccctgc tttccccaca gacatgcctt ccgtttggag ggccgcggca ccccgtccga 180
ggcgaaggaa cccccccagc cgcgagggag agaaatgaag ggaatttctg cagcggcatg 240
aaagctctgc agctaggtcc tctcatcagc catttgtcct ttcaaactgt attgtgatac 300
gggcaggatc agtccacggg agagaagacg agcctcccgg ctgtttctcc gccggtctac 360
ttcccatatt tcttttcttt gccctcctga ttcttggctg gcccagggat gacttcctcg 420
ctgcagcggc cctggcgggt gccctggcta ccatggacca tcctgctggt cagcactgcg 480
gctgcttcgc agaatcaaga acggctatgt gcgtttaaag atccgtatca gcaagacctt 540
gggataggtg agagtagaat ctctcatgaa aatgggacaa tattatgctc gaaaggtagc 600
acctgctatg gcctttggga gaaatcaaaa ggggacataa atcttgtaaa acaaggatgt 660
tggtctcaca ttggagatcc ccaagagtgt cactatgaag aatgtgtagt aactaccact 720
cctccctcaa ttcagaatgg aacataccgt ttctgctgtt gtagcacaga tttatgtaat 780
gtcaacttta ctgagaattt tccacctcct gacacaacac cactcagtcc acctcattca 840
tttaaccgag atgagacaat aatcattgct ttggcatcag tctctgtatt agctgttttg 900
atagttgcct tatgctttgg atacagaatg ttgacaggag accgtaaaca aggtcttcac 960
agtatgaaca tgatggaggc agcagcatcc gaaccctctc ttgatctaga taatctgaaa 1020
ctgttggagc tgattggccg aggtcgatat ggagcagtat ataaaggctc cttggatgag 1080
cgtccagttg ctgtaaaagt gttttccttt gcaaaccgtc agaattttat caacgaaaag 1140
aacatttaca gagtgccttt gatggaacat gacaacattg cccgctttat agttggagat 1200
gagagagtca ctgcagatgg acgcatggaa tatttgcttg tgatggagta ctatcccaat 1260
ggatctttat gcaagtattt aagtctccac acaagtgact gggtaagctc ttgccgtctt 1320
gctcattctg ttactagagg actggcttat cttcacacag aattaccacg aggagatcat 1380
tataaacctg caatttccca tcgagattta aacagcagaa atgtcctagt gaaaaatgat 1440
ggaacctgtg ttattagtga ctttggactg tccatgaggc tgactggaaa tagactggtg 1500
cgcccagggg aggaagataa tgcagccata agcgaggttg gcactatcag atatatggca 1560
ccagaagtgc tagaaggagc tgtgaacttg agggactgtg aatcagcttt gaaacaagta 1620
gacatgtatg ctcttggact aatctattgg gagatattta tgagatgtac agacctcttc 1680
ccaggggaat ccgtaccaga gtaccagatg gcttttcaga cagaggttgg aaaccatccc 1740
acttttgagg atatgcaggt tctcgtgtct agggaaaaac agagacccaa gttcccagaa 1800
gcctggaaag aaaatagcct ggcagtgagg tcactcaagg agacaatcga agactgttgg 1860
gaccaggatg cagaggctcg gcttactgca cagtgtgctg aggaaaggat ggctgaactt 1920
atgatgattt gggaaagaaa caaatctgtg agcccaacag tcaatccaat gtctactgct 1980
atgcagaatg aacgcaacct gtcacataat aggcgtgtgc caaaaattgg tccttatcca 2040
gattattctt cctcctcata cattgaagac tctatccatc atactgacag catcgtgaag 2100
aatatttcct ctgagcattc tatgtccagc acacctttga ctatagggga aaaaaaccga 2160
aattcaatta actatgaacg acagcaagca caagctcgaa tccccagccc tgaaacaagt 2220
gtcaccagcc tctccaccaa cacaacaacc acaaacacca caggactcac gccaagtact 2280
ggcatgacta ctatatctga gatgccatac ccagatgaaa caaatctgca taccacaaat 2340
gttgcacagt caattgggcc aacccctgtc tgcttacagc tgacagaaga agacttggaa 2400
accaacaagc tagacccaaa agaagttgat aagaacctca aggaaagctc tgatgagaat 2460
ctcatggagc actctcttaa acagttcagt ggcccagacc cactgagcag tactagttct 2520
agcttgcttt acccactcat aaaacttgca gtagaagcaa ctggacagca ggacttcaca 2580
cagactgcaa atggccaagc atgtttgatt cctgatgttc tgcctactca gatctatcct 2640
ctccccaagc agcagaacct tcccaagaga cctactagtt tgcctttgaa caccaaaaat 2700
tcaacaaaag agccccggct aaaatttggc agcaagcaca aatcaaactt gaaacaagtc 2760
gaaactggag ttgccaagat gaatacaatc aatgcagcag aacctcatgt ggtgacagtc 2820
accatgaatg gtgtggcagg tagaaaccac agtgttaact cccatgctgc cacaacccaa 2880
tatgccaatg ggacagtact atctggccaa acaaccaaca tagtgacaca tagggcccaa 2940
gaaatgttgc acgaatcagtt tattggtgag gacacccggctgaatattaa ttccagtcct 3000
gatgagcatg agcctttact gagacgagag caacaagctg gccatgatga aggtgttctg 3060
gatcgtcttg tggacaggag ggaacggcca ctagaaggtg gccgaactaa ttccaataac 3120
aacaacagca atccatgttc agaacaagat gttcttgcac agggtgttcc aagcacagca 3180
gcagatcctg ggccatcaaa gcccagaaga gcacagaggc ctaattctct ggatctttca 3240
gccacaaatg tcctggatgg cagcagtata cagataggtg agtcaacaca agatggcaaa 3300
tcaggatcag gtgaaaagat caagaaacgt gtgaaaactc cctattctct taagcggtgg 3360
cgcccctcca cctgggtcat ctccactgaa tcgctggact gtgaagtcaa caataatggc 3420
agtaacaggg cagttcattc caaatccagc actgctgttt accttgcaga aggaggcact 3480
gctacaacca tggtgtctaa agatatagga atgaactgtc tgtgaaatgt tttcaagcct 3540
atggagtgaa attatttttt gcatcattta aacatgcaga agatgtttaa aaataaaaaa 3600
aaaactgctt t 3611
<210>125
<211>3871
<212>DNA
<213>Homo sapiens
<400>125
ggcctccgca ccctggatat gttttctccc agacctggat atttttttga tatcgtgaaa 60
ctacgaggga aataatttgg gggatttctt cttggctccc tgctttcccc acagacatac 120
cttccgtttg gagggccgcg gcaccccgtc cgaggcgaag gaaccccccc atccgcgagg 180
gagagaaatg aagggaattt ctgcagcggc atgaaagctc tgcagctagg tcctctcatc 240
agccatttgt cctttcaaac tgtattgtga tacgggcagg atcagtccac gggagagaag 300
acgagcctcc cggctgtttc tccgccggtc tacttcccat atttcttttc tttgccctcc 360
tgattcttgg ctggcccagg gatgacttcc tcgctgcagc ggccctggcg ggtgccctgg 420
ctaccatgga ccatcctgct ggtcagcact gcggctgctt cgcagaatca agaacggcta 480
tgtgcgttta aagatccgta tcagcaagac cttgggatag gtgagagtag aatctctcat 540
gaaaatggga caatattatg ctcgaaaggt agcacctgct atggcctttg ggagaaatca 600
aaaggggaca taaatcttgt aaaacaagga tgttggtctc acattggaga tccccaagag 660
tgtcactatg aagaatgtgt agtaactacc actcctccct caattcagaa tggaacatac 720
cgtttctgct gttgtagcac agatttatgt aatgtcaact ttactgagaa ttttccacct 780
cctgacacaa caccactcag tccacctcat tcatttaacc gagatgagac aataatcatt 840
gctttggcat cagtctctgt attagctgtt ttgatagttg ccttatgctt tggatacaga 900
atgttgacag gagaccgtaa acaaggtctt cacagtatga acatgatgga ggcagcagca 960
tccgaaccct ctcttgatct agataatctg aaactgttgg agctgattgg ccgaggtcga 1020
tatggagcag tatataaagg ctccttggat gagcgtccag ttgctgtaaa agtgttttcc 1080
tttgcaaacc gtcagaattt tatcaacgaa aagaacattt acagagtgcc tttgatggaa 1140
catgacaaca ttgcccgctt tatagttgga gatgagagag tcactgcaga tggacgcatg 1200
gaatatttgc ttgtgatgga gtactatccc aatggatctt tatgcaagta tttaagtctc 1260
cacacaagtg actgggtaag ctcttgccgt cttgctcatt ctgttactag aggactggct 1320
tatcttcaca cagaattacc acgaggagat cattataaac ctgcaatttc ccatcgagat 1380
ttaaacagca gaaatgtcct agtgaaaaat gatggaacct gtgttattag tgactttgga 1440
ctgtccatga ggctgactgg aaatagactg gtgcgcccag gggaggaaga taatgcagcc 1500
ataagcgagg ttggcactat cagatatatg gcaccagaag tgctagaagg agctgtgaac 1560
ttgagggact gtgaatcagc tttgaaacaa gtagacatgt atgctcttgg actaatctat 1620
tgggagatat ttatgagatg tacagacctc ttcccagggg aatccgtacc agagtaccag 1680
atggcttttc agacagaggt tggaaaccat cccacttttg aggatatgca ggttctcgtg 1740
tctagggaaa aacagagacc caagttccca gaagcctgga aagaaaatag cctggcagtg 1800
aggtcactca aggagacaat cgaagactgt tgggaccagg atgcagaggc tcggcttact 1860
gcacagtgtg ctgaggaaag gatggctgaa cttatgatga tttgggaaag aaacaaatct 1920
gtgagcccaa cagtcaatcc aatgtctact gctatgcaga atgaacgcaa cctgtcacat 1980
aataggcgtg tgccaaaaat tggtccttat ccagattatt cttcctcctc atacattgaa 2040
gactctatcc atcatactga cagcatcgtg aagaatattt cctctgagca ttctatgtcc 2100
agcacacctt tgactatagg ggaaaaaaac cgaaattcaa ttaactatga acgacagcaa 2160
gcacaagctc gaatccccag ccctgaaaca agtgtcacca gcctctccac caacacaaca 2220
accacaaaca ccacaggact cacgccaagt actggcatga ctactatatc tgagatgcca 2280
tacccagatg aaacaaatct gcataccaca aatgttgcac agtcaattgg gccaacccct 2340
gtctgcttac agctgacaga agaagacttg gaaaccaaca agctagaccc aaaagaagtt 2400
gataagaacc tcaaggaaag ctctgatgag aatctcatgg agcactctct taaacagttc 2460
agtggcccag acccactgag cagtactagt tctagcttgc tttacccact cataaaactt 2520
gcagtagaag caactggaca gcaggacttc acacagactg caaatggcca agcatgtttg 2580
attcctgatg ttctgcctac tcagatctat cctctcccca agcagcagaa ccttcccaag 2640
agacctacta gtttgccttt gaacaccaaa aattcaacaa aagagccccg gctaaaattt 2700
ggcagcaagc acaaatcaaa cttgaaacaa gtcgaaactg gagttgccaa gatgaataca 2760
atcaatgcag cagaacctca tgtggtgaca gtcaccatga atggtgtggc aggtagaaac 2820
cacagtgtta actcccatgc tgccacaacc caatatgcca ataggacagt actatctggc 2880
caaacaacca acatagtgac acatagggcc caagaaatgt tgcagaatca gtttattggt 2940
gaggacaccc ggctgaatat taattccagt cctgatgagc atgagccttt actgagacga 3000
gagcaacaag ctggccatga tgaaggtgtt ctggatcgtc ttgtggacag gagggaacgg 3060
ccactagaag gtggccgaac taattccaat aacaacaaca gcaatccatg ttcagaacaa 3120
gatgttcttg cacagggtgt tccaagcaca gcagcagatc ctgggccatc aaagcccaga 3180
agagcacaga ggcctaattc tctggatctt tcagccacaa atgtcctgga tggcagcagt 3240
atacagatag gtgagtcaac acaagatggc aaatcaggat caggtgaaaa gatcaagaaa 3300
cgtgtgaaaa ctccctattc tcttaagcgg tggcgcccct ccacctgggt catctccact 3360
gaatcgctgg actgtgaagt caacaataat ggcagtaaca gggcagttca ttccaaatcc 3420
agcactgctg tttaccttgc agaaggaggc actgctacaa ccatggtgtc taaagatata 3480
ggaatgaact gtctgtgaaa tgttttcaag cctatggagt gaaattattt tttgcatcat 3540
ttaaacatgc agaagatgtt taccgggcgg ggtgacagga gagagcgtca gcggcaagct 3600
gtggaggatg gggctcagaa tgcagacctg ggctggccgc atggcctctc cctgagccct 3660
gatttgtggt agggaagcag tatgggtgca gtcccctcct aggcctccct ctggggtccc 3720
ccgatcctat cccacctctt cagggtgagc cagcctcacc tcttcctagt cctgagggtg 3780
agggcaggct gaggcaacga gtgggaggtt caaacaagag tgggctggag ccaagggaaa 3840
atagagatga tgtaatttct ttccggaatt c 3871
<210>126
<211>88
<212>PRT
<213>Homo sapiens
<400>126
Cys Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg
1 5 10 15
Ser Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro
20 25 30
Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro
35 40 45
Ser Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg
50 55 60
Val Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val
65 70 75 80
Arg Leu Val Ala Ser Cys Lys Cys
85
<210>127
<211>82
<212>PRT
<213>Homo sapiens
<400>127
Cys Arg Pro Ile Asn Ala Thr Leu Ala Val Glu Lys Glu Gly Cys Pro
1 5 10 15
Val Cys Ile Thr Val Asn Thr Thr Ile Cys Ala Gly Tyr Cys Pro Thr
20 25 30
Met Thr Arg Val Leu Gln Gly Val Leu Pro Ala Leu Pro Gln Val Val
35 40 45
Cys Asn Tyr Arg Asp Val Arg Phe Glu Ser Ile Arg Leu Pro Gly Cys
50 55 60
Pro Arg Gly Val Asn Pro Val Val Ser Tyr Ala Val Ala Leu Ser Cys
65 70 75 80
Gln Cys
<210>128
<211>82
<212>PRT
<213>Homo sapiens
<400>128
Cys Glu Leu Thr Asn Ile Thr Ile Ala Ile Glu Lys Glu Glu Cys Arg
1 5 10 15
Phe Cys Ile Ser Ile Asn Thr Thr Trp Cys Ala Gly Tyr Cys Tyr Thr
20 25 30
Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr
35 40 45
Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro Gly Cys
50 55 60
Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val Ala Thr Gln Cys
65 70 75 80
His Cys
<210>129
<211>84
<212>PRT
<213>Homo sapiens
<400>129
Cys Ile Pro Thr Glu Tyr Thr Met His Ile Glu Arg Arg Glu Cys Ala
1 5 10 15
Tyr Cys Leu Thr Ile Asn Thr Thr Ile Cys Ala Gly Tyr Cys Met Thr
20 25 30
Arg Asp Ile Asn Gly Lys Leu Phe Leu Pro Lys Tyr Ala Leu Ser Gln
35 40 45
Asp Val Cys Thr Tyr Arg Asp Phe Ile Tyr Arg Thr Val Glu Ile Pro
50 55 60
Gly Cys Pro Leu His Val Ala Pro Tyr Phe Ser Tyr Pro Val Ala Leu
65 70 75 80
Ser Cys Lys Cys
<210>130
<211>83
<212>pRT
<213>Homo sapiens
<400>130
Cys Asn Asp Ile Thr Ala Arg Leu Gln Tyr Val Lys Val Gly Ser Cys
1 5 10 15
Lys Ser Glu Val Glu Val Asp Ile His Tyr Cys Gln Gly Lys Cys Ala
20 25 30
Ser Lys Ala Met Tyr Ser Ile Asp Ile Asn Asp Val Gln Asp Gln Cys
35 40 45
Ser Cys Cys Ser Pro Thr Arg Thr Glu Pro Met Gln Val Ala Leu His
50 55 60
Cys Thr Asn Gly Ser Val Val Tyr His Glu Val Leu Asn Ala Met Glu
65 70 75 80
Cys Lys Cys
<210>131
<211>80
<212>PRT
<213>Homo sapiens
<400>131
Cys Ser Thr Val Pro Val Thr Thr Glu Val Ser Tyr Ala Gly Cys Thr
1 5 10 15
Lys Thr Val Leu Met Asn His Cys Ser Gly Ser Cys Gly Thr Phe Val
20 25 30
Met Tyr Ser Ala Lys Ala Gln Ala Leu Asp His Ser Cys Ser Cys Cys
35 40 45
Lys Glu Glu Lys Thr Ser Gln Arg Glu Val Val Leu Ser Cys Pro Asn
50 55 60
Gly Gly Ser Leu Thr His Thr Tyr Thr His Ile Glu Ser Cys Gln Cys
65 70 75 80
<210>132
<211>80
<212>PRT
<213>Homo sapiens
<400>132
Cys Arg Thr Val Pro Phe Ser Gln Thr Ile Thr His Glu Gly Cys Glu
1 5 10 15
Lys Val Val Val Gln Asn Asn Leu Cys Phe Gly Lys Cys Gly Ser Val
20 25 30
His Phe Pro Gly Ala Ala Gln His Ser His Thr Ser Cys Ser His Cys
35 40 45
Leu Pro Ala Lys Phe Thr Thr Met His Leu Pro Leu Asn Cys Thr Glu
50 55 60
Leu Ser Ser Val Ile Lys Val Val Met Leu Val Glu Glu Cys Gln Cys
65 70 75 80
<210>133
<211>85
<212>PRT
<213>Homo sapiens
<400>133
Cys Lys Thr Gln Pro Leu Lys Gln Thr Ile His Glu Glu Gly Cys Asn
1 5 10 15
Ser Arg Thr Ile Ile Asn Arg Phe Cys Tyr Gly Gln Cys Asn Ser Phe
20 25 30
Tyr Ile Pro Arg His Ile Arg Lys Glu Glu Gly Ser Phe Gln Ser Cys
35 40 45
Ser Phe Cys Lys Pro Lys Lys Phe Thr Thr Met Met Val Thr Leu Asn
50 55 60
Cys Pro Glu Leu Gln Pro Pro Thr Lys Lys Lys Arg Val Thr Arg Val
65 70 75 80
Lys Gln Cys Arg Cys
85
<210>134
<211>86
<212>PRT
<213>Homo sapiens
<400>134
Cys Glu Ala Lys Asn Ile Thr Gln Ile Val Gly His Ser Gly Cys Glu
