一组用于肺腺癌早期诊断的circRNA标志物及其应用的制作方法

本发明属于肿瘤基因检测技术领域，涉及一种用于肺腺癌早期诊断的circRNA标志物、相关试剂盒及它们的用途。

背景技术：

肺癌是严重危害人类健康的第一大恶性肿瘤，其发病率(120万/年)和死亡率(110万/年)均居全球癌症首位。2014年《中国肿瘤登记年报》显示，在我国肺癌也是发病率和死亡率最高的恶性肿瘤(我国每年新发肺癌患者人数60万以上)。肺癌5年生存率仅约15.6％，主要原因是多数患者在诊断时已属晚期，因此肺癌的早期发现早期诊断至关重要。

环状RNA是一类由特殊的选择性剪切产生的首尾相接的非编码RNA。起初它们被认为是基因组转录的“噪音”，不具有生物学功能。然而，近年来的研究表明circRNA在人体中发挥着巨大的基因调节功能。与线性RNA分子相比，circRNA作为生物分子标志物具有如下优势：(1)circRNA形成特殊的共价闭合环状结构，3’端没有多聚腺苷酸尾，不会被核酸外切酶R所酶切，因此稳定性高，便于样品的保存；(2)circRNA可以通过外泌体而进入血液、组织液及痰液中，便于取样；(3)circRNA长度多在200-400碱基，使用qPCR即可定量检测，可操作性强。目前已经在食管癌、胃癌、肝癌等恶性肿瘤中相继发现了具有早期诊断价值的circRNA，但是在肺癌领域中尚未见相关circRNA的报道。

技术实现要素：

解决的技术问题：本发明的目的在于提供一组用于肺腺癌早期诊断的circRNA标志物及其应用，为肺腺癌的早期诊断提供参考依据。本发明所提供的circRNA生物标志物对于人肺腺癌具有很高的灵敏度和特异性，尤其对人早期肺腺癌具有很好的检测效果，可以作为新型的生物标志物用于肺腺癌的检测。

技术方案：一组用于肺腺癌早期诊断的circRNA标志物，标志物包括：SEQ ID No:1所示的circRNA_100323、SEQ ID No:2所示的circRNA_69774、SEQ ID No:3所示的circRNA_403738、SEQ ID No:4所示的circRNA_404449四种circRNA。

上述肺腺癌为人早期肺腺癌。

上述circRNA标志物的引物组合，所述circRNA引物的组合包括：针对circRNA_100323的特异性引物、针对circRNA_69774的特异性引物、针对circRNA_403738的特异性引物、针对circRNA_404449的特异性引物。

上述circRNA标志物的引物组合，所述针对circRNA_100323的特异性引物包括如SEQ ID No：9所示的上游引物，如SEQ IDNo：10所示的下游引物；所述针对circRNA_69774的特异性引物包括如SEQ ID No：11所示的上游引物，如SEQ ID No：12所示的下游引物；所述针对circRNA_403738的特异性引物包括如SEQ ID No：13所示的上游引物，如SEQ ID No：14所示的下游引物；所述针对circRNA_404449的特异性引物包括如SEQ ID No：15所示的上游引物，如SEQ ID No：16所示的下游引物。

上述circRNA标志物的引物组合，所述circRNA引物的组合还包括：针对SEQ ID No:5所示的circRNA_104855的特异性引物、针对SEQ ID No:6所示的circRNA_100983的特异性引物、针对SEQ ID No:7所示的circRNA_1011969的特异性引物、针对SEQ ID No:8所示的circRNA_006718的特异性引物。

上述circRNA标志物的引物组合，所述针对circRNA_104855的特异性引物包括：如SEQ ID No：17所示的上游引物和如SEQ IDNo：18所示的下游引物；所述针对circRNA_100983的特异性引物包括：如SEQ ID No：19所示的上游引物和如SEQ IDNo：20所示的下游引物；所述针对circRNA_1011969的特异性引物包括：如SEQ ID No：21所示的上游引物和如SEQ IDNo：22所示的下游引物；所述针对circRNA_006718的特异性引物包括：如SEQ ID No：23所示的上游引物和如SEQ ID No：24所示的下游引物。

上述circRNA标志物的引物组合在制备或筛选人肺腺癌的肿瘤诊断药物中的用途。

一种人肺腺癌的肿瘤诊断试剂盒，包括所述的circRNA标志物的引物组合。

一种检测人肺腺癌的circRNA芯片，所述circRNA芯片包括固相载体以及固定于固相载体上的针对如上所述的circRNA生物标志物的探针。

本发明所提供的人肺腺癌早期诊断用circRNA生物标志物，可用于肺腺癌的早期诊断。其区分早期肺腺癌和配对正常肺组织的AUC可达0.841，显著性高于这4个circRNAs单独诊断早期肺腺癌的AUC(P<0.05)，其ROC曲线表明这4个circRNAs诊断早期肺腺癌的灵敏度和特异性分别为83.4％和73.5％，显著性高于单个circRNA用于肺腺癌诊断的灵敏度和特异性(P<0.05)。

有益效果：(1)本方法通过定量PCR对一组circRNA的检测，实现对肺腺癌的早期诊断，肺癌的早期发现和诊断提供参考价值。(2)本方法特异性强、敏感性高、结果稳定等优点，具有广泛的临床应用前景和巨大的商业价值。

附图说明

图1.本发明8个circRNA联合起来区分训练集(n＝30)肺腺癌及其配对正常肺组织的ROC曲线图；

图2.本发明优化的4个circRNA联合起来区分训练集(n＝30)肺腺癌及其配对正常肺组织的ROC曲线图；

图3.本发明优化的4个circRNA联合起来区分验证集(n＝30)肺腺癌及其配对正常肺组织的ROC曲线图。

具体实施方式

以下通过特定的具体实例说明本发明的实施方式。

实施例1

1临床样本收集：

收集东南大学附属中大医院2013-2014年期间存档的早期(IA期)肺腺癌石蜡组织标本及其配对正常肺组织60对。所有病人对参与科学研究均签署知情同意书。

2 circRNA定量PCR实验：

2.1 RNA抽提及定量PCR

利用Trizol从组织中抽提总RNA，用微体积分光光度计对RNA进行定量。

2.2引物

本发明所提供的一组circRNA包括circRNA_100323、circRNA_69774、circRNA_403738、circRNA_404449、circRNA_104855、circRNA_100983、circRNA_1011969、circRNA_006718等8种circRNA。它们均是从早期肺腺癌患者circRNA芯片检测的结果中挑选的，以GAPDH为内参基因(SEQ ID No：27)，引物序列如表1所示：

表1定量PCR使用的引物序列

2.3逆转录反应

使用TakaRa PrimeScript RT reagent Kit试剂盒进行逆转录，RNA起始量为1μg，逆转录反应组分的用量如表2所示，反应条件：37℃15min，85℃5sec完成后低温保存备用。

表2逆转录反应体系组成

2.4实时定量PCR反应

实时定量PCR使用TaKaRa公司的SYBR Premix Ex Taq(Tli RnaseH Plus)试剂盒，定量仪器为BioRad公司CFX96型实时PCR仪。反应体系如表3所示，反应条件如表5所示步骤，每个实时定量PCR反应分别做三个重复。

表3实时定量PCR反应体系

反应程序为：95℃2min；95℃30sec，56℃50sec，40个循环。

数据以平均值±标准差的形式表示，使用SPSS 18.0软件对数据进行统计分析。除非有特殊的说明。肺腺癌与其配对正常肺组织中circRNA的表达差异统计使用配对样本t检验的方法，所有P值均为双侧，P<0.05被认为有统计学意义。

2.5 8个circRNA区分肺腺癌及其配对正常肺组织的能力评估

我们利用ROC曲线来评估这8个区分肺腺癌及其配对正常肺组织的能力。单个circRNA用于肺腺癌诊断的AUC为0.53-0.75，灵敏度为54.4％-77.4％，特异性为49.1％-77.5％(表4)。我们将这8个circRNA联合起来用于30对肺腺癌样本的诊断，其AUC值可达到0.854(图1)，在选择合适阈值之后，灵敏度和特异性分别为80.1％和83.3％。

表4 8个circRNA在训练集(30对样本)中的表达情况

2.6优选的4个circRNA区分肺腺癌及其配对正常肺组织的能力评估

通过线性逻辑回归分析，我们从8个circRNA中分析优选得到了4个circRNA。我们利用ROC曲线来评估4个在训练集中区分肺腺癌及其配对正常肺组织的能力(所用30对样本与2.5相同)。这4个circRNA结合起来区分早期肺腺癌和配对正常肺组织的AUC可达0.820(图2所示)，接近8个circRNA联合检测水平，并显著高于这4个circRNA单独诊断早期肺腺癌的AUC(P<0.05)。在选择合适的阈值之后，ROC曲线表明这4个circRNA诊断早期肺腺癌的灵敏度和特异性分别为83.3％和80.0％，显著高于单个circRNA用于肺腺癌诊断的灵敏度和特异性(P<0.05)。

表5 4个circRNA在验证集(30对样本)中的诊断结果

我们在另外一组30例肺腺癌样本及其配对正常肺组织(验证集)中验证从训练集筛选出的这4个circRNA的检测特性。这4个circRNA在肺腺癌及其配对正常肺组织均中有显著性差异表达(P<0.001)。单个circRNA用于检测肺腺癌的AUC为0.73-0.82，灵敏度为65.6％-79.3％，特异性为67.9％-76.3％(表5)。这4个circRNA联合检测60对肺腺癌样本的AUC可达0.841(图3)，在选择合适的阈值之后，ROC曲线表明其灵敏度为83.4％，特异性为73.5％，均显著高于任何单个circRNA的检测能力(P<0.05)。并且，这组circRNA在两组独立样本(训练集和验证集)中具有类似的检测能力，说明这组circRNA可以作为肺腺癌早期检测的生物标志物。

以上所述，仅为本发明的较佳实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还将可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。凡熟悉本专业的技术人员，在不脱离本发明的精神和范围的情况下，当可利用以上所揭示的技术内容而做出的些许更动、修饰与演变的等同变化，均为本发明的等效实施例；同时，凡依据本发明的实质技术对上述实施例所作的任何等同变化的更动、修饰与演变，均仍属于本发明的技术方案的范围内。

序列表

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cuuugcaacu acaugcagua gauguuuuaa gaggguaggu aggauauuua aauuuaaccu 5100

uuuugugcca cugugugaga gugggcuucu gaaaauggag gggggaagca ucucuccuug 5160

guuaguaggc auucaagugg aagauauguu auaaaaaccu aguuguaucu uauaggaugc 5220

uaaaagcaag gugacugaac uucuaacagg gcauucuaca uugaguaugu gcuuuucucu 5280

auaauuaggc uaaaaaaagg uugguaagua auaugaacuu aaaaucaaga uuaaccccca 5340

auuuacaaac ccaugauaaa aaguguuguu gauuacuugg auccuaucuu uucugcaguu 5400

uauguuucua gugacuuacu caauaguuuu uucuuacucu uucccuggac agaauaugua 5460

auauaagaaa cauaaguccu uugaguugag ggagaucaga uagauuuaau aaaagucauu 5520

uagacuuuau ugcauauucu ggaaguccaa agaagaauga cucugguugc auagcacuuc 5580

uaauaaagcc acaaaaucau uaccugacuc agugccuguu cuuguuauca uauuuuuacu 5640

uuauguuuug guauuucauu uauuuauuac guuucagcug ugagaguacc uucuacaaaa 5700

cauuuuaaac uuuuuucuau uuucauuaag uugcaguccc acuccaccca guccagccuc 5760

cuaauucuag ccuuuauaca gcuaagauug aggcaaucag uuauaaggac gccugcucau 5820

aauuaccuuc ucagaaggua auuauauuaa uacugaauuu auuuaguggu augcugucau 5880

caaaaaaauu cauuaaaaau aaaaucaaug aaggccgggc gcaguggcuc acgcuuguaa 5940

ucccuccacu uugggaggcc gaggugggug gaucaccuga ggucaagagu ucuagaccag 6000

ccuggccaac augaugaaac cccaucucua cugaaaauac aaaaaauuag cugggcgugg 6060

uggcacacac cuguaauccc agcuacucag gaggcugagg caggagaauc gcuugagccc 6120

gggaggugga gguugcagug aaccaagauc gugccacugc ccuccagccu gggcaacaag 6180

agcaaaacuc ugucuccaaa aaaaaaaaag aaacuaaaca cauuuaauaa auuucaagug 6240

cauaaauaca uuacaaaaca acauucauaa aaauaaacau ucauuaaaac aaaaaauaau 6300

uuuauuacaa aauauuacau auaaauucua auauaaauua acaaguaaca auaaaguauu 6360

uaaaaauagu gaaaccauuc acaaaaauac guaaugaaaa uuaaaauacu uuaauguuau 6420

cuuucgaaau cagguuuauc ugugguguca uuguuuaagu gcgugcgugu gugugugugu 6480

guauauauau auauauauau auauauauau auuuuuuuuu uuuuuuuuuu uuuuuuuuuu 6540

uuuuugagac agagucucac ugucacccag gcuggagugc aguggugaga ucuugguuca 6600

cuucaaccuc ugucuccggg guucaugcaa uucucaugcc ucagccucca gaguggcuga 6660

gacuacaggu gcaugccacc acgcccagcu gauuuuugua uuuuuaguag agaugggguu 6720

uugccacguu ggccaggcug gucucaagcu cccaaccucg agugauccac cuaccacgcc 6780

ucccaaguug cuaggauuac aggcaugagc caccaugccc ggccuaagug cauauauauu 6840

uuugggcaca uuuuuacaac uuuuaaaaaa agcuuuuuuu uuuuuuugag acggagucuu 6900

gcucugucgc ccaggcugga gugcaguggc gugaucucgg cucacugcaa gcucugccuc 6960

ccggguucac gccauucucc ugcgucagcc ucccaaguag cugggacuac aggugcccgc 7020

cacacgccca gcuaauuuuu uguauuuuua guagagaugg gguuucacca uguuagccag 7080

gauggucuca aucuccugac cucgugaucc gcccgccugg gccucccaaa gugcugggau 7140

uacaggcaug agccaccaca cccggccccu aaaaaaagcu uuuuugacuu aguagugccc 7200

aggagacagu ucuaagcaaa uuguaagcau uuucuucuga cuccuuuguc uucagauaau 7260

cucaccucuu guuugauaac uuauugagca acuuuguuuc uguuuuuuug cagggacauc 7320

aguuuuuuuc uugguagcaa gcuguagauu uuguuucaag gaaagcaucu ucaucuucuc 7380

uaguuucauc auguauagau ggagauuccg augcagguau cuguaucaau uucaauacag 7440

ucacauuugu guuuauuuga acucuagaac uagaaaagga auuacuuuuu ucuuugauuu 7500

ucuuuuucuu ccuucucuug aggaucauga aaguauaaaa gaauacuuuc uaaaugaggg 7560

ugccuuuuuc uuuuucuuuu uuuuuuuuuu acaauuuuua cauuuggaau uaaaauuuua 7620

acuagaaaag aguuuuuauu aagcaaguuu uuuuaaaaaa aucuuaaguu guuaauccug 7680

cucucaagau guaaguaagg uguguuucag acauuauuaa aauacugaaa uagugguauu 7740

uguaccaaaa cacuaguauc ucauuacuua ccaugauaua uaacacugua uaacugaaua 7800

guggaauacc aaaauugaaa uugcacacug caucuaaucc uguaugcauc caaguauauu 7860

cuucugugcc uguacugucu gccuuuuuca uguuuuggac aaaacuguca uccuuugugu 7920

accuccucuc uguguccacg uuccuauucu ccucccucag ugccuuuauu cucucccuuc 7980

ccauugcuuc cuuuguaucu gcuuacacau guucauaugu uucucuuauu uuggaaaaga 8040

aagaaaaagg ucauucauuu aaucuuaacu ugacuauuag uuucguuuuc uuuccuuccu 8100

uccuuccuuc cuucuuucuu uccuuuuuuu uuuuuuuuuu gacagugucu ugcucuguug 8160

cccagccugg agugcagugg gcacaaucuu ggcacacugc aaccucagcc uuccgagugg 8220

cuaggacuac aggugugcgc caccacgccu ggcuauuuuu uuuuuuugua cuuuuaguag 8280

agaugggguu ucaucauguu ugccaggcag cucuugaauu ccugaccuca gaucugucca 8340

ccucggccuc ccaaagugcu gggaugacag gcgugagcca ccaugcccag ccauauuagu 8400

uucuucaguu uuauaaacca aacuucuaac uaggggauuu gcugcuuuuu cacuuuacuu 8460

uaguauguug uuaucuggcu ucaguccuug ccuuuuccuu gaaauucuuu uuuuaauuuu 8520

aaagauaggg ucuugcucug ucgcccuggc uggaguucag uggcacaauc auagcuuacu 8580

gcagccugga acuagugggc ucaagugauc cucccaccuc agccucccaa guagcuggga 8640

cuacaggugc augccaccac accuggcuaa uuuuauuuau uuuauuuuuu uuuuuugugg 8700

agaugagguc ucacuauguu gcccaggcug gccucgaacu cuuggccuca agcaguccuc 8760

cugcaucggc cucccaaagu gcugggauua uaggcaugag ccaccacaaa uuccauuuuu 8820

ugaaagaauc uuguaaguua gcaaauugcu aaauccaggg aucuuuuuca guucucauuu 8880

gacacuguua auucucuacu guuuaagaau ccaucucagg uguaugaacu uggcagaaua 8940

augaagcccg uuugaccuca guuuuccugu auuaaaacuu aaaacagcuc cuaaguuuuu 9000

uugaguauca aaugcaacaa ugugucugaa aauaucucgc aucuaguuag uagcgcaccc 9060

caaccugacg gucugugaug cuuuaguugc ugccuggcuc gaaauaucua agauaguuuu 9120

uuuuccuauu uuuuuuccuc ccuccaccuu cuuugaauaa agacauucuc uaaggcgcau 9180

ucuuugaacu uuaucucuuu gccuuaucug uuggaaaucu caucuacuug cagagcuuua 9240

gcugauaaau uugggcugcc agcaaccaga uagaguacgu ccucacuuaa uguuauuaau 9300

agauucuugg aaauggucac uuuaagugaa augacaucaa ugaugucauu uuaauucagu 9360

guuguuucau uauaacauug augagaaaag aaaguugguu uucuuuuaca ucauuucacu 9420

uaaaguugca guuuccaaga gccuauugag gacacgaagg cugucaaccu ugaggcuaca 9480

uaccuugagg cuguccuagg cuaaacucug gugauccauu ucugauaacc ucuuucaaac 9540

cuucauuuga aaugcuuuuu aucaccccaa guggaaugua uaugaaacca aaccccuugu 9600

uuuuauuccc cuuuccgaca uaccuuuuaa gaguacuaaa uacauaauag cguuuuaaga 9660

guacuaauau uucugccaac cagaaaaccu caccaccauc uuugauuccc cccaucccgc 9720

cuaccuuuuu uuaaaggucu agugauuuuu cuuuccauug ugugcagaau uuuuuccuuc 9780

ucuuauuugu cuuaacacgg guuucaugca gcugaccucc ugauugaucc aguggcugau 9840

acuccccacu cugcccugau aauuggucac agugccuuga ugguguuuau guguuacaca 9900

aaaauaugua augacuuccc ucuugccucu gagcuugucc acaaacauaa agaauuucag 9960

gcccaguuua ucuuucucau cuugccccaa ccauucuucu gaugguuuac uucuuguucu 10020

cagaacaugc cuauauucuu ucacauuguc aguacagaaa agagguauau gcagaaaagg 10080

agugauguau uuucaaguua gccacuccau gagugacuag uacugaaucc cacugaaauc 10140

