JP2022521766A - 次世代シーケンシングのための組成物および方法 - Google Patents
次世代シーケンシングのための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2019年2月25日出願の米国仮特許出願第62/810,321号、2019年10月14日出願の米国仮特許出願第62/914,904号、および2019年10月25日出願の米国仮特許出願第62/926,336号に基づく利益を主張するものであり、これら出願はすべてその全体を参照することで本明細書に引用される。
本明細書で言及される刊行物、特許、および特許出願はすべて、あたかも個々の刊行物、特許、または特許出願がそれぞれ参照により引用されるように具体的かつ個々に指示されるのと同じ程度にまで、参照により本明細書に引用される。
ポリヌクレオチドプライマーは、図1Cに表されるように、バーコード(またはインデックス)などの規定の配列を含む。バーコードは、例えばバーコード、アダプターでライゲートされた試料ポリヌクレオチド(図1D、108)を生成するために、PCRとバーコード化プライマー(113a)または(113b)を使用して、ユニバーサルアダプターに付けることができる。図1Cと1Dに表されるユニバーサルプライマー結合部位(107a)または(107b)などのプライマー結合部位は、バーコード・プライマー・ライブラリのすべての員、または員の部分集団を同時に増幅することを促す。いくつかの例では、プライマー結合部位(107a)または(107b)は、次世代シーケンシング中にフローセルまたは他の固体担体に結合する領域を含む。いくつかの例では、バーコード化プライマーは、P5(5’-AATGATACGGCGACCACCGA-3’)またはP7(5’-CAAGCAGAAGACGGCATACGAGAT-3’)配列を含む。いくつかの例では、プライマー結合部位(112a)または(112b)は、ユニバーサルアダプター配列(102a)または(102b)に結合するように構成され、バーコード化アダプターの増幅と生成を促進する。いくつかの例では、バーコード化プライマーは長さ60以下の塩基である。いくつかの例では、バーコード化プライマーは長さ55以下の塩基である。いくつかの例では、バーコード化プライマーは長さ50~60の塩基である。いくつかの例では、バーコード化プライマーは長さ約60の塩基である。いくつかの例では、本明細書に記載のバーコードは、メチル化シトシンなどのメチル化核酸塩基を含む。
98C、30秒;
98C、10秒;63C、10秒;72C、10秒;12のサイクルを繰り返す
72C、2分
Claims (59)
- ポリヌクレオチドであって、該ポリヌクレオチドは、
第1の末端アダプタ領域、第1の非相補的領域、および第1のヨーク領域を含む第1の鎖と、
第2の末端アダプタ領域、第2の非相補的領域、および第2のヨーク領域を含む第2の鎖と
を含み、
前記第1のヨーク領域と前記第2のヨーク領域は相補的であり、前記第1の非相補的領域と前記第2の非相補的領域は相補的ではなく、前記第1のヨーク領域または前記第2のヨーク領域は少なくとも1つの核酸塩基アナログを含む、ポリヌクレオチド。 - 前記核酸塩基アナログは、前記第1のヨーク領域を前記第2のヨーク領域に結合するTmを増加させる、請求項1に記載のポリヌクレオチド。
- 前記核酸塩基アナログはロックド核酸(LNA)または架橋核酸(BNA)である、請求項1または2に記載のポリヌクレオチド。
- 相補的な前記第1のヨーク領域と前記第2のヨーク領域は、それぞれ長さ15未満の塩基である、請求項1から3のいずれか1つに記載のポリヌクレオチド。
- 相補的な前記第1のヨーク領域と前記第2のヨーク領域は、それぞれ長さ10未満の塩基である、請求項1から3のいずれか1つに記載のポリヌクレオチド。
- 相補的な前記第1のヨーク領域と前記第2のヨーク領域は、それぞれ長さ6未満の塩基である、請求項1から3のいずれか1つに記載のポリヌクレオチド。
- 前記ポリヌクレオチドはバーコードまたはインデックス配列を含まない、請求項1から6のいずれか1つに記載のポリヌクレオチド。
- ポリヌクレオチドであって、該ポリヌクレオチドは、
二重試料核酸と、
前記二重試料核酸の5’末端にライゲートされる第1のポリヌクレオチドと、
前記二重試料核酸の3’末端にライゲートされる第2のポリヌクレオチドと
を含み、
前記第1のポリヌクレオチドまたは前記第2のポリヌクレオチドは、
第1の末端アダプタ領域、第1の非相補的領域、および第1のヨーク領域を含む第1の鎖と、