1 5 10 15
Ala Lys Ser Ile Gln Asn Arg Ala Cys Leu Gly Gln Cys Phe Ser Tyr
20 25 30
Ser Val Pro Asn Thr Phe Pro Gln Ser Thr Glu Ser Leu Val His Cys
35 40 45
Asp Ser Cys Met Pro Ala Gln Ser Met Trp Glu Ile Val Thr Leu Glu
50 55 60
Cys Pro Gly His Glu Glu Val Pro Arg Val Asp Lys Leu Val Glu Lys
65 70 75 80
Ile Leu His Cys Ser Cys
85
<210>135
<211>70
<212>PRT
<213>Homo sapies
<400>135
Cys Ile Arg Thr Pro Lys Ile Ser Lys Pro Ile Lys Phe Glu Leu Ser
1 5 10 15
Gly Cys Thr Ser Met Lys Thr Tyr Arg Ala Lys Phe Cys Gly Val Cys
20 25 30
Thr Asp Gly Arg Cys Cys Thr Pro His Arg Thr Thr Thr Leu Pro Val
35 40 45
Glu Phe Lys Cys Pro Asp Gly Glu Val Met Lys Lys Asn Met Met Phe
50 55 60
Ile Lys Thr Cys Ala Cys
65 70
<210>136
<211>70
<212>PRT
<213>Homo sapiens
<400>136
Cys Leu Arg Thr Lys Lys Ser Leu Lys Ala Ile His Leu Gln Phe Lys
1 5 10 15
Asn Cys Thr Ser Leu His Thr Tyr Lys Pro Arg Phe Cys Gly Val Cys
20 25 30
Ser Asp Gly Arg Cys Cys Thr Pro His Asn Thr Lys Thr Ile Gln Ala
35 40 45
Glu Phe Gln Cys Ser Pro Gly Gln Ile Val Lys Lys Pro Val Met Val
50 55 60
Ile Gly Thr Cys Thr Cys
65 70
<210>137
<211>70
<212>PRT
<213>Homo sapiens
<400>137
Cys Ser Lys Thr Lys Lys Ser Pro Glu Pro Val Arg Phe Thr Tyr Ala
1 5 10 15
Gly Cys Leu Ser Val Lys Lys Tyr Arg Pro Lys Tyr Cys Gly Ser Cys
20 25 30
Val Asp Gly Arg Cys Cys Thr Pro Gln Leu Thr Arg Thr Val Lys Met
35 40 45
Arg Phe Arg Cys Glu Asp Gly Glu Thr Phe Ser Lys Asn Val Met Met
50 55 60
Ile Gln Ser CysLys Cys
65 70
<210>138
<211>205
<212>PRT
<213>Homo sapiens
<400>138
Gln His Tyr Leu His Ile Arg Pro Ala Pro Ser Asp Asn Leu Pro Leu
1 5 10 15
Val Asp Leu Ile Glu His Pro Asp Pro Ile Phe Asp Pro Lys Glu Lys
20 25 30
Asp Leu Asn Glu Thr Leu Leu Arg Ser Leu Leu Gly Gly His Tyr Asp
35 40 45
Pro Gly Phe Met Ala Thr Ser Pro Pro Glu Asp Arg Pro Gly Gly Gly
50 55 60
Gly Gly Ala Ala Gly Gly Ala Glu Asp Leu Ala Glu Leu Asp Gln Leu
65 70 75 80
Leu Arg Gln Arg Pro Ser Gly Ala Met Pro Ser Glu Ile Lys Gly Leu
85 90 95
Glu Phe Ser Glu Gly Leu Ala Gln Gly Lys Lys Gln Arg Leu Ser Lys
100 105 110
Lys Leu Arg Arg Lys Leu Gln Met Trp Leu Trp Ser Gln Thr Phe Cys
115 120 125
Pro Val Leu Tyr Ala Trp Asn Asp Leu Gly Ser Arg Phe Trp Pro Arg
130 135 140
Tyr Val Lys Val Gly Ser Cys Phe Ser Lys Arg Ser Cys Ser Val Pro
145 150 155 160
Glu Gly Met Val Cys Lys Pro Ser Lys Ser Val His Leu Thr Val Leu
165 170 175
Arg Trp Arg Cys Gln Arg Arg Gly Gly Gln Arg Cys Gly Trp Ile Pro
180 185 190
Ile Gln Tyr Pro Ile Ile Ser Glu Cys Lys Cys Ser Cys
195 200 205
<210>139
<211>197
<212>PRT
<213>Gallus gallus
<400>139
Gln His Tyr Leu His Ile Arg Pro Ala Pro Ser Asp Asn Leu Pro Leu
1 5 10 15
Val Asp Leu Ile Glu His Pro Asp Pro Ile Phe Asp Pro Lys Glu Lys
20 25 30
Asp Leu Asn Glu Thr Leu Leu Arg Ser Leu Met Gly Gly His Phe Asp
35 40 45
Pro Asn Phe Met Ala Met Ser Leu Pro Glu Asp Arg Leu Gly Val Asp
50 55 60
Asp Leu Ala Glu Leu Asp Leu Leu Leu Arg Gln Arg Pro Ser Gly Ala
65 70 75 80
Met Pro Gly Glu Ile Lys Gly Leu Glu Phe Tyr Asp Gly Leu Gln Pro
85 90 95
Gly Lys Lys His Arg Leu Ser Lys Lys Leu Arg Arg Lys Leu Gln Met
100 105 110
Trp Leu Trp Ser Gln Thr Phe Cys Pro Val Leu Tyr Thr Trp Asn Asp
115 120 125
Leu Gly Ser Arg Phe Trp Pro Arg Tyr Val Lys Val Gly Ser Cys Tyr
130 135 140
Ser Lys Arg Ser Cys Ser Val Pro Glu Gly Met Val Cys Lys Pro Ala
145 150 155 160
Lys Ser Val His Leu Thr Ile Leu Arg Trp Arg Cys Gln Arg Arg Gly
165 170 175
Gly Gln Arg Cys Thr Trp Ile Pro Ile Gln Tyr Pro Ile Ile Ala Glu
180 185 190
Cys Lys Cys Ser Cys
195
<210>140
<211>196
<212>PRT
<213>Xenopus laevis
<400>140
Gln HisTyr Leu His Ile Arg Pro Ala Pro Ser Glu Asn Leu Pro Leu
1 5 10 15
Val Asp Leu Ile Glu His Pro Asp Pro Ile Tyr Asp Pro Lys Glu Lys
20 25 30
Asp Leu Asn Glu Thr Leu Leu Arg Thr Leu Met Val Gly His Phe Asp
35 40 45
Pro Asn Phe Met Ala Thr Ile Leu Pro Glu Glu Arg Leu Gly Val Glu
50 55 60
Asp Leu Gly Glu Leu Asp Leu Leu Leu Arg Gln Lys Pro Ser Gly Ala
65 70 75 80
Met Pro Ala Glu Ile Lys Gly Leu Glu Phe Tyr Glu Gly Leu Gln Ser
85 90 95
Lys Lys His Arg Leu Ser Lys Lys Leu Arg Arg Lys Leu Gln Met Trp
100 105 110
Leu Trp Ser Gln Thr Phe Cys Pro Val Leu Tyr Thr Trp Asn Asp Leu
115 120 125
Gly Thr Arg Phe Trp Pro Arg Tyr Val Lys Val Gly Ser Cys Tyr Ser
130 135 140
Lys Arg Ser Cys Ser Val Pro Glu Gly Met Val Cys Lys Ala Ala Lys
145 150 155 160
Ser Met His Leu Thr Ile Leu Arg Trp Arg Cys Gln Arg Arg Val Gln
165 170 175
Gln Lys Cys Ala Trp Ile Thr Ile Gln Tyr Pro Val Ile Ser Glu Cys
180 185 190
Lys Cys Ser Cys
195
<210>141
<211>195
<212>PRT
<213>Takifugu rubripes
<400>141
Gln Pro Tyr Tyr Leu Leu Arg Pro Ile Pro Ser Asp Ser Leu Pro Ile
1 5 10 15
Val Glu Leu Lys Glu Asp Pro Gly Pro Val Phe Asp Pro Lys Glu Arg
20 25 30
Asp Leu Asn Glu Thr Glu Leu Lys Ser Val Leu Gly Asp Phe Asp Ser
35 40 45
Arg Phe Leu Ser Val Leu Pro Pro Ala Glu Asp Gly His Ala Gly Asn
50 55 60
Asp Glu Leu Asp Asp Phe Asp Ala Gln Arg Trp Gly Gly Ala Leu Pro
65 70 75 80
Lys Glu Ile Arg Ala Val Asp Phe Asp Ala Pro Gln Leu Gly Lys Lys
85 90 95
His Lys Pro Ser Lys Lys Leu Lys Arg Arg Leu Gln Gln Trp Leu Trp
100 105 110
Ala Tyr Ser Phe Cys Pro Leu Ala His Ala Trp Thr Asp Leu Gly Ser
115 120 125
Arg Phe Trp Pro Arg Phe Val Arg Ala Gly Ser Cys Leu Ser Lys Arg
130 135 140
Ser Cys Ser Val Pro Glu Gly Met Thr Cys Lys Pro Ala Thr Ser Thr
145 150 155 160
His Leu Thr Ile Leu Arg Trp Arg Cys Val Gln Arg Lys Val Gly Leu
165 170 175
Iys Cys Ala Trp Ile Pro Met Gln Tyr Pro Val Ile Thr Asp Cys Lys
180 185 190
Cys Ser Cys
195
<210>142
<211>196
<212>PRT
<213>Danio rerio
<400>142
Gln His Tyr Tyr Leu Leu Arg Pro Ile Pro Ser Asp Ser Leu Pro Ile
1 5 10 15
Val Glu Leu Lys Glu Asp Pro Asp Pro Val Leu Asp Pro Lys Glu Arg
20 25 30
Asp Leu Asn Glu Thr Glu Leu Arg Ala Ile Leu Gly Ser His Phe Glu
35 40 45
Gln Asn Phe Met Ser Ile Asn Pro Pro Glu Asp Lys His Ala Gly Gln
50 55 60
Asp Glu Leu Asn Glu Ser Glu Leu Met Lys Gln Arg Pro Asn Gly Ile
65 70 75 80
Met Pro Lys Glu Ile Lys Ala Met Glu Phe Asp Ile Gln His Gly Lys
85 90 95
Lys His Lys Pro Ser Lys Lys Leu Arg Arg Arg Leu Gln Leu Trp Leu
100 105 110
Trp Ser Tyr Thr Phe Cys Pro Val Val His Thr Trp Gln Asp Leu Gly
115 120 125
Asn Arg Phe Trp Pro Arg Tyr Leu Lys Val Gly Ser Cys Tyr Asn Lys
130 135 140
Arg Ser Cys Ser Val Pro Glu Gly Met Val Cys Lys Pro Pro Lys Ser
145 150 155 160
Ser His Leu Thr Val Leu Arg Trp Arg Cys Val Gln Arg Lys Gly Gly
165 170 175
Leu Lys Cys Ala Trp Ile Pro Val Gln Tyr Pro Val Ile Ser Glu Cys
180 185 190
Lys Cys Ser Cys
195
<210>143
<211>188
<212>PRT
<213>Mus musculus
<400>143
Gln Gly Trp Gln Ala Phe Arg Asn Asp Ala Thr Glu Val Ile Pro Gly
1 5 10 15
Leu Gly Glu Tyr Pro Glu Pro Pro Pro Glu Asn Asn Gln Thr Met Asn
20 25 30
Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro Tyr Asp Ala Lys
35 40 45
Gly Val Ser Glu Tyr Ser Cys Arg Glu Leu His Tyr Thr Arg Phe Leu
50 55 60
Thr Asp Gly Pro Cys Arg Ser Ala Lys Pro Val Thr Glu Leu Val Cys
65 70 75 80
Ser Gly Gln Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg
85 90 95
Val Lys Trp Trp Arg Pro Asn Gly Pro Asp Phe Arg Cys Ile Pro Asp
100 105 110
Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly Gly Ala Ala
115 120 125
Pro Arg Ser Arg Lys Val Arg Leu Val Ala Ser Cys Lys Cys Lys Arg
130 135 140
Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly Pro Glu
145 150 155 160
Thr Ala Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Gly Ala Arg Gly
165 170 175
Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
180 185