JP6769969B2 - 核酸配列決定ライブラリーを作製するためのプロセス及びシステム、並びにこれらを使用して作製したライブラリー - Google Patents
核酸配列決定ライブラリーを作製するためのプロセス及びシステム、並びにこれらを使用して作製したライブラリー Download PDFInfo
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Description
本出願は、米国特許仮出願番号第62/102,420号(2015年1月12日出願)、及び米国特許仮出願番号第62/262,769号(2015年12月3日)の利益を主張し、前記出願は、それら全体があらゆる目的のために本明細書に参考として組み込まれる。
参照文献の援用
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
(a)鋳型核酸配列、dNTP、dUTP、プライマー、ポリメラーゼ、dUTP除去酵素、及び、オリゴヌクレオチドアダプター配列セグメントを含む複数のビーズを提供する工程と、
(b)前記鋳型核酸を、前記ポリメラーゼ、dNTP、dUTP及びランダム六量体で増幅して、場合によりdUTPを含む相補性核酸配列を提供する工程と、
(c)前記組み込まれたdUTPを、dUTP除去酵素で除去し、前記相補性核酸配列内にニックをもたらして配列決定ライブラリーを提供する工程と、
を含む、配列決定ライブラリーの作製方法。
(項目2)
前記ニックを有する相補性核酸配列を増幅する工程(d)と、核酸伸長法を用いて、前記増幅核酸配列の前記配列を伸長する工程(e)と、を更に含む、項目1に記載の方法。
(項目3)
前記工程は単一の反応で実施する、項目1または2に記載の方法。
(項目4)
前記複数のビーズはプールされたビーズの母集団である、項目1、2、または3に記載の方法。
(項目5)
前記プールされたビーズの母集団の前記ビーズが、工程(a)に記載した前記構成成分の1つ以上と共に分画され、前記分画が所望により、エマルション中に液滴を含む、項目1〜4のいずれかに記載の方法。
(項目6)
前記ビーズは、化学分解可能なビーズ、光分解可能なビーズ、及び熱分解可能なビーズから選択される分解可能なビーズを含む、項目1〜5のいずれかに記載の方法。
(項目7)
前記ビーズは化学還元可能な架橋剤を含む、項目1〜6のいずれかに記載の方法。
(項目8)
前記化学還元可能な架橋剤はジスルフィド結合を含む、項目7に記載の方法。
(項目9)
工程(b)での前記増幅は等温である、項目1〜8のいずれかに記載の方法。
(項目10)
前記ポリメラーゼはphi29 DNAポリメラーゼである、項目1〜9のいずれかに記載の方法。
(項目11)
前記核酸伸長法は、ライゲーション酵素、核酸伸長酵素及びトランスポーゼースからなる群から選択される、項目2に記載の方法。
(項目12)
前記増幅核酸配列のライブラリーは一本鎖DNAを含み、前記ライゲーション酵素はATP非依存性酵素を含む、項目11に記載の方法。
(項目13)
前記ATP非依存性酵素は熱安定性5’App DNA/RNAリガーゼを含む、項目12に記載の方法。
(項目14)
前記ライゲーション酵素はトポイソメラーゼを含む、項目11に記載の方法。
(項目15)
前記トポイソメラーゼはトポイソメラーゼIである、項目14に記載の方法。
(項目16)
前記ライゲーション酵素はT4 DNAリガーゼを含む、項目11に記載の方法。
(項目17)
(a)鋳型核酸、dNTP、dUTP、プライマー、ポリメラーゼ、dUTP除去酵素、核酸伸長法、及び、オリゴヌクレオチドバーコード配列セグメントを含む複数のビーズを提供することと、
(b)前記鋳型核酸を、前記ポリメラーゼ、dNTP、dUTP及びランダム六量体で増幅して、場合によりdUTPを含む相補性核酸配列を提供する工程と、
(c)前記組み込んだdUTPをdUTP除去酵素で除去し、前記相補性核酸配列内にニックを提供することと、
(d)前記ニックを有する相補性核酸配列を増幅して、増幅核酸配列のライブラリーを提供することと、
(e)前記バーコード配列セグメントを前記プールされたビーズの母集団から分離することと、
(f)前記バーコード配列セグメント及び核酸伸長法を使用して前記増幅核酸配列の配列を伸長し、バーコードライブラリーを提供するか、あるいは、核酸ライゲーション酵素を使用して、前記バーコード配列セグメントを増幅核酸配列のライブラリーにライゲーションし、バーコードライブラリーを提供することと、