ccacugaaac uucccaggag gcuuaugaaa ugaaucuuag aaccagcuuc cauauuggua 10200

gcccuacagc uauuaacuuc ccauacuucc agguagugaa ugaguaaaua cagagcagug 10260

cuuuuugguu ggaccugccu gaagucaguc acagcuuaca agaaauugau ccuccauagc 10320

uggcauaaga uguuggguca ggaaguuuuu gaaaugguac auagcaugug ucuauaaugg 10380

ugugaaaguu aaaaauucca gaagauacag aagaauguag aaugagaagu uacgucucuu 10440

uuccuuuuuu guauucuaga aaaaguuugc caaccccugu ucuagucauu cugguuccuu 10500

uccuggaaac auucaucauu aaccuguuuc uugagacgug guguguauuu augauacuua 10560

caccauccac auguacacau acuuaguaua uacuuuuucu caacuucaaa auaucuuaau 10620

gauuuucuau auuaguguau agaacauucu uauuauucuu uuagcucuau aauauuccgu 10680

uauguggauc uaccauuuau uuaacuaguu uucuaucaau ggacauuuag uuguuuuuuu 10740

cuuucucuuu guuuugagac agggucucac ucuguugccc aggcuggagu gcagugaugu 10800

caucucugcu cacugcaacu uguaccuccu gggcucaagc gauccucuca ccucacagcc 10860

ucccaaauag cuggaaacua caggugugug ccaccacacc cagcuacuuu uguauuuuuu 10920

guagagacag ggucucacuu uguugcccag gcuggucuug aacuccuggg cucaagggcu 10980

ccacccaucu cccaaagugc ugggauuaca ggcaugagcc acugagccca gccgacauuu 11040

aguuauuuug ucucuuuauu acaaaugaua gcauuacauu uauacauauu uguaauccga 11100

aaaggucaau uccuugagug uuucugucuu gaacuuuuuu cuguaauagg ccucccauac 11160

ucauugccca caguuugcau ucaguuuuau uguagugggu caggaucauu aagagcugga 11220

guugcuggga uaggccuuuc ucaagagguu cuacuugagu uggaccuuga ggaaucugga 11280

ugaagagggg gauaacgaaa aggagguggg aagggaaaaa ggacugugug gcugaaggcu 11340

ugugguuagc aaaagccugu caugcuuucg agcugcacug cccagcacug uaaccaugag 11400

ccaugaguau guguggcugu gagcacuuga uauguggcua auccagaguu gaggugugcg 11460

gugaguaaau accuaccagg gucugaagau uuaauaugaa aaaaagaaug uuaaaauauc 11520

ucaguaguuu uaaaaauauu gcuuauaauu uaaauaguag cauuuuggau auauuggguu 11580

aaguaaaaug uuauuaaaau uuuuaccugg uuuuacuuuu aaauauaugg cuaccagaaa 11640

auguaaaauu guauuaugug gccuaccuuu guggcugcau gauuuuuugu uagacucugc 11700

ucuggcucau ccuucaggau ggagaagcag guucauuugg ggaaccuggu augugcuuca 11760

gugagaacug uuggauaguu accagaauca aguauuuggu augaaaagac cauuacguuu 11820

cuuaaaacag ugaaguaaca ugaaauuagu uucaggaaga uucaacuguu cauauuuugu 11880

ggcacuacaa aaacuaauug agcacuuacu guguacugag cacuguccua aagggcuuua 11940

uucauuuaau ccucacagca acccuuugag acauagguag cccuuauguu acagaugaac 12000

uugagucaca ggggggugua ccuauuggcc caaggucacg ccguaacuga uaaugccuug 12060

gcuaugaacu ggcagucuga uuccagagcc uauacacuua accacuacac ugugucccug 12120

ugaaggugaa uuagacaaag aagaugaucc uugcacauag cagugaagga augguaaugg 12180

aucacuuuuu aauccuguua auauuuuaau uaaaaaagau cuucuaucuu cacgguaccc 12240

cgauacuuuu cguuuuaagu ucuugucacc augauugguu guaugauuuu ggccacccag 12300

gaccagcuua guauguaaca agcuuuaugu uuauuuuucu uguguuuugu guguaggaag 12360

guuuuaagaa uauguagcau cgcuuaauga uggggaugug uucugagaaa cucauuauca 12420

ggcaauuuca uugugcagac guccuagagu guacucaaca caaaccuaga uguauaaccu 12480

gcuauacacc uaggcuaaau gguauagccu auggcuuuua ggcuacaaau cuguacagcg 12540

uguuacuaua uuaaauacug uaggcaguug uaacauuuua uauauauaaa aaaacauaga 12600

aaagguaaag uaaaaaauuu gguacuguaa ucuuauggga cuacugcugc auauucggcc 12660

caucauugau caaauuguca ucauguggug caugucugua cucuuaaagc aaauuuuauu 12720

uuaucccuac auuuuacaga ggaacagaga uuaaauaaug uggcugaagu uucauggcug 12780

ggaauuauaa aaccaugaga cuguguagcu uugaucacua uuguguuuga uuuaaaaagu 12840

aaacauuuug uguuugagcu uagagcuaag ugaucauaaa ugguguauau uuauuccuaa 12900

aauuuuucug ggauuucaga uccugaaauu uuauacaaac cuuuaaaaag cauuuucagg 12960

aggaaaaugu gucagagcca aguugaaauu ugaaaugccc uuuuuuuuuu uuuuaauaua 13020

aggauucuua auauuggaag agaaaggaag uuguuguuuu gagaaggggg cuugcuccau 13080

cacccaggcu ggagugcaau ggugccauua cagcucacug caggaagcuc guuuuuaaag 13140

gaccgucaac guagguggaa ccaaaauaau ggagagaaag caagaagccc uuaaaaugau 13200

acuugcuuaa uuaauuaaac ucaauucauu gagagccagc ugucaaggca acaaauacuu 13260

uccauuuugu uaaauuucuc caguauuuag cucagagguc uagucuuaau gguaaugccu 13320

aaauuuuucu gaucuuuacu guggaauuuu auaaucuuua uguuaugugu uaaggaauga 13380

caugcacacu aagaauuuau gauuuuauuc uuaccuguga cuagggccuu uguaauaaau 13440

cuguuuuuac gcuguccaaa auuacuaugu ucuuggguuu cuuuuucuuu aucucuuggg 13500

uuucuagaga uucauaagcu uaaaaaauua aaaauaaguu auuaggauug gaagagaccu 13560

uuggaagugg uuuaucuagc ccagggcguc ucagucuggg aacuguugac auuuuggaua 13620

uauaauucuu gguuguggaa gggcuguccu gugcauugua ggauguuuag cagcguuucu 13680

ggccucuacc cacuagaugc caguaguucc ccuuugauug uaacuaaaaa uguccgcaag 13740

cauugucaga uguccccugg gagacaaaau cgcccugguu gagaaccgcu ugucuagccc 13800

auuuccuggg aguggugguu cccuucucug gaacucagac guugagaaga gaaggguauu 13860

uaccaccucc ucuagcaguc uguuccaacu uugggugcgu cuuuggagac agaaaucucu 13920

ccucucuguu aagcuaaaac cugccaucuc uaacuuuuua guucugccuc uuaggaccgu 13980

auggauugga uagauucacu uaaaaacuuu cccaauuauu ggaacaugau accccguccu 14040

uccugguccc ucacgggauu guuuuagagc caagucagca aacuucuugu aguugccaug 14100

uauuugcagg cuaccaaucu cugaugcaua aucuuccuuu ccuucccucc cuccuccuug 14160

ccucccacca gccuucccuc cuuuucucuu ucuucuuauu ucuuguaacu ucuuaaaaau 14220

guaaaaaacc uuuuuuugcu cuuauaggcu ggguuuuggu ucaguaacuu gccaucccug 14280

guuuuagagu cugacaucug cuaaucuuca gagggcagug cagugcuuua gaacuguaua 14340

uagaacuuug gggaaggucu gagcagcaua gaauaacguu ggacuuguca uuaacuccuu 14400

caugcgaaga gcuuacugcu uuuuugaagc uuugucacau uuacagcgua augacagcca 14460

agacacuggu uugucuuuuu cauuaggcca cuuuaccuuc uuuuuuuuug agacagaguu 14520

ucacucauug cccauugugc aaugggcgca gucucagcuc acugcaaccu ccgccuccca 14580

gguugaagca auucucccgu cucagccucc caaguaacug ggauuauagg cuuccgccac 14640

caugccacuu uaccuucuaa gauauuuuua gacuucagcg uaggacgauc uguguuaaca 14700

gcuguauuaa acuugucuua gcuggaacca acucucuaua cccugcugag guuugugggu 14760

cuuacucugu ccuucagagu guuaaugaaa uuuuucuuag cuucccgucg uucaaauguu 14820

uuuuaaacau accugggucu uucaugcaag uuacuaauac aaauuugaau gagauguagc 14880

uaagaacuaa aucugaaauc acaaaugccu aacaaauaag guaauuuugg ccaagcgugg 14940

uggcucacgc cuguaaucuc agcacuuugg gaggcugagg uggguggauc acuugagguc 15000

aggaguuuga gaccagccug gccaacauga ugagaaaccc ugucuugacu aaaaauacaa 15060

aaauuagcug ggcuuggugg ugcauaccua uaaucccagc uacuugugag gcugaggcag 15120

gagaaucgcu ugaaccuggg agguggaggu ugcagugagc caagaucaca ccacugcacu 15180

ccagccugag ugacagagug agauuuuguc ucaaaaaaaa aaaaaaaaag ggaauuuuaa 15240

ugcauggaua uagcaggucu guacucuguu cuuaaaauug uuuuggagaa uuauauguaa 15300

aucugcauua uacauguuua guauccucaa ucuaaaaucc acagugcucc aaaaucugaa 15360

acuugagcac ugacauacau gaaaugcuca auggaacauu uuggauuucu ggauuagggg 15420