第2の末端アダプタ領域、第2の非相補的領域、および第2のヨーク領域を含む第2の鎖と
を含み、
前記第1のヨーク領域と前記第2のヨーク領域は相補的であり、前記第1の非相補的領域と前記第2の非相補的領域は相補的ではなく、前記第1のヨーク領域または前記第2のヨーク領域は少なくとも1つの核酸塩基アナログを含む、ポリヌクレオチド。 - 前記二重試料核酸はDNAである、請求項8に記載のポリヌクレオチド。
- 前記二重試料核酸はゲノムDNAである、請求項8に記載のポリヌクレオチド。
- 前記ゲノムDNAはヒト由来のものである、請求項10に記載のポリヌクレオチド。
- 前記第1のポリヌクレオチドまたは前記第2のポリヌクレオチドは、少なくとも1つのバーコードを含む、請求項8から11のいずれか1つに記載のポリヌクレオチド。
- 前記少なくとも1つのバーコードは、少なくとも長さ8の塩基である、請求項12に記載のポリヌクレオチド。
- 前記少なくとも1つのバーコードは、少なくとも長さ12の塩基である、請求項12に記載のポリヌクレオチド。
- 前記少なくとも1つのバーコードは、少なくとも長さ16の塩基である、請求項12に記載のポリヌクレオチド。
- 前記少なくとも1つのバーコードは、長さ8~12の塩基である、請求項12に記載のポリヌクレオチド。
- 前記第1のポリヌクレオチドは第1のバーコードと第2のバーコードを含み、前記第2のポリヌクレオチドは第3のバーコードと第4のバーコードを含む、請求項12から15のいずれか1つに記載のポリヌクレオチド。
- 前記第1のバーコードと前記第3のバーコードが同じ配列を有し、前記第2のバーコードと前記第4のバーコードが同じ配列を有する、請求項17に記載のポリヌクレオチド。
- 前記ポリヌクレオチドにおける各バーコードは固有の配列を含む、請求項17に記載のポリヌクレオチド。
- 試料核酸を標識する方法であって、該方法は、
(1)アダプタでライゲートされた試料核酸を生成するために少なくとも1つのポリヌクレオチドを少なくとも1つの試料核酸にライゲートする工程であって、前記ポリヌクレオチドは、第1のプライマー結合領域、第1の非相補的領域、および第1のヨーク領域を含む第1の鎖と、第2のプライマー結合領域、第2の非相補的領域、および第2のヨーク領域を含む第2の鎖とを含み、前記第1のヨーク領域と前記第2のヨーク領域は相補的であり、前記第1の非相補的領域と前記第2の非相補的領域は相補的でない、工程と、
(2)少なくとも1つのアダプタでライゲートされた試料核酸を第1のプライマーおよびポリメラーゼと接触させる工程であって、前記第1のプライマーは、第3のプライマー結合領域と、第4のプライマー結合領域と、少なくとも1つのバーコードとを含み、前記第3のプライマー結合領域は、少なくとも1つのポリヌクレオチドの長さ未満に対して相補的であり、前記第1のプライマー結合領域に相補的である、工程と、
(3)少なくとも1つのアダプタでライゲートされた増幅試料核酸を生成するために前記アダプタでライゲートされた試料核酸を伸長させる工程であって、前記アダプタでライゲートされた増幅試料核酸は少なくとも1つのバーコードを含む、工程と
を含む、方法。 - 前記第1のプライマーと前記第2のプライマーは、それぞれ長さ30未満の塩基である、請求項20に記載の方法。
- 前記プライマーは長さ20未満の塩基である、請求項20に記載の方法。
- 前記ポリヌクレオチドはバーコードを含まない、請求項20に記載の方法。
- 前記プライマーは1つのバーコードを含む、請求項20から23のいずれか1つに記載の方法。
- 前記少なくとも1つのバーコードがインデックス配列を含む、請求項20から24のいずれか1つに記載の方法。
- 前記少なくとも1つのバーコードは、少なくとも長さ8の塩基である、請求項20から25のいずれか1つに記載の方法。
- 前記少なくとも1つのバーコードは、少なくとも長さ12の塩基である、請求項20から25のいずれか1つに記載の方法。
- 前記少なくとも1つのバーコードは、少なくとも長さ16の塩基である、請求項20から25のいずれか1つに記載の方法。
- 前記少なくとも1つのバーコードは、長さ8~12の塩基である、請求項20から25のいずれか1つに記載の方法。
- 前記インデックス配列は、同じソース由来の試料核酸のライブラリによくみられるものである、請求項25から29のいずれか1つに記載の方法。
- 前記少なくとも1つのバーコードは固有の分子識別子(UMI)を含む、請求項24から30のいずれか1つに記載の方法。
- 2つのポリヌクレオチドが前記少なくとも1つの試料核酸にライゲートされる、請求項20から31のいずれか1つに記載の方法。