を含む、バーコード配列決定ライブラリーの作製方法。
(項目18)
前記工程は単一の反応で実施する、項目17に記載の方法。
(項目19)
前記複数のビーズはプールされたビーズの母集団である、項目17または18に記載の方法。
(項目20)
前記プールされたビーズの母集団の前記ビーズが、工程(a)に記載した前記構成成分の1つ以上と共に分画され、前記分画が所望により、エマルション中に液滴を含む、項目17〜19のいずれかに記載の方法。
(項目21)
前記ビーズは、化学分解可能なビーズ、光分解可能なビーズ、及び熱分解可能なビーズから選択される分解可能なビーズを含む、項目17〜20のいずれか一項に記載の方法。
(項目22)
前記ビーズは化学還元可能な架橋剤を含む、項目17〜21のいずれか一項に記載の方法。
(項目23)
前記化学還元可能な架橋剤はジスルフィド結合を含む、項目22に記載の方法。
(項目24)
工程(b)での前記増幅は等温である、項目17〜23のいずれか一項に記載の方法。
(項目25)
前記ポリメラーゼはphi29 DNAポリメラーゼである、項目17〜24のいずれか一項に記載の方法。
(項目26)
前記核酸伸長法は、ライゲーション酵素、核酸伸長酵素及びトランスポーゼースからなる群から選択される、項目17〜25のいずれか一項に記載の方法。
(項目27)
前記増幅核酸配列のライブラリーは一本鎖DNAを含み、前記ライゲーション酵素はATP非依存性酵素を含む、項目26に記載の方法。
(項目28)
前記ATP非依存性酵素は熱安定性5’App DNA/RNAリガーゼを含む、項目27に記載の方法。
(項目29)
前記ライゲーション酵素はトポイソメラーゼを含む、項目26に記載の方法。
(項目30)
前記トポイソメラーゼはトポイソメラーゼIである、項目29に記載の方法。
(項目31)
前記ライゲーション酵素はT4 DNAリガーゼを含む、項目26に記載の方法。
(項目32)
前記バーコード配列セグメントは、少なくとも4個のヌクレオチド、少なくとも10個のヌクレオチド、または少なくとも20個のヌクレオチドを含む、項目17〜31のいずれか一項に記載の方法。
(項目33)
前記バーコード配列セグメントは、少なくとも1000個の異なるバーコード配列セグメントを含む、項目17〜32のいずれか一項に記載の方法。
(項目34)
少なくとも1,000,000個のオリゴヌクレオチド分子が各ビーズに結合している、項目17〜33のいずれか一項に記載の方法。
(項目35)
前記プールされたビーズの母集団は少なくとも10個の異なるビーズの母集団を含む、項目19〜34のいずれか一項に記載の方法。
(項目36)
前記プールされたビーズの母集団は少なくとも100個の異なるビーズの母集団を含む、項目19〜35のいずれか一項に記載の方法。
(項目37)
前記プールされたビーズの母集団は少なくとも500個の異なるビーズの母集団を含む、項目19〜36のいずれか一項に記載の方法。
(項目38)
前記オリゴヌクレオチドバーコード配列セグメントは少なくとも1個の機能性配列を含む、項目17〜37のいずれか一項に記載の方法。
(項目39)
前記機能性配列は、アダプター、プライマー配列、プライマーアニーリング配列、付着配列、及び配列決定プライマー配列から選択される、項目38に記載の方法。
(項目40)
前記機能性配列は封鎖され、加熱及び化学的切断からなる一覧から選択される刺激を含む分離工程において分離可能である、項目38または39に記載の方法。
(項目41)
前記分離工程は、オリゴヌクレオチドバーコード配列セグメントを含む前記ビーズの母集団の前記ビーズの少なくとも一部を分解することを含む、項目40に記載の方法。
(項目42)
前記ビーズを分解することは、前記バーコード配列セグメントと前記ビーズとの間のジスルフィド架橋結合を含む化学結合を切断することを含み、前記分離工程は、前記ビーズを還元剤にさらすことを含む、項目41に記載の方法。
(項目43)
前記還元剤は、DTT及びTCEPからなる群から選択される還元剤を含む、項目42に記載の方法。
ニック部位における重合による、プライミングを用いない増幅を用いたライブラリー調製