uacucagcua ugauauaaau auuccaaaau cuaaaaaaau ccaaaauucc aacuacuucu 15480

ggucccauac auuucaggua agggauacuc aaauuguagc aaccaucguc agagguuacc 15540

gucguuacug auggcuuuca gagugauuag acaguaaaua aguguaauga ccaugacaag 15600

aaaauuuuca aaaaaacuaa aucuuauuua cgugcaaaau aaaauaauuu ugaauaauga 15660

uuuuaagaag uaacugauuu uuuuuuucca gaaaauauuu acaccagcag cuccaguuca 15720

uaccaauaaa gaagauccug cuacccaaac uaauuuggga uuuauccaug cauuugucgc 15780

ugccauauca guuauuauug uaucugaauu gggugauaag acauuuuuua uagcagccau 15840

cauggcaaug cgcuauaacc gccugaccgu gcuggcuggu gcaaugcuug ccuugggacu 15900

aaugacaugc uugucag 15917

<210> 3

<211> 239

<212> RNA

<213> Homo sapiens

<400> 3

gaucagcauu gaggcccgca agucacccaa gcugccccgg gcugcucagg agcucucccg 60

guccccacgg uugccccugc gcaagcccuc ugugggcucg cccagccuga cucggagaga 120

guuuccuuuu gaagacauca cucagcacaa cuaucuugcu caggucacgu cuaauaucug 180

gggaaccaaa uuuaagauug ugggcuuggc ugcuuuccug ccaaccaacc ucggugcag 239

<210> 4

<211> 389

<212> RNA

<213> Homo sapiens

<400> 4

gcaauuuuua cccagaaaag caagccgggg ccugacccgu uggacacgag acgcuugcag 60

ggcuuucggc uggaggagua ucugauaggg caguccauug guaagggcug cagugcugcu 120

guguaugaag ccaccaugcc uacauugccc cagaaccugg aggugacaaa gagcaccggg 180

uugcuuccag ggagaggccc agguaccagu gcaccaggag aagggcagga gcgagcuccg 240

ggggccccug ccuuccccuu ggccaucaag augaugugga acaucucggc agguuccucc 300

agcgaagcca ucuugaacac aaugagccag gagcuggucc cagcgagccg aguggccuug 360

gcuggggagu auggagcagu cacuuacag 389

<210> 5

<211> 471

<212> RNA

<213> Homo sapiens

<400> 5

agggguguuu gaugcuuccc ucaaaauggc uggcuucuau ggauuguaua ccuggcugac 60

ucauacuaug uuuggcauca auauugucuu cauaccauca gcauuagcag caauccuugg 120

agcagugcca uuccugggga cauacugggc agcaguaccu gcaguucuug accuguggcu 180

gacacaaggg uuaggaugca aggccauuuu acuguugauu uuucaucucu ugccaacaua 240

cuuuguagau acugcaaucu acucugacau aucaggaggu ggccauccuu accugacagg 300

cuuggcagug gccgguggag cauacuaccu aggccuggaa ggagcaauca ucgguccuau 360

ucuucucugc auacuugugg uugcuuccaa uaucuauagu gccaugcuag ugagucccac 420

gaauucaguu cccacgccaa accagacccc auggccugcu cagccucagc g 471

<210> 6

<211> 359

<212> RNA

<213> Homo sapiens

<400> 6

guacuuuaau uaucggacua ccagguuccu ggcugaggag ggguuuuaua aauuccauaa 60

cugguuugau gaccgagccu gguacccuuu gggacgaauc auuggaggaa caauuuaccc 120

agguuuaaug aucaccucug cugcaaucua ccauguacuc cauuuuuucc acaucaccau 180

cgacauucgg aaugucugug uguuccuggc cccucucuuc uccuccuuca ccaccaucgu 240

cacguaccac cuuaccaaag agcucaagga ugcaggggcu gggcuucuug cugcugccau 300

gauugcugua guuccuggau auaucucccg aucuguggcu ggcuccuaug auaaugaag 359

<210> 7

<211> 146

<212> RNA

<213> Homo sapiens

<400> 7

uggcuggcgu ggcucaccga uuccacagua cuugcggcaa gaacgucacu cuagaggagg 60

auggcacgag ggcagugcgu gccgcuggcu augcucaugg ccuugucuuc aguaccaagg 120

agcugagggc ugaggaaguc uuugag 146

<210> 8

<211> 266

<212> RNA

<213> Homo sapiens

<400> 8

cuuggcuugu ggagauguug aaggaaaguu ugauauuuua uucaauagag uucaagcaau 60

ucagaagaaa aguggaaacu uugaucugcu guugugugua ggaaauuucu uuggcuccac 120

ccaagaugcu gaaugggagg aguauaagac uggcaucaag aaagcuccua uucagacaua 180

ugugcuuggu gcuaauaacc aggaaacagu aaaauauuuc caggaugcug auggauguga 240

auuagcugaa aacauuacuu aucugg 266

<210> 9

<211> 21

<212> DNA

<213> 人工序列

<400> 9

gtttgctggc tgggcttttc c 21

<210> 10

<211> 24

<212> DNA

<213> 人工序列

<400> 10

gggacctcta atagctgggg gttc 24

<210> 11

<211> 23

<212> DNA

<213> 人工序列

<400> 11

tgcttgcctt gggactaatg aca 23

<210> 12

<211> 20

<212> DNA

<213> 人工序列

<400> 12

cggcggctaa actggagtca 20

<210> 13

<211> 23

<212> DNA

<213> 人工序列

<400> 13

tttaagattg tgggcttggc tgc 23

<210> 14

<211> 17

<212> DNA

<213> 人工序列

<400> 14

gcgggcctca atgctga 17

<210> 15

<211> 20

<212> DNA

<213> 人工序列

<400> 15

gtggccttgg ctggggagta 20

<210> 16

<211> 23

<212> DNA

<213> 人工序列

<400> 16

ccggcttgct tttctgggta aaa 23

<210> 17

<211> 20

<212> DNA

<213> 人工序列

<400> 17

acgccaaacc agaccccatg 20

<210> 18

<211> 22

<212> DNA

<213> 人工序列

<400> 18

agccagccat tttgagggaa gc 22

<210> 19

<211> 24

<212> DNA

<213> 人工序列

<400> 19

tgtggctggc tcctatgata atga 24

<210> 20

<211> 25

<212> DNA

<213> 人工序列

<400> 20

atttataaaa cccctcctca gccag 25

<210> 21

<211> 24

<212> DNA

<213> 人工序列

<400> 21

ctgagggctg aggaagtctt tgag 24

<210> 22

<211> 20

<212> DNA

<213> 人工序列

<400> 22

agagtgacgt tcttgccgca 20

<210> 23

<211> 24

<212> DNA

<213> 人工序列

<400> 23

tgtggctggc tcctatgata atga 24

<210> 24

<211> 25

<212> DNA

<213> 人工序列

<400> 24

atttataaaa cccctcctca gccag 25

<210> 25

<211> 20

<212> DNA

<213> 人工序列

<400> 25

ttcttttgcg tcgccagccg 20

<210> 26

<211> 20

<212> DNA

<213> 人工序列

<400> 26

ggtgaccagg cgcccaatac 20

<210> 27

<211> 1455

<212> RNA

<213> Homo sapiens

<400> 27

ggcaccgcag gccccgggau gcuagugcgc agcgggugca ucccuguccg gaugcugcgc 60

cugcgguaga gcggccgcca uguugcaacc gggaaggaaa ugaaugggca gccguuagga 120

aagccugccg gugacuaacc cugcgcuccu gccucgaugg guggagucgc guguggcggg 180

gaagucaggu ggagcgaggc uagcuggccc gauuucuccu ccgggugaug cuuuuccuag 240

auuauucucu gauuuggucg uauugggcgc cuggucacca gggcugcuuu uaacucuggu 300

aaaguggaua uuguugccau caaugacccc uucauugacc ucaacuacau gguuuacaug 360

uuccaauaug auuccaccca uggcaaauuc cauggcaccg ucaaggcuga gaacgggaag 420

cuugucauca auggaaaucc caucaccauc uuccaggagc gagaucccuc caaaaucaag 480

uggggcgaug cuggcgcuga guacgucgug gaguccacug gcgucuucac caccauggag 540

aaggcugggg cucauuugca ggggggagcc aaaaggguca ucaucucugc ccccucugcu 600

gaugccccca uguucgucau gggugugaac caugagaagu augacaacag ccucaagauc 660

aucagcaaug ccuccugcac caccaacugc uuagcacccc uggccaaggu cauccaugac 720

aacuuuggua ucguggaagg acucaugacc acaguccaug ccaucacugc cacccagaag 780

acuguggaug gccccuccgg gaaacugugg cgugauggcc gcggggcucu ccagaacauc 840

aucccugccu cuacuggcgc ugccaaggcu gugggcaagg ucaucccuga gcugaacggg 900

aagcucacug gcauggccuu ccgugucccc acugccaacg ugucaguggu ggaccugacc 960

ugccgucuag aaaaaccugc caaauaugau gacaucaaga agguggugaa gcaggcgucg 1020

gagggccccc ucaagggcau ccugggcuac acugagcacc agguggucuc cucugacuuc 1080

aacagcgaca cccacuccuc caccuuugac gcuggggcug gcauugcccu caacgaccac 1140

uuugucaagc ucauuuccug guaugacaac gaauuuggcu acagcaacag ggugguggac 1200

cucauggccc acauggccuc caaggaguaa gaccccugga ccaccagccc cagcaagagc 1260

acaagaggaa gagagagacc cucacugcug gggagucccu gccacacuca gucccccacc 1320

acacugaauc uccccuccuc acaguugcca uguagacccc uugaagaggg gaggggccua 1380

gggagccgca ccuugucaug uaccaucaau aaaguacccu gugcucaacc aguuaaaaaa 1440

aaaaaaaaaa aaaaa 1455