- 第1のポリヌクレオチドが前記試料核酸の5’末端に、第2のポリヌクレオチドが前記試料核酸の3’末端にライゲートされる、請求項32に記載の方法。
- 前記方法が、
(4)少なくとも1つのアダプタでライゲートされた試料核酸を第2のプライマーおよびポリメラーゼと接触させる工程であって、前記第2のプライマーは、
第5のプライマー結合領域と、
第6のプライマー結合領域と、
少なくとも1つのバーコードと
を含み、前記第6のプライマー結合領域は、少なくとも1つのポリヌクレオチドの長さ未満に対して相補的であり、前記第5のプライマー結合領域は前記第2のプライマー結合領域に相補的である、工程と、
(5)少なくとも1つのアダプタでライゲートされた増幅試料核酸を生成するために前記ポリヌクレオチドを伸長させる工程であって、前記アダプタでライゲートされた増幅試料核酸は少なくとも1つのバーコードを含む、工程と
をさらに含む、請求項20から33のいずれか1つに記載の方法。 - 前記アダプタでライゲートされた試料核酸を配列決定する工程をさらに含む、請求項20から34のいずれか1つに記載の方法。
- 組成物であって、該組成物は、
アダプタでライゲートされた試料核酸の1つ以上の領域に結合するよう構成される少なくとも3つのポリヌクレオチドブロッカーであって、前記アダプタでライゲートされた試料核酸は、
i)第1の非相補的領域、第1のインデックス領域、第2の非相補的領域、第1のヨーク領域、および
ii)第3の非相補的領域、第2のインデックス領域、第4の非相補的領域、および第2のヨーク領域
を含み、前記第1のヨーク領域と前記第2のヨーク領域は相補的であり、前記第1の非相補的領域と前記第2の非相補的領域は相補的でなく、
前記アダプタでライゲートされた試料核酸はさらに、
iii)前記第1のヨーク領域および前記第2のヨーク領域に隣接するゲノムインサート
を含み、少なくとも1つのポリヌクレオチドブロッカーは、前記第1のヨーク領域または前記第2のヨーク領域に相補的ではなく、かつ、前記ポリヌクレオチドブロッカーと前記アダプタでライゲートされた試料核酸との結合を増大させるように構成される少なくとも1つのヌクレオチドアナログを含む、組成物。 - 少なくとも2つのポリヌクレオチドブロッカーが、前記第1のヨーク領域または前記第2のヨーク領域に相補的ではなく、かつ、それぞれ、前記ポリヌクレオチドブロッカーと前記アダプタでライゲートされた試料核酸との結合を増大させるように構成される少なくとも1つの修飾核酸塩基を含む、請求項36に記載の組成物。
- 少なくとも1つのインデックス領域はバーコードまたは固有の分子識別子を含む、請求項36に記載の組成物。
- 少なくとも1つのインデックス領域は長さ5~15の塩基である、請求項36に記載の組成物。
- 前記ポリヌクレオチドブロッカーの少なくとも1つは、少なくとも1つのユニバーサル塩基を含む、請求項36に記載の組成物。
- 前記少なくとも1つのユニバーサル塩基は、5-ニトロインドールまたは2-デオキシイノシンである、請求項40に記載の組成物。
- 前記少なくとも1つのユニバーサル塩基は、少なくとも1つのインデックス配列と重なるように構成される、請求項40に記載の組成物。
- 少なくとも2つのユニバーサル塩基は、少なくとも2つのインデックス配列と重なるように構成される、請求項40に記載の組成物。
- 前記ポリヌクレオチドブロッカーの少なくとも2つが少なくとも1つのユニバーサル塩基を含み、前記少なくとも1つのユニバーサル塩基はそれぞれ、少なくとも1つのインデックス配列と重なる、請求項40に記載の組成物。
- 重なりは長さ2~10の塩基である、請求項42または43に記載の組成物。
- 前記組成物は4つ以下のポリヌクレオチドブロッカーを含む、請求項36に記載の組成物。
- 前記ポリヌクレオチドブロッカーは、1つ以上のロックド核酸(LNA)または1つ以上の架橋核酸(BNA)を含む、請求項36から46のいずれか1つに記載の組成物。
- 前記ポリヌクレオチドブロッカーは、少なくとも5つのヌクレオチドアナログを含む、請求項36から46のいずれか1つに記載の組成物。
- 前記ポリヌクレオチドブロッカーは、少なくとも10のヌクレオチドアナログを含む、請求項36から46のいずれか1つに記載の組成物。
- 前記ポリヌクレオチドブロッカーのTmは少なくとも78℃である、請求項36から46のいずれか1つに記載の組成物。
- 前記ポリヌクレオチドブロッカーのTmは少なくとも80℃である、請求項36から46のいずれか1つに記載の組成物。
- 前記ポリヌクレオチドブロッカーのