JP5986572B2 - 固定化プライマーを使用した標的dnaの直接的な捕捉、増幅、および配列決定 - Google Patents
固定化プライマーを使用した標的dnaの直接的な捕捉、増幅、および配列決定 Download PDFInfo
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Description
本出願は、2010年9月24日に出願された米国仮特許出願第61/386,390号、および2011年5月11日に出願された第61/485,062号の利益を主張するものであり、それらの出願は、それらの全体が本明細書に組み込まれる。
本発明は、国立衛生研究所(National Institutes of Health)によって授与された契約第HG000205号の下、政府の支援を受けてなされた。政府は、本発明において特定の権利を有する。
多くの配列決定法、特に再配列決定法(すなわち、遺伝子座が再配列決定される方法)では、最初に標的が捕捉され、次いで配列決定される。いくつかの標的捕捉方法が開発され、ハイスループットな配列決定システムと統合されてきた。具体的には、標的DNAを捕捉するために、ビーズまたはマイクロアレイを使用したハイブリダイゼーションに基づくアッセイ、および分子反転プローブまたはゲノム環状化オリゴヌクレオチドを使用した溶液中の技法を適用することができる。次いで、捕捉されたDNAは、配列決定のために調製される。濃縮されたDNAサンプルを調製するために複雑な分子生物学プロトコルが用いられることが多く、場合によっては、配列決定用ライブラリーの生成は、多くの酵素反応、精製ステップ、およびゲル電気泳動によるサイズ選択を伴う。標的捕捉DNA配列のためのサンプル調製プロセスは、労働集約的であり得、その後のサンプル操作は、DNA含有量の偏りを引き起こし、配列決定の誤差率を増加させる可能性がある。
本明細書で特に定義されない限り、本明細書に使用される全ての技術および科学的用語は、本発明が属する技術の当業者に一般に理解されるのと同様の意味を持つ。本明細書に説明されるものと類似、または同等のあらゆる方法および材料は、本発明の実践または試験において使用され得るが、好ましい方法および材料を説明する。
主題の方法の特定の特徴を、断片の基質へのハイブリダイゼーション前にアダプターが断片にライゲートされる実施形態を例示する図1を参照して説明する。代替の実施形態において、アダプターは、プロトコルの後半に加えられてもよい。本方法は、概して、互いに空間的に散在する異なる配列の少なくとも2つの表面結合オリゴヌクレオチドを含有する基質を得ることを含む。そのような基質は、現在のところIllumina社のSolexa配列決定技術に用いられており、様々な参考文献、例えば、米国特許第7,115,400号、ならびに公開番号第US20080160580号および第US20080286795号に記載される(これらは、そのような開示のために、参照により組み込まれる)。以下に記載する実施形態のうちのいくつかは、ゲノムの断片を単離するための方法の使用について説明し得る。これらの実施形態は、他の種類の配列、例えば、cDNAまたは合成DNAに、容易に適合させることができる。
前述のように主題の方法を実践するためのキットも本開示によって提供される。特定の実施形態において、主題のキットは、a)表面結合オリゴヌクレオチドの第1の集団および表面結合オリゴヌクレオチドの第2の集団を含む基質であって、表面結合オリゴヌクレオチドの第1および第2の集団は、基質上で空間的にアドレス指定されていない、基質と、b)第1の集団の第1のメンバーとハイブリダイズする領域およびゲノム配列を含有する領域を含有する選択オリゴヌクレオチドと、を備えてもよい。またキットは、本方法において用いられてもよい前述および後述の他の試薬、例えば、アダプター、リガーゼ、ハイブリダイゼーションバッファー等を含んでもよい。
ゲノムDNAサンプル Coriell InstituteからNA18507のゲノムDNAを得た。結腸直腸癌患者から新鮮な冷凍組織サンプルを得た。Stanford Cancer Centerからインフォームドコンセントとともに患者材料を得、試験はStanford University School of Medicineの治験審査委員会(IRB)によって承認された。冷凍組織片を調製し、ヘマトキシリン・エオシン染色を行い、病理学的検査により各サンプルの腫瘍組成を決定した。細胞組成がそれぞれ90%腫瘍であるかまたは純粋に正常である領域から腫瘍組織および正常組織を代表するサンプルを切除した。E.Z.N.A SQ DNA/RNA Protein Kit(Omega Bio−Tek、Norcross,GA)を使用してゲノムDNAを抽出した。SNP6.0アレイ(Affymetrix、Santa Clara,CA)を使用してサンプルを分析するために、DNAの調製、アレイハイブリダイゼーション、および走査のための標準プロトコルを使用した。Genotyping ConsoleソフトウェアおよびBirdseed V2アルゴリズム(Affymetrix)を使用してデータ分析を行った。SNPコールの品質を評価するために、試験サンプルと合わせて13個の追加のマイクロアレイデータセットを分析した。P値の閾値0.01を用いてSNP6.0アレイデータをフィルタリングした。
さらなるオリゴヌクレオチド配列
0) オリゴヌクレオチド
OS−Seqオリゴヌクレオチド:
5’−NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNAGATCGGAAGAGCGGTTCAGCAGGAATGCCGAGACCGATCTCGTATGCCGTCTTCTGCTTG−3’(汎用捕捉オリゴヌクレオチド、N=特有の40−mer配列、配列番号37)
Ad_top_FC_capture_A_tail:
5’−CGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCT−3’(配列番号38)
Ad_bot_FC_capture_A_tail:
5’−GATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’(配列番号39)
フローセルプライマー「C」:
5’−PS−TTTTTTTTTTAATGATACGGCGACCACCGAGAUCTACAC−3’(U=2−デオキシウリジン)(配列番号40)
フローセルプライマー「D」:
5’−PS−TTTTTTTTTTCAAGCAGAAGACGGCATACGAGoxoAT−3’, (Goxo=8−オキソグアニン) (配列番号41)
配列決定プライマー1:
5’−ACACTCTTTCCCTACACGACGCTCTTCCGATCT−3’(配列番号42)
配列決定プライマー2:
5’−CGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCT−3’(配列番号43)
1) フローセルの修飾
アニール
3’ −GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN−5’(OS−Seqオリゴヌクレオチド)(配列番号44)
FC−CAAGCAGAAGACGGCATACGAGAT−3’(フローセルプライマー「D」)(配列番号45)
伸長
3’−GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN−5’(OS−Seqオリゴヌクレオチド)(配列番号46)
FC −CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN−3’(プライマー・プローブ)(配列番号47)
変性
FC −CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN−3’(プライマー・プローブ)(配列番号48)
2)ライブラリーの調製
断片化、末端修復
5’−NNNNNNNNNNNNNNNNNNNNNN−3’(ゲノムDNA)
3’−NNNNNNNNNNNNNNNNNNNNNN−5’(ゲノムDNA)
A−テーリング
5’−NNNNNNNNNNNNNNNNNNNNNNA−3’(A−テーリング後のゲノムDNA)
3’−ANNNNNNNNNNNNNNNNNNNNNN−5’(A−テーリング後のゲノムDNA)
アダプターライゲーション
OS−Seq dsアダプター
5’−GATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’ (Ad_bot_FC_capture_A_tail) (配列番号49)
3’−TCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGC−5’ (Ad_top_FC_capture_A_tail) (配列番号50)
OS−Seq dsAdライブラリー(これはOS−Seq−アダプターライブラリーの構造である, N=断片化によって定義されるランダムなゲノムDNA配列)
5’−CGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’(配列番号51)
3’−GCTCTAGATGTGAGAAAGGGATGTGCTGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGC−5’(配列番号52)
ライブラリーPCR
OS−Seqアダプターライブラリー増幅(Ad_top_FC_capture_A_tail、単一プライマーPCRを使用してアダプターライブラリーを増幅する)
5’−CGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCT−3’
(Ad_top_FC_capture_A_tail) (配列番号53)
3’−GCTCTAGATGTGAGAAAGGGATGTGCTGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGC−5’ (OS−Seqライブラリー断片)(配列番号54)
5’−CGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’ (OS−Seqライブラリー断片)(配列番号55)
3’−TCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGC−5’ (Ad_top_FC_capture_A_tail) (配列番号56)
5’−CGAGATCTACACTCTTTCCCTACACGACGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’(増幅したOS−Seqライブラリー断片) (配列番号57)
3’−GCTCTAGATGTGAGAAAGGGATGTGCTGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGC−5’(増幅したOS−Seq ライブラリー断片) (配列番号58)
3)捕捉
アニール
OS−Seqアダプターライブラリーのアニーリング(N=40−mer特異的捕捉部位)
3’− GCTCTAGATGTGAGAAAGGGATGTGCTGCGAGAAGGCTAGAgenomicdna (配列番号59)
NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGC−5’(増幅したOS−Seq ライブラリー断片) (配列番号60)
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN−3’ (プライマー・プローブ)(配列番号61)
伸長
OS−Seq捕捉
3’−GCTCTAGATGTGAGAAAGGGATGTGCTGCGAGAAGGCTAGAgenomicdna (配列番号62)
NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGC−5’(増幅したOS−Seq ライブラリー断片) (配列番号63)
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’(捕捉されたDNA) (配列番号64)
変性
OS−Seqライブラリー
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’(捕捉されたDNA) (配列番号65)
4)アダプターの完成
40Cでのハイブリダイゼーション
OS−Seq_ライブラリー(OS−SeqアダプターとOligo−Cの間には12−merの相同性が存在する)
FC −CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCG−3’ (捕捉されたDNA)(配列番号66)
3’ −CACATCTAGAGCCACCAGCGGCATAGTAA−FC (オリゴ「C」)(配列番号67)
伸長
FC −CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCGGTGGTCGCCGTATCATT−3’(完成したDNA) (配列番号68)
3’−GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGCCACCAGCGGCATAGTAA−FC (完成したDNA) (配列番号69)
変性
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCGGTGGTCGCCGTATCATT−3’(完成したDNA) (配列番号70)
3’ −GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGCCACCAGCGGCATAGTAA−FC (完成したDNA) (配列番号71)
5) クラスターの作製
アニール
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCGGTGGTCGCCGTATCATT−3’ (完成したDNA) (配列番号72)
3’−CACATCTAGAGCCACCAGCGGCATAGTAA−FC (オリゴ「C」)(配列番号73)
FC−CAAGCAGAAGACGGCATACGAGAT−3’ (配列番号74)
(オリゴ「D」)
3’−GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGCCACCAGCGGCATAGTAA−FC (完成したDNA) (配列番号75)
伸長
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCGGTGGTCGCCGTATCATT−3’ (完成したDNA) (配列番号76)
3’−GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGCCACCAGCGGCATAGTAA−FC(完成したDNA) (配列番号77)
変性
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCGGTGGTCGCCGTATCATT−3’(クラスター化されたDNA)(配列番号78)
3’−GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGCCACCAGCGGCATAGTAA−FC(クラスター化されたDNA)(配列番号79)
6)配列決定
FC−CAAGCAGAAGACGGCATACGAGATCGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCTNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaAGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGTAGATCTCGGTGGTCGCCGTATCATT−3’(クラスター化されたDNA)(配列番号80)
3’− <−−−−TCTAGCCTTCTCGCAGCACATCCCTTTCTCACA−5’(配列決定プライマー1)(配列番号81)
5’− CGGTCTCGGCATTCCTGCTGAACCGCTCTTCCGATCT−−−−> (配列決定プライマー 2) (配列番号82)
3’−GTTCGTCTTCTGCCGTATGCTCTAGCCAGAGCCGTAAGGACGACTTGGCGAGAAGGCTAGANNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNgenomicdnaTCTAGCCTTCTCGCAGCACATCCCTTTCTCACATCTAGAGCCACCAGCGGCATAGTAA−FC (クラスター化されたDNA) (配列番号83)
この項では、標的再配列決定アプローチに見られる限界の多くを解決する、オリゴヌクレオチド選択的配列決定(OS−Seq)と称される標的再配列決定のための新規アプローチについて記載する。他の方法とは概念的に異なり、OS−Seqは、ゲノム標的の捕捉と配列決定の両方がIllumina社のフローセル等の(図1a)NGS固相支持体上で行われる統合化アプローチである。OS−Seqの調製のために、ゲノムDNAから単一アダプター配列決定用ライブラリーを調製し、標的特異的オリゴヌクレオチドを合成してフローセル上のプライマー・プローブを構築するために使用する。次いで、フローセル上の固定化プライマー・プローブを使用して、単一アダプターゲノムDNAライブラリーから単一分子標的を捕捉する。
Claims (17)
- 選択された配列を捕捉および増幅する方法であって、
a)i)表面結合オリゴヌクレオチドの第1の集団およびii)表面結合オリゴヌクレオチドの第2の集団を含む叢を含む基質を得ることであって、前記表面結合オリゴヌクレオチドの第1および第2の集団のメンバーは基質の表面全体にランダムに分布され、前記基質は空間的にまたは光学的にアドレス指定された単一ヌクレオチドの集団を含まないものであることと、
b)前記表面結合オリゴヌクレオチドの第1の集団の第1のメンバーを、前記第1のメンバーとハイブリダイズする領域およびゲノム配列を含有する領域を含む合成選択オリゴヌクレオチドとハイブリダイズさせることと、
c)前記表面結合オリゴヌクレオチドの第1の集団の前記第1のメンバーを伸長させて、前記ゲノム配列に相補的な配列を含む支持体結合選択プライマーを生成することと、
d)前記支持体結合選択プライマーを、前記ゲノム配列を含む核酸断片を含む断片化されたゲノムとハイブリダイズさせることであって、前記核酸断片が5’末端にアダプターを含むものであることと、
e)前記支持体結合選択プライマーを伸長させて、ゲノム内の前記ゲノム配列に隣接する隣接配列を含有する伸長産物を生成することであって、前記伸長産物が、d)工程のアダプターに相補的な配列を3’末端に含むものであることと、
f)前記表面結合オリゴヌクレオチドの第1および第2の集団の伸長されていないメンバーを使用して、前記基質上で前記伸長産物をブリッジPCRによって増幅して、前記隣接配列を含むPCR産物を生成することであって、前記表面結合オリゴヌクレオチドの第2の集団のメンバーが、e)工程の伸長産物の3’末端のアダプターに相補的な配列とハイブリダイズし、前記隣接配列を含むPCR産物を生成すること
を含む方法。 - d)工程の前記5’末端アダプターは、前記断片化されたゲノムにライゲートされた末端に配列決定プライマーのための結合部位を含む、請求項1に記載の方法。
- 前記表面結合オリゴヌクレオチドの第2の集団は、
i.表面結合オリゴヌクレオチドの最初の第2の集団のメンバーを、前記表面結合オリゴヌクレオチドの第2の集団の前記メンバーとハイブリダイズする領域および前記核酸断片の配列に相補的な領域を含むオリゴヌクレオチドとハイブリダイズさせることと、
ii.前記表面結合オリゴヌクレオチドの最初の第2の集団の前記メンバーを伸長させて、前記表面結合オリゴヌクレオチドの第2の集団を生成することと、によって作製される、請求項1に記載の方法。 - 前記選択オリゴヌクレオチドは、前記第1のメンバーとハイブリダイズする前記領域と前記ゲノム配列を含有する前記領域との間に配列決定プライマーのための結合部位を含む、請求項1に記載の方法。
- f)工程の前記PCR産物の第1の鎖を配列決定して、前記ゲノム配列に隣接する前記配列のヌクレオチド配列の少なくとも一部を得ることをさらに含む、請求項1に記載の方法。
- f)工程の前記PCR産物の第2の鎖を配列決定して、前記ゲノム配列に隣接する前記配列のヌクレオチド配列の少なくとも一部を得ることをさらに含む、請求項1に記載の方法。
- 断片化されたゲノムを生成するために哺乳動物のゲノムを断片化することと、前記断片化されたゲノムにアダプターを付加することと、前記基質に前記断片化されたゲノムを適用することと、を含む、請求項1に記載の方法。
- 前記断片化は、物理的に、化学的に、または制限酵素を使用して行われる、請求項7に記載の方法。
- 前記断片化は、超音波処理または剪断によって行われる、請求項8に記載の方法。
- 前記ハイブリッド形成は、複数の異なる個体からの複数の断片化されたゲノムを調製することと、プールを生成するために前記複数の断片化されたゲノムをプールすることと、前記断片化されたゲノムのプールを前記基質に適用することと、前記異なる個体の前記ゲノム配列に隣接する配列を含むPCR産物を得ることと、によって行われる、請求項7に記載の方法。
- 前記PCR産物の少なくとも前記第1の鎖を配列決定して、前記異なる個体の前記ゲノム配列に隣接する前記配列のヌクレオチド配列の少なくとも一部を得ることをさらに含む、請求項10に記載の方法。
- プールすることの前に、異なるアダプターが、前記異なる個体からの前記断片化されたゲノムにライゲートされ、前記アダプターは、前記PCR産物が配列決定された後に、前記アダプターをライゲートしたゲノム断片の源が同定されることを可能にするバーコード配列を含む、請求項10に記載の方法。
- 第1のバーコード配列を含む第1のアダプターを使用して、第1の対象からの断片化されたゲノムDNAにアダプターをライゲートして、第1の産物を生成することと、
第2のバーコード配列を含む第2のアダプターを使用して、第2の対象からの断片化されたゲノムDNAにアダプターをライゲートして、第2の産物を生成することと、
前記第1および第2の産物を組み合わせて、混合鋳型を生成することと、
前記混合鋳型を使用して請求項1の方法を行って、各々が前記バーコード配列を含有する第1および第2のPCR産物を提供することと、を含む、請求項12に記載の方法。 - 前記混合された鋳型は、少なくとも1,000の対象からの断片化されたゲノムDNAを含む、請求項13に記載の方法。
- i.前記核酸断片を、配列決定プライマーのための部位および前記第2の表面結合オリゴヌクレオチドと同じヌクレオチド配列を含有するアダプターにライゲートすることと、
ii.前記アダプターをライゲートした断片を、前記表面結合オリゴヌクレオチドの第1の集団の第1のメンバーとハイブリダイズさせることと、
iii.前記アダプターをライゲートした断片がハイブリダイズされた前記表面結合オリゴヌクレオチドの第1の集団の前記第1のメンバーを伸長させることと、
iv.前記伸長産物の前記アダプターを含有する末端を、第2の支持体結合ポリヌクレオチドとハイブリダイズさせ、それによってブリッジを生成し、ブリッジPCRを促進することと、を含む、請求項1に記載の方法。 - 前記表面結合オリゴヌクレオチドの第2の集団は、前記核酸断片の配列に相補的な領域を含むオリゴヌクレオチドを表面結合オリゴヌクレオチドの最初の第2の集団にライゲートして、前記表面結合オリゴヌクレオチドの第2の集団を生成することによって作製される、請求項1に記載の方法。
- 前記核酸断片は、ゲノム断片またはcDNAである、請求項1に記載の方法。
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RU2565550C2 (ru) | 2015-10-20 |
EP2619329A4 (en) | 2014-03-05 |
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CA2810931C (en) | 2018-04-17 |
AU2011305445A1 (en) | 2013-04-04 |
IL225109A (en) | 2017-05-29 |
CN103228798A (zh) | 2013-07-31 |
CA2810931A1 (en) | 2012-03-29 |
US20150017635A1 (en) | 2015-01-15 |
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