ニック部位において重合によるプライミングを用いない増幅(プライミングを用いない増幅)を用いる、本明細書に記載のとおりに作製した配列決定ライブラリーは、従来のプライマーベースの増幅(プライミング増幅)ライブラリー作製アプローチと比較した場合に、優れた配列決定の結果、例えば全ゲノム配列決定の結果をもたらす。有利には、例えば、プライミングを用いない増幅アプローチは、プライミング増幅の結果と比較した場合、広範囲のGC塩基含量にまたがる、一層均一な配列決定カバレッジをもたらす。更に、プライミングを用いない増幅において、改善された配列決定カバレッジの均一性が達成され、プライミング増幅に関する分布と比較した場合、一層のポアソン分布をもたらす。
II.ビーズまたは粒子
ビーズの特徴
分解可能なビーズ
ビーズの分解方法
分解工程のタイミング
オリゴヌクレオチドで予め機能化したビーズの調製
バーコード及びランダムN量体(導入)
予め機能化したビーズへの、内容物の結合
III.バーコードライブラリー
IV.サンプル
サンプルの種類
バーコードのサンプルへの結合方法
マイクロ流体デバイス及び液滴
V.増幅
液滴内での増幅、及びサンプルのインデックス化
VII.デジタルプロセッサー
VIII.キット
IX.用途
バーコード化サンプル材料
ポリヌクレオチドの配列決定
少数の細胞からの配列決定
遺伝子発現の分析
細胞またはタンパク質からの、ポリヌクレオチドの分画
エピジェネティック用途
少ない入力DNAの用途
追加の配列決定アプローチ
追加のバーコード化ライブラリー
追加の断片化及びバーコード化
バーコード化ライブラリーの追加の処理
追加のシステム及びキット
X.実施例
実施例1:プライミングを用いない増幅鋳型の分子バーコード化
実施例2:ニック部位における、重合によるプライミングを用いない増幅はチミジン(T)塩基バイアスをもたらす
1.)4℃/∞
2.)98℃/5:00分−傾斜 2℃/S
3.)4℃/30秒−傾斜 2℃/S
4.)45℃/1秒−傾斜 0.1℃/s
5.)70℃/20秒−傾斜 2℃/S
6.)98℃/30秒−傾斜 2℃/S
7.)工程2、14Xに移動
8.)4℃/∞
(B)プライマー配合物を用いない増幅プロトコール(重合によるプライミングを用いない増幅):
2.)65℃/10:00分
3.)4℃/∞
重合反応によるプライミングを用いない増幅を使用して、dUTP(U)を鋳型に組み込んだ。鋳型内にニックを作製するリアーゼ酵素により「U」の除去を行うことにより、ポリメラーゼ用の反応開始位置を得た。Uを除去した結果、反応が開始したため、観察した配列に反映される、塩基チミジン(T)のバイアスが存在している。
実施例3:GCカバレッジ:プライミング増幅とプライミングを用いない増幅
実施例4:GCカバレッジにおける効果に対するdUTPの滴定
実施例5:キメラ減少に対するdUTPの滴定
実施例6:DTTの添加がDPCVを減少させる
実施例7:全ゲノム分析に対する、重合条件の最適化
実施例8:重合反応時間の経過
実施例9:DPCV及び増幅率における、鋳型変性の影響
実施例10:アダプター濃度の滴定
実施例11:バーコード化ライゲーション反応時間の影響
実施例12:プライミングを用いない増幅の生成物の、T4リガーゼによる分子バーコード化
実施例13:配列決定カバレッジの均一性−プライミング増幅とプライミングを用いない増幅
実施例14:DPCVへの、N量体(μM)の濃度の影響
実施例15:DPCVにおける、SPRIストリンジェンシーカットの影響
実施例16:DPCVへの、合計反応時間の影響
実施例17:DPCVへの、USER濃度の影響
Claims (29)
- バーコード化核酸分子を調製する方法であって、
(a)鋳型核酸分子、デオキシヌクレオチドトリホスフェート(dNTP)、デオキシウリジントリホスフェート(dUTP)、ランダムプライマー、ポリメラーゼ、ウラシルを除去可能な酵素、およびビーズに付着した複数のオリゴヌクレオチドバーコード分子を含むビーズを提供する工程と、
(b)前記鋳型核酸分子、前記ポリメラーゼ、前記dNTP、前記dUTPおよび前記ランダムプライマーを使用して、第1の鎖を含む二本鎖核酸分子を合成する工程であって、前記第1の鎖はウラシルを含む工程と、
(c)前記酵素で前記二本鎖核酸分子から前記ウラシルを除去し、前記二本鎖核酸分子内にニックをもたらす工程と、
(d)前記ポリメラーゼを使用して前記二本鎖核酸分子を増幅し、それにより、複数の一本鎖核酸分子を得る工程であって、前記ポリメラーゼが、前記ニックで前記二本鎖核酸分子に係合する工程と、
(e)前記複数のオリゴヌクレオチドバーコード分子のうちの1つを(d)の一本鎖核酸分子またはその相補鎖に結合させて、前記一本鎖核酸分子またはその相補鎖の配列を含むバーコード化核酸分子を生成する工程と
を含む方法。 - (d)の後に、(i)前記一本鎖核酸分子を使用して追加の二本鎖核酸分子を生成すること、および(ii)前記オリゴヌクレオチドバーコード分子を前記追加の二本鎖核酸分子の末端にライゲーションして前記バーコード化核酸分子を生成することをさらに含む、請求項1に記載の方法。
- 前記バーコード化核酸分子が二本鎖である、請求項2に記載の方法。
- (a)〜(e)が、単一の反応体積中で実施される、請求項1に記載の方法。
- 前記ビーズ、前記鋳型核酸分子、前記dNTP、前記dUTP、前記ランダムプライマー、前記ポリメラーゼ、及び前記酵素が、分画で提供される、請求項1に記載の方法。
- 前記分画が、エマルション中の液滴である、請求項5に記載の方法。
- 前記分画が、ウェルである、請求項5に記載の方法。
- 前記ビーズが、化学分解可能なビーズ、光分解可能なビーズ、及び熱分解可能なビーズからなる群から選択される分解可能なビーズである、請求項1に記載の方法。
- 前記ビーズが化学分解可能なビーズであり、前記化学分解可能なビーズが化学還元可能な架橋剤を含む、請求項8に記載の方法。
- 前記化学還元可能な架橋剤が、ジスルフィド結合を含む、請求項9に記載の方法。
- (e)において、前記バーコード化核酸分子が、ライゲーション酵素、ポリメラーゼ酵素、またはトポイソメラーゼの使用を介して生成される、請求項1に記載の方法。
- 前記複数のオリゴヌクレオチドバーコード分子のそれぞれが、少なくとも4ヌクレオチド長であるバーコード配列を含む、請求項1に記載の方法。
- 前記ビーズが、それに付着した少なくとも1,000,000オリゴヌクレオチドバーコード分子を含む、請求項1に記載の方法。
- 前記複数のオリゴヌクレオチドバーコード分子のそれぞれが、1つまたは複数の機能性配列を含む、請求項1に記載の方法。
- 前記1つまたは複数の機能性配列が、アダプター配列、プライマー配列、プライマーアニーリング配列、付着配列、及び配列決定プライマー配列からなる群から選択される、請求項14に記載の方法。
- 前記複数のオリゴヌクレオチドバーコード分子のそれぞれがプライマー配列を含み、(e)において、前記バーコード化核酸分子が、前記プライマー配列の核酸伸長によって生成される、請求項15に記載の方法。
- 前記1つまたは複数の機能性配列が、5〜100ヌクレオチド長のランダムN量体配列を含む、請求項14に記載の方法。
- 前記ランダムN量体配列が、5〜25ヌクレオチド長である、請求項17に記載の方法。
- 前記複数のオリゴヌクレオチドバーコード分子の少なくともサブセットが、前記ビーズに分離可能に付着されている.請求項1に記載の方法。
- 前記オリゴヌクレオチドバーコード分子のサブセットを前記ビーズから分離することをさらに含む、請求項19に記載の方法。
- 前記分離することが、前記ビーズを分解することを含む、請求項20に記載の方法。
- 前記分離することが、還元剤を使用して前記複数のオリゴヌクレオチドバーコード分子と前記ビーズとの間のジスルフィド結合を切断することを含む、請求項20に記載の方法。
- (a)において、前記dNTPが、前記dUTPの濃度より高い濃度で提供される、請求項1に記載の方法。
- 前記バーコード化核酸分子またはその由来物を配列決定することをさらに含む、請求項1に記載の方法。
- (b)が、(i)前記ランダムプライマーを前記鋳型核酸分子に結合すること、および(ii)前記ランダムプライマーを伸長して前記ウラシルを含む前記第1の鎖を合成することを含む、請求項1に記載の方法。
- (d)において、前記増幅がプライマーとは無関係な伸長プロセスを含み、前記ポリメラーゼが鎖置換活性を含む、請求項1に記載の方法。
- 前記複数のバーコードオリゴヌクレオチド分子のそれぞれが、不安定な結合を介して前記ビーズに分離可能に付着している、請求項1に記載の方法。
- 前記不安定な結合が、熱で切断可能な結合、化学的に不安定な結合、および感光性結合からなる群から選択される、請求項27に記載の方法。
- 前記不安定な結合が、エステル結合、隣接ジオール結合、ディールス−アルダー結合、スルホン結合、シリルエーテル結合、グリコシド結合、ペプチド結合、およびホスホジエステル結合からなる群から選択される結合を含む、請求項28に記載の方法。
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