JP7416846B2 - 連結型ライゲーション - Google Patents
連結型ライゲーション Download PDFInfo
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- JP7416846B2 JP7416846B2 JP2022041170A JP2022041170A JP7416846B2 JP 7416846 B2 JP7416846 B2 JP 7416846B2 JP 2022041170 A JP2022041170 A JP 2022041170A JP 2022041170 A JP2022041170 A JP 2022041170A JP 7416846 B2 JP7416846 B2 JP 7416846B2
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- C12Q2525/191—Modifications characterised by incorporating an adaptor
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Description
本出願は、2016年12月9日に出願された米国仮出願62/432,277号および2017年10月9日に出願された米国仮出願62/569,824号の利益およびこれらの仮出願に対する優先権を主張し、両仮出願は本明細書に参照により援用される。
本発明は、概して、核酸の捕捉、増幅およびシーケンシングに関する。
ハイスループットゲノムシーケンシングプラットフォームは、大量のデータを手頃な価格で生じるが、それらは十分に正確ではない。最良のシーケンシング技法であってもエラー率が約1パーセントである。これは単一のヒトゲノムの配列における何十万ものエラーに変換される。不正確な塩基呼び出し(base calling)により、配列の誤アラインメントおよび突然変異の誤識別が導かれる。塩基呼び出しおよびアラインメントアルゴリズムが利用可能であるが、増幅およびシーケンシングのエラーによって品質が負の影響を受ける。
二重にシードされたクラスターを使用したKRASアンプリコンのシーケンシングのエラーの減少
フローセルクラスターに単一の鋳型分子をシードした。単一の鋳型コピーは、図17に示されている通り、連結鋳型分子を1つのみフローセルに結合させた連結鋳型のライブラリーに由来するものであった。次いで、KRASアンプリコンにアラインメントされた最初の3000の単独でシードされたクラスターを、35よりも大きいという質の閾値を適用することでシーケンシングのエラーについて分析した。図16に示されている通り、単独でシードされたクラスターでは、約3000の平均深度で0.13%の平均エラーが生じた。単独でシードされたフローセルでは連結鋳型ライブラリーを使用したので、結果は、非連結鋳型分子を用いた標準の単一のシーディング方法を使用して生じるものよりも低いエラー率を表す可能性がある。
参照による組み込み
等価物
Claims (11)
- 標的核酸にアダプターを選択的にライゲートするための方法であって、前記方法が:
1つまたは複数の第1の連結型ライゲーションアダプターであって、各々が(1)前記標的核酸に相補的でないアダプター、および(2)前記標的核酸の一部と相補的な一本鎖プローブを含む、第1の連結型ライゲーションアダプターを提供すること;
1つまたは複数の第2の連結型ライゲーションアダプターであって、各々が(1)前記標的核酸に相補的でないアダプター、および(2)前記標的核酸の一部と相補的な一本鎖プローブを含む、第2の連結型ライゲーションアダプターを提供すること;
前記1つまたは複数の第1の連結型ライゲーションアダプターおよび前記1つまたは複数の第2の連結型ライゲーションアダプターが、異種混合物において少なくとも第1の断片と特異的にハイブリダイズする条件下において、異なる核酸配列を含む試料を、前記1つまたは複数の第1の連結型ライゲーションアダプターおよび前記1つまたは複数の第2の連結型ライゲーションアダプターと組み合わせること、ここで、前記第1の断片は前記標的核酸を含む;
前記第1の連結型ライゲーションアダプターの1つを前記第1の断片の5’末端にライゲートすること;および
前記第2の連結型ライゲーションアダプターの1つを前記第1の断片の3’末端にライゲートし、これにより、前記標的核酸を含むライゲーション産物を生産すること、
を含む、方法。 - 前記連結型ライゲーションアダプターの各々のアダプターが、ユニバーサルプライミング部位、固有の分子識別子、バーコード、またはこれらのいずれかの組み合わせを含む、請求項1に記載の方法。
- 前記標的核酸が、約100~約500ヌクレオチドの長さを有する、請求項1に記載の方法。
- 前記1つまたは複数の連結型ライゲーションアダプターが、前記第1の断片と特異的にハイブリダイズし、そして、前記連結型ライゲーションアダプターの末端と前記第1の断片の末端が一緒に連結する条件下において、前記試料、前記1つまたは複数の連結型ライゲーションアダプター、およびリガーゼを組み合わせ、これにより、前記ライゲーション産物を生産することを含む、請求項1に記載の方法。
- 前記1つまたは複数の連結型ライゲーションアダプターが、異なる標的核酸部分に相補的な異なる一本鎖プローブを含む複数の連結型ライゲーションアダプターを含む、請求項1に記載の方法。
- 前記1つまたは複数の連結型ライゲーションアダプターが、注目の前記標的核酸の第1の部分に相補的な第1の一本鎖プローブを含む第1の連結型ライゲーションアダプター、および前記標的核酸の第2の部分に相補的な一本鎖プローブを含む第2の連結型ライゲーションアダプターを含む、請求項1に記載の方法。
- 前記1つまたは複数の連結型ライゲーションアダプターの少なくとも1つが、修飾されたDNA塩基を含む、請求項1に記載の方法。
- 前記1つまたは複数の連結型ライゲーションアダプターの少なくとも1つが、ブロックされて伸長が阻害される、請求項1に記載の方法。
- 前記1つまたは複数の連結型ライゲーションアダプターの少なくとも1つが、切断部位を含む、請求項1に記載の方法。
- 前記標的核酸を増幅することをさらに含む、請求項1に記載の方法。
- 標的DNA断片の富化の方法であって、前記方法が:
(a)請求項1の方法の、核酸断片の混合物を1つまたは複数の第1の連結型ライゲーションアダプターおよび1つまたは複数の第2の連結型ライゲーションアダプターと組み合わせることにより、ライゲーション産物の混合物を生成すること;および
(b)前記連結型ライゲーションアダプターのいずれか1つにライゲートされていない前記混合物から断片を除去すること
を含む、方法。
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US20220186298A1 (en) | 2022-06-16 |
US11268137B2 (en) | 2022-03-08 |
EP3551769A2 (en) | 2019-10-16 |
JP2024038253A (ja) | 2024-03-19 |
WO2018104908A3 (en) | 2018-08-16 |
US11879151B2 (en) | 2024-01-23 |
WO2018104908A2 (en) | 2018-06-14 |
US20240052403A1 (en) | 2024-02-15 |
EP3551769A4 (en) | 2020-10-28 |
US20190300942A1 (en) | 2019-10-03 |
JP7048609B2 (ja) | 2022-04-05 |
JP2020513741A (ja) | 2020-05-21 |
JP2022081635A (ja) | 2022-05-31 |
CA3048420A1 (en) | 2018-06-14 |
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