JP5634936B2 - 組み合せたリガーゼ検出およびポリメラーゼ連鎖反応を用いる核酸配列相違の検出 - Google Patents
組み合せたリガーゼ検出およびポリメラーゼ連鎖反応を用いる核酸配列相違の検出 Download PDFInfo
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Description
本発明は、組み合せたリガーゼ検出反応(LDR)およびポリメラーゼ連鎖反応(PCR)を用いて検出配列の相違を検出することに関する。本発明の1つの実施態様は、ポリメラーゼ連鎖反応に組み合せたリガーゼ検出反応の使用である。本発明の他の実施態様は、1次ポリメラーゼ連鎖反応と組み合わせた2次ポリメラーゼ連鎖反応と組み合せたリガーゼ検出反応である。本発明の第3の実施態様は、1次ポリメラーゼ連鎖反応と組み合わせた2次ポリメラーゼ連鎖反応である。
高度に多形的な座の大規模多重解析が、父親検定および法医学(Reynolds et al., Anal. Chem., 63:2-15(1991))、臓器移植のドナーとレシピエントの組み合わせ(Buyse et al., Tissue Antigens, 41:1-14(1993) and Gyllensten et al., PCR Meth. Appl, 1:91-98(1991))、遺伝疾患の診断、予後および出産前の相談(Chamberlain et al., Nucleic Acids Res., 16:11141-11156(1988) and L. C. Tsui, Human Mutat., 1:197-203(1992))および発ガン変異(Hollstein et al., Science, 253:49-53(1991))などについて個体の実際的な同定に必要である。さらに、核酸解析による感染疾患診断の費用効率はパネル試験における多重規模で直接的に変動する。これらの適用の多くは、時に密接なスペース座の多重性において単一塩基の相違の識別力に依存している。
ミクロサテライトとして知られる縦列反復DNA配列は、ヒトゲノム中の遺伝子要素の非常に一般的で高度に多型性類を表す。小さい反復配列を含むこれらのミクロサテライトマーカーは、初期の遺伝子マッピングや連鎖解析に使用されている。Weber, J. L. et al., Am. J. Hum. Genet. 44:388-396(1989); Weissenbach, J. et al., Nature (London) 359:794-800(1992)。これらの反復体のPCR増幅によって、ヘテロ結合喪失を迅速に測定し、腫瘍抑制遺伝子マッピング方法を著しく簡素化することができる。Ruppert, J. M., et al., Cancer Res. 53:5093-94(1993); van der Riet, et al., Cancer Res. 54:1156-58(1994); Nawroz, H., et al., Cancer Res. 54:1152-55(1994); Cairns, P., et al., Cancer Res. 54: 1422-24(1994)。さらに最近、ハンチントン舞踏病、脆弱X症候群、筋緊張性ジストロフィー、脊髄小脳性運動失調I型、脊髄延髄性筋萎縮および遺伝性歯状赤色淡蒼球性萎縮(dentatorubral-pallidoluysian atrophy)を含む特定の遺伝性疾患における特異的変異を同定するために使用されている。The Huntington's Disease Collaborative Research Group Cell 72:971-83(1993); Kremer, E. J., et al., Science 252: 1711-14(1991); Imbert, G., et al., Nat. Genet. 4:72-76(1993); Orr, H.T., et al., Nat. Genet. 4:221-226(1993); Biancalana, V., et al., Hum. Mol. Genet. 1:255-258(1992); Chung, M.-Y., et al., Nat. Genet. 5:254-258(1993); Koide, R., et al., Nat. Genet. 6:9-13(1994)。これらの遺伝性疾患は、感受性遺伝子中のトリヌクレオチド反復ユニットの伸長が原因のようである。さらに広範なミクロサテライト不安定性は、腫瘍組織の反復要素の伸長および欠失から証明され、最初、結腸直腸腫瘍についてPeinado, M. A., et al. Proc. Natl. Acad. Sci. USA 89:10065-69(1992); Ionov, Y., Nature (London) 363:558-61(1993); Thibodeau, S. N., et al., Science 260:816-819(1993)また後にいくつかの他の腫瘍型について(Risinger, J.I., Cancer Res. 53:5100-03(1993); Han, H.-J., et al., Cancer Res. 53:5087-89(1993); Peltomaki, P., Cancer Res. 53:5853-55(1993); Gonzalez-Zulueta, M., et al., Cancer Res. 53: 5620-23(1993); Merlo, A., et al., Cancer Res. 54:2098-2101(1994) 報告された。遺伝性非ポリポーシス結腸直腸癌患者において、この遺伝子不安定性はミスマッチ修復遺伝子における遺伝性および体細胞性変異によるようである。Leach, F., et al., Cell 75:1215-1225(1993); Fishel, R., et al., Cell 75: 1027-38(1993); Papadopoulos, N., et al., Science 263:1625-29(1994); Bronner, C. E., et al., Nature (London) 368:258-61(1994)。
PCRはまたヒト同定、例えば父親検定、犯罪捜査および軍部の人員同定に使用されている。A. Syvanen et. al., “Identification of Individuals by Analysis of Biallelic DNA Markers, Using PCR and Solid-Phase Mini-Sequencing” Am. J. Hum. Genet. 52(1):46-59(1993) にヒト同定についてのミニ配列決定技法が記載されている。この技法は、単一PCRチューブで多くても4PCR反応が一度に行われ、個体マーカーのPCR増幅を要する。ミニ配列決定は個体の多型性を測定するのに行われる。
G. Deng, et. al., “An Improved Method of Competitive PCR for Quantitation of Gene Copy Number,” Nucl. Acids. Res. 21:4848-49(1993)は競合PCRプロセスを記述している。各遺伝子およびその等価標準について用いるプライマーの異なるセットを2PCR工程に利用する。
本発明の一つの実施態様は、複数の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法に関する。この方法は、第1ポリメラーゼ相、第2ポリメラーゼ相およびリガーゼ検出相を含む。このプロセスは、複数の配列相違がある1以上の標的ヌクレオチド配列を含有するかも知れないサンプルを分析することを含む。
本発明の第2態様は、複数の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失および転座によって相違している1以上の複数配列を同定する方法に関する。この方法はリガーゼ検出反応相に続いてポリメラーゼ連鎖反応相を有する。この方法は、複数の配列相違を有する1以上の標的ヌクレオチド配列を含有する可能性のあるサンプルを準備することを含む。
本発明の第三の実施態様は、1以上の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法に関する。この方法は、複数の配列相違がある1以上の標的ヌクレオチド配列を含有するかも知れないサンプルを2つの連続するポリメラーゼ連鎖反応相にかけることを含む。
発明の詳細な記述
I.1次PCR/2次PCR/LDRプロセス
本発明の一つの実施態様は、複数の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法に関する。この方法は、第1ポリメラーゼ相、第2ポリメラーゼ相およびリガーゼ検出相を含む。このプロセスは、複数の配列相違がある1以上の標的ヌクレオチド配列を含有するかも知れないサンプルを分析することを含む。
本発明の第2態様は、複数の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失および転座によって相違している1以上の複数配列を同定する方法に関する。この方法はリガーゼ検出反応相に続いてポリメラーゼ連鎖反応相を有する。この方法は、複数の配列相違を有する1以上の標的ヌクレオチド配列を含有する可能性のあるサンプルを準備することを含む。
本発明の第三の実施態様は、1以上の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法に関する。この方法は、複数の配列相違がある1以上の標的ヌクレオチド配列を含有するかも知れないサンプルを2つの連続するポリメラーゼ連鎖反応相にかけることを含む。
図23は、ミクロサテライト反復体における挿入および欠失によるヘテロ接合性の喪失を検出するために、本発明による1次PCR/2次PCRプロセスを表す模式図である。第1工程の1次PCR相は、94℃でのサンプルDNAの変性から始められる。ユニークDNA周ミクロサテライト反復変異に相補的な3’末および2次PCR相で使用される2プライマーの1つに同じ配列を含有する5’末を有する長いPCRオリゴヌクレオチドプライマーは、65℃で標的DNAにアニールする。1次PCR相を10−15サイクル実施する。1次PCR相で使用された長いプライマーは、重複長の範囲を有する対立遺伝子を増幅しない限り、多重化され得る。これらの反応は腫瘍または対応正常DNA上で実施されて、情報的(すなわち、ヘテロ接合)部座が同定されねばならない。第2工程(すなわち2次PCR増幅)において、1次PCRプライマー(1つは蛍光標識されている)の5’末に相補的なプライマーが用いられて、ほぼ等しい効率で1次PCR伸長産物を増幅する。2次PCR伸長産物は分離され、ゲル電気泳動およびジーンスキャン672ソフトウェア−パッケージを用いた373A DNA(Applied Biosystems, Inc.)で解析される。情報部位でのヘテロ接合の喪失領域が同定される。図23の解析は、RBIおよびNM23を含有する両対立遺伝子(すなわち、染色体)およびp53についてのヘテロ接合の喪失(すなわち、1つの染色体上の対立遺伝子の喪失)を示す。
リガーゼ検出反応は、Barany et al.によるWO90/17239、 F. Barany et al., “Cloning, Overexpression and Nucleotide Sequence of a Thermostable DNA Ligase-encoding Gene,” Gene, 109:1-11(1991),および F.Barany, “Genetic Disease Detection and DNA Amplification Using Cloned Thermostable Ligase,” Proc. Natl. Acad. Sci. USA, 88:189-193(1991)(出典明示により本明細書の一部とする)に一般的に記載されている。本発明において、リガーゼ検出反応で2セットの相補的オリゴヌクレオチドが用いられる。これはリガーゼ鎖反応として知られるもので上記3引用に記載されている。他方、リガーゼ検出反応には、オリゴヌクレオチド連結反応検出法として知られる単一サイクル法もある。参照、Landegren, et al., “A Ligase-Mediated Gene Detection Technique,” Science 241:1077-80(1988); Landegren, et al., “DNA Diagnostics -- Molecular Techniques and Automation,” Science 242:229-37(1988); およびLandegren et al. による米国特許第4,988,617号(出典明示により本発明の一部とする)。
実施例1―ゲノムDNAの調製
ゲノムDNAを男女2人の健常者ボランティアの血液から標準技術に従って調製した。簡単に説明すると、EDTAを含有する集血管で約12mlの血液を採取した。そのサンプル血を4容量の溶解緩衝液(10mM Tris pH8.0、10mM EDTA)に混合して赤血球を溶解した。10分間氷上でときどき攪拌した後、懸濁物を遠心分離し上澄み液をデカントした。白血球ペレットを20mlの溶解緩衝液に再懸濁させ、上記のプロセスを繰り返した。その後、各ペレットを15mlの消化緩衝液(50 mM Tris pH 8.0、5 mM EDTA、100 mM NaCl、1% SDS)に懸濁し、それに3mg(0.2 mg/ml)のプロテイナーゼKを加えた。細胞を37℃で5時間消化した。消化産物を等量のフェノールで2度抽出し、それから等量の1:1フェノール:クロロホルム混合液で1度抽出し、最後に等量のクロロホルムで抽出した。抽出をするごとに混合液を遠心分離し、次の抽出に使用するために水相を除去した。最後の抽出の後に、水相を除去してから1/10量の3M酢酸ナトリウム、pH 6.5を加えた。次いで2倍量の氷温100% EtOHをそれぞれの溶液に加えてゲノムDNAを沈澱させ、溶液からガラスピペットにスプールした。そのDNA沈澱物を0.75ml量の70% EtOH中で2度洗った。つまり、2度とも手短かに遠心分離して上澄み液を除去できるようにした。2度目に上澄み液を除去した後、残存するEtOHを蒸発させてDNAを0.5mlのTE(10mM Tri-HCl pH 8.0、1mM EDT含有)溶液中に懸濁した。各DNA溶液の1/5希釈物もまたTE中で調製した。
すべてのオリゴヌクレオチドは394A DNAシンセサイザー(Applied Biosystems Division of Perkin−Elmer Corp,Forter City,Ca.)で合成した。6−FAM標識のオリゴヌクレオチドは、合成サイクルに製造業者の指示する修飾(Applied Biosystems Inc.,1994)を使用して、合成し、55℃で4時間経過して脱保護した。LDRオリゴヌクレオチドは、55℃で一晩脱保護した後、エタノール沈澱で精製した。PCR増幅に使用するオリゴヌクレオチドのプライマー特異的部分は10%Aアクリルアミド/7M尿素ゲル上のポリアクリルアミドゲル電気泳動によって精製した。オリゴヌクレオチドは電気泳動の後に照明スクリーン上で紫外線遮蔽法で視覚化し、ゲル(Applied Biosystems Inc.,1192)から削除した。次いでそれらオリゴヌクレオチドはTNE(すなわち、TrisナトリウムEDTA)緩衝液(100mM Tris/HCl、pH8.0、500mM NaClおよび5mM EDTA含有)の中で64℃で一晩溶離し、業者の指示に従ってSep Pakカートリッジ(Millipore Corp.,Milford,MA.)を使用して溶解液から回収した。
LDRプローブの濃度を表1に示す。リガーゼ検出反応のオリゴヌクレオチドプローブに相補的なオリゴヌクレオチドの濃度は他と比較して高かった。上記の公式で算出すると、ZipALg1Fは3.75μg/μl、ZipBLg2Rは2.01μg/μl、すなわち、それぞれ524pm/μlおよび281pm/μlであった。
非キナーゼプローブを次の方法で製造した。
A.LDR緩衝液および試薬:次のLDR緩衝液および試薬を選択した。
10X STリガーゼ緩衝液(0.2M Tris pH 8.5、0.1M MgCl2) [これはまたTris pH 7.6 でもって試験した。]
10X TTリガーゼ緩衝液(0.2M Tris pH 7.6、0.5M KCL、0.1M MgCl2、5mM EDTA)
NAD(10mM)
DTT(200mM)
各LDRプライマー混合液の1/10の濃度を含むLDRプライマー溶液(1μlにつき各LDRプライマー50fm)
Tth DNAリガーゼ(625U/μl)
B.PCR緩衝液および試薬:次のPCR緩衝液および試薬を選択した。
10X Stoffel 緩衝液(0,1M KCl、0.1M Tris-HCl pH 8.3、Perkin Elemer)
dNTP 溶液(総量100Mm、各dNTP 25mM、Perkin Elmer)。この溶液をdHOH 中で5倍に希釈して、各dNTP 5mM の最終濃度にした。
ZipALg1F(10pm/μl)
ZipBLg2R(10pm/μl)
各DNAについて、4つのLDR/PCRプロセスを実施して、22、24、26、30サイクルに増幅したPCR増幅反応管で試験し1つの反応が指数増殖期において停止するかどうかを確認した。各LDR反応(20μl)は熱循環であり、次いでLDRプローブのプライマー特異的部分に相補的な部分を有するプライマーを含むPCR混合物(30μl)を各標本に加えて指数増幅した。反応管のあいだの差異を最小にするために、LDRおよびPCR試薬の原混合液を作成した。
LDR反応の完結でそれぞれの管を94℃で維持し、一方で30mlのPCR試混合液(Stoffelフラグメントを含む)をそれらの管に加えた。PCR増幅を94℃で15秒、次いで60℃で50秒間の熱循環により実施した。それぞれ22、24、26、30サイクルで、それら4つの各DNA標本の同一反応管の1つを取りだしドライアイスおよびETOHのスラリー中でクエンチした。
26および30サイクル反応標本10マイクロリッターアリコートを2%アガロースゲル上で検定した。臭化エチジウムによる染色で予想したサイズ(104bp)のバンドが現れた。
遺伝子特異的LDR/PCR産物を分離するために、10μlアリコートの22、24、26サイクル反応物を各5UのHaeIIIおよびHinP1I制限酵素(共にNew England BioLabs製)、2μlの10X制限酵素緩衝液No2(New England BioLabs製)、および8μlのdHOH(すなわち、蒸留水)を含有する10μlの溶液を加えて消化した。消化物を37℃で1時間インキュベートし、次いで1μlの0.5M EDTA(pH 8.0)を加えて消化を停止した。制限消化物は元のLDT/PCR産物の1/2希釈で得た。5μlの各制限消化物を20μlのTE緩衝液に加えて各サンプルの1/10希釈液調製した。
サンプルを可視距離12cm、厚味0.4mmの10%ポリアクリルアミド/7M尿素ゲル上で、Applied Biosystems 373A DNAシーケンサーの中で分析した。ゲルマトリックスを1.2xTBE(106mM Tris-ホウ酸塩、2.4mM EDTA、pH 8.3)および、0.6×TBE(53.4mM Tris-ホウ酸塩、1.2mM EDTA、pH 8.3)を含む電気泳動チェンバー緩衝液とで処理した。ゲルを電極逆方向性(ゲルの頂上にあるサンプルウエルを有するチェンバーの陽極)でもって、サンプル装填に先立って1600ボルトで30分間試運転した。装填の後、遺伝子特異的LDR/PCR産物を1200ボルトで電気泳動し、ABI762 Data Collection Software、V1.1(Applied Biosystems)を使用して第一次のデータを得た。
実施例7−オリゴヌクレオチド合成法
オリゴヌクレオチドを標準ホスホラミジト化学によってExpedite DNAシンセサイザー(Perspective Biosystems, Framingham,MA)の上に集めた。6−FAM、TET、HEXによる5’−末標識のオリゴヌクレオチドを適切なダイ・ホスホルアミジド(Perkin Elmer-Applied Biosystems)を使用して合成し、製造業者のプロトコル(Applied Biosystems Division-Perkin Elmer Crop.,「ダイ・ホスホルアミジドを使用した蛍光標識オリゴヌクレオチドの合成と精製」“User Bulletin、第78号、Applied Biosystems Division, Foster City,Ca,(1994)(出典明示により本明細書の一部とする))に従って、オリゴヌクレオチド精製カートリッジ(Perkin Elmer-Applied Biosystems)で精製した。すべてのオリゴヌクレオチドを、mPAGE−3カラム(J&W Scientific, Folsom,CA)を使用してApplied Biosystems 270−HTの毛管電気泳動器で精製度をチェックした。精製度95%以上のオリゴヌクレオチドだけを実験に使用した。オリゴヌクレオチドを250ml TE(10mM Tris/HClおよび5mM EDTA、pH 8.0)中に再懸濁した。典型的濃度は未精製貯蔵溶液で300〜500mMであり、OPC(すなわち、Oligonucleotide Purification Columns, Applied Biosystems市販)について100−200mMである。PCRおよびLDRについては、オリゴヌクレオチドを希釈して、10mM(10 pmoles/ml)または5mM(5pmoles/ml)を使用溶液とした。
12LDR共通オリゴヌクレオチドを5’末で蛍光標識オリゴヌクレオチドとに連結反応できるようにリン酸化した。そのオリゴヌクレオチドを下記の表に示す。
2 M.Armstrong, et al., “A Polymorphic Cfo I Site In Exon 6 of the Human Cytochrome P450 CYPD6 Gene Detected by the Polymerase Chain Reaction, ”Human Genetics 91:616-17 (1993), which is hereby incorporated by reference.
3 S.C. Bock, et al., ”Antithrombin III Utah: Proline-407 to Leucine Mutation in a Highly Conserved Region Near the Inhibitor Reactive Site, ”Biochemistry 28:3628(1991), which is hereby incorporated by reference.
4 G. Dewald, et al., ”Polymorphism of Human Complement Component C6: An Amino Acid Substitution(glu/ala)Within the Second Thrombospondin Repeat Differentiates Between the Two Common Allotypes C6 A and C6 B, ”Biochem, Biophys. Res. Commun.194:458-64(1993), which is hereby incorporated by reference.
5 P.A. Velden, et al., ”Amino Acid Dimorphism in IL1A is Detectable by PCR Amplification,” Hum. Mol. Genet. 2:1753(1993), which is hereby incorporated by reference.
6 R.M. Cawthon, et al., ”Identification and Characterization of Transcripts From Theneurofibromatosis 1 Region: The Sequence and Genomic Structure of EV12 and Mapping of Other Transcripts,” Genomics 7:555-65(1990), which is hereby incorporated by reference.
7 C.C. Brooks, et al.,” Association of the Widespread A149P Hereditary Fructose Intolerance Mutation With Newly Identified Sequence Polymprphisms in the Aldolase B Gene,” Am. J. Human Genetics 52:835-40(1993),which is hereby incorporated by reference.
8 W, Poller , et al., ”Sequence Polymorphism in the Human Alpha-2- Macroglobulin (A2M) Gene, ”Nucleic Acid Res. 19:198(1991), which is hereby incorporated by reference.
9 T. Gloudemans, “ An Ava IIRestriction Fragment Length Polymorphism in the Insulin-Like Growth Factor IIGene and the Occurrence of Smooth Muscle Tumors, ”Cancer Res.53:5754-58(1993) , which is hereby incorporated by reference.
10 C.M Diepstraten, et al., ”A CCA/CCG Neutral Dimorphism in the Codon for Pro 626 of the Human Protein S Gene Pa(PROS1),” Nucleic Acids Res. 19:5091(1991), which is hereby incorporated by reference.
11 M. Reina, et al., ”SSCP Polymorphism in the Human Hepatic Triglyceride Lipase(LIPC)Gene,”Hum.Mol.Genet.1:453(1992), which is hereby incorporated by reference.
12 S. Matuura, et al., “Investigation of the Polymorphic AvaII Site by a PCR-based Assay at the Human CD18 Gene Locus ,”Human Genetics 93:721(1994), which is hereby incorporated by reference.
13 L. Warnich, et al., ”Detection of a Frequent Polymorphism in Exon 10 of the Low-Density Lipoprotein Receptor Gene,” Human Genetics 89:362(1992), which is hereby incorporated by reference.
それぞれの領域はよく特徴が出ており、2つの公知の対立遺伝子だけが単塩基変異として表れている。PCR増幅は全血から製造業者の掲示に従ってパージーンDNA単離キット(Gentra Systems, Inc., Minneapolis, MI)で分離したゲノムDNAを使用して実施した。
表11 1次PCRプライマー配列
一次PCRプロセスを次の條件で実行した。
96℃15''
94℃15''、65℃1’x15
65℃ Hold(維持)
二次PCRプロセスを次の條件で実行した。
94℃15''、55℃ 1’×25
4℃ Hold(維持)
標識PCR産物がリガーゼ産物の配列の検出を妨げるのを避けるために、PCR産物をLDRの標識として使用する非標識PCRのユニバーサルプライマーを使って、PCR産物を増幅した。PCR内のポリメラーゼを解凍法によるか、あるいはEDTA/プロテイナーゼKを加えて、それぞれ5mMおよび100mg/mlの最終濃度にし、37℃で30分間、さらに95℃10分間加熱することによって不活性化した。
プロテイナーゼK消化を次の條件で行った:
95℃で10分間、プロテイナーゼK加熱停止
LDRプロセスを次のとおり実行した。
0.5μlの625u/ml +3.2μl 10X緩衝液 +27.5μl H2O
LDRサイクリングの條件は次のとおり:
94℃ 2’
94℃ 30'', 65℃×20
4℃ Hold(維持)
Claims (31)
- 1以上の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法であって、下記工程:
1以上の単一塩基の変更、挿入、欠失、または転座により相違している2以上の標的ヌクレオチド配列を潜在的に含有するサンプルを準備する工程;
1以上の1次オリゴヌクレオチドプライマーセットを準備する工程、
ここで各セットは、(a)標的特異的部分および5’上流の2次プライマー特異的部分を有する第1のオリゴヌクレオチドプライマー、ならびに(b)標的特異的部分および5’上流の2次プライマー特異的部分を有する第2のオリゴヌクレオチドプライマーを特徴とする;
該サンプル、該1次オリゴヌクレオチドプライマーおよびポリメラーゼを含む1次ポリメラーゼ連鎖反応混合物を、2以上のポリメラーゼ連鎖反応サイクルに供して、1以上の単一塩基の変更、挿入、欠失、または転座により相違している2以上の標的ヌクレオチド配列の1次伸張産物を形成させる工程;
1または複数の2次オリゴヌクレオチドプライマーセットを提供する工程、
ここで各セットは、(a)第1の1次オリゴヌクレオチドプライマーの5’上流部分と同じ配列を含有する第1の2次プライマー、ならびに(b)第1の2次プライマーにより含まれる第1の1次オリゴヌクレオチドプライマーと同じ1次オリゴヌクレオチドプライマーセットからの第2の1次オリゴヌクレオチドプライマーの5’上流部分と同じ配列を含有する第2の2次プライマーを特徴とする;および、
該1次伸張産物、該2次オリゴヌクレオチドプライマーおよび該ポリメラーゼを含む2次ポリメラーゼ連鎖反応混合物を、2以上のポリメラーゼ連鎖反応サイクルに供して、該1次伸張産物の各々に相補的な2次伸張産物を形成させる工程;
を含む方法。 - 2次伸張産物を配列決定することをさらに含む、請求項1の方法。
- 2次伸張産物に標識を連結させること、および該2次伸張産物に連結した該標識を検出することをさらに含む、請求項1の方法。
- 検出が、1以上の単一塩基の変更、挿入、欠失または転座により相違しているサンプル中の複数の標的ヌクレオチド配列の2以上を区別することを含む、請求項3の方法。
- 検出が、2次伸張産物を配列決定することを含む、請求項3の方法。
- 2次伸張産物が固体支持物上に固定される、請求項1の方法。
- 1以上の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法であって、下記工程:
1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の標的ヌクレオチド配列の2以上を潜在的に含有するサンプルを準備する工程;
ポリメラーゼ反応混合物において1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の標的ヌクレオチド配列の2以上の各々に相補的な1次伸張産物を形成させる工程、
ここで、該ポリメラーゼ反応混合物は、1以上の1次オリゴヌクレオチドプライマーセットを含み、各オリゴヌクレオチドプライマーセットは、5’2次プライマー特異的部分を含む第1の1次オリゴヌクレオチドプライマー、および5’2次プライマー特異的部分を含む第2の1次オリゴヌクレオチドプライマーを特徴とする、および
該1次伸張産物の各々は、5’2次プライマー特異的部分、標的特異的部分、および3’2次プライマー特異的部分を含んでおり、該5’2次プライマー特異的部分の配列は、該3’2次プライマー特異的部分の配列と異なる;および
2次ポリメラーゼ反応混合物において該1次伸張産物の各々と相補的である2次伸張産物を形成させる工程、
ここで、該2次ポリメラーゼ反応混合物は、1以上の2次オリゴヌクレオチドプライマーセットを含み、各オリゴヌクレオチドプライマーセットは、第1および第2の2次オリゴヌクレオチドプライマーを特徴とし、第1および第2の2次オリゴヌクレオチドプライマーの各々は、1次オリゴヌクレオチドプライマーセットから形成される1次伸張産物の3’2次プライマー特異的部分にハイブリダイズすることができる;
を含む、方法。 - 2次伸張産物を配列決定することをさらに含む、請求項7の方法。
- 2次伸張産物各々が、上流プライマー部分、標的特異的部分、および下流標的特異的部分を含む、請求項7の方法。
- 2次伸張産物に標識を連結させること、および
該2次伸張産物に連結した該標識を検出することをさらに含む、請求項7の方法。 - 検出が、1以上の単一塩基の変更、挿入、欠失または転座により相違しているサンプル中の複数の標的ヌクレオチド配列の2以上を区別することを含む、請求項10の方法。
- 検出が、2次伸張産物を配列決定することを含む、請求項10の方法。
- 1次伸張産物が、さらなる部分を含む、請求項7の方法。
- 一つの1次伸張産物のさらなる部分が、異なる1次伸張産物のさらなる部分と相違する、請求項13の方法。
- 2次伸張産物が固体支持物上に固定される、請求項7の方法。
- 1以上の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法であって、下記工程:
1以上の標的ヌクレオチド配列を潜在的に含有するサンプルを準備する工程;
ポリメラーゼ反応を含む反応プロセスにおいて、1次産物を形成させる工程、
ここで、各1次産物は、5’プライマー特異的部分、標的ヌクレオチド配列特異的部分、および3’プライマー特異的部分を含み、ここで、該5’プライマー特異的部分と該3’プライマー特異的部分とは互いに異なり、かつ該標的特異的部分と同一または相補的ではない;
1以上のオリゴヌクレオチドプライマーセットを準備する工程、
ここで、各オリゴヌクレオチドプライマーセットは、第1および第2のオリゴヌクレオチドプライマーを特徴とし、ここで、第1のオリゴヌクレオチドプライマーは、1次産物の3’プライマー特異的部分にハイブリダイズすることができ、第2のオリゴヌクレオチドプライマーは、1次産物の相補鎖の3’プライマー特異的部分にハイブリダイズすることができる;および
1以上のオリゴヌクレオチドプライマーセットを含むポリメラーゼ反応混合物において、2次産物を形成させる工程、
ここで、該2次産物は、形成された1次産物またはその相補鎖の各々と相補的である;
を含む、方法。 - 2次産物を配列決定することをさらに含む、請求項16の方法。
- 2次産物に標識を連結させること、およびポリメラーゼ反応混合物中に形成された2次産物に連結した該標識を検出することをさらに含む、請求項16の方法。
- 検出に基づき、1以上の単一塩基の変更、挿入、欠失または転座により相違しているサンプル中の2以上の標的ヌクレオチド配列を区別することをさらに含む、請求項18の方法。
- 検出に基づき、2次産物を配列決定することを含む、請求項18の方法。
- 1次産物が、さらなる部分を含む、請求項16の方法。
- 一つの1次産物のさらなる部分が、異なる1次産物のさらなる部分と相違する、請求項21の方法。
- 2次産物が固体支持物上に固定される、請求項16の方法。
- 1以上の標的ヌクレオチド配列における1以上の単一塩基の変更、挿入、欠失または転座により相違している複数の配列の2以上を同定するための方法であって、下記工程:
1以上の標的ヌクレオチド配列およびその相補鎖を潜在的に含有するサンプルを準備する工程;
ポリメラーゼ反応を含む反応プロセスにおいて、サンプル中の1以上の標的ヌクレオチド配列およびその相補鎖に、互いに異なる5’プライマー特異的部分および3’プライマー特異的部分を付加し、1以上のプライマー標識標的ヌクレオチド配列およびその相補鎖を形成させる工程;および
1以上のオリゴヌクレオチドプライマーセットを含むポリメラーゼ反応混合物において、1以上のプライマー標識標的ヌクレオチド配列およびその相補鎖に相補的な伸張産物を形成させる工程、
ここで、各オリゴヌクレオチドプライマーセットは、第1および第2のオリゴヌクレオチドプライマーを特徴とし、ここで、第1のオリゴヌクレオチドプライマーは、プライマー標識標的ヌクレオチド配列の3’プライマー特異的部分にハイブリダイズすることができ、第2のオリゴヌクレオチドプライマーは、プライマー標識標的ヌクレオチド配列の相補鎖の3’プライマー特異的部分にハイブリダイズすることができる;
を含む、方法。 - 伸張産物を配列決定することをさらに含む、請求項24の方法。
- 伸張産物に標識を連結させること、およびポリメラーゼ反応混合物中に形成された伸張産物に連結した該標識を検出することをさらに含む、請求項24の方法。
- 検出に基づき、1以上の単一塩基の変更、挿入、欠失または転座により相違しているサンプル中の2以上の標的ヌクレオチド配列を区別することをさらに含む、請求項26の方法。
- 検出に基づき、伸張産物を配列決定することを含む、請求項26の方法。
- プライマー標識標的ヌクレオチド配列およびその相補鎖が、さらなる部分を含む、請求項24の方法。
- 一つのプライマー標識標的ヌクレオチド配列またはその相補鎖のさらなる部分が、異なるプライマー標識標的ヌクレオチド配列またはその相補鎖のさらなる部分と相違する、請求項29の方法。
- 伸張産物が固体支持物上に固定される、請求項24の方法。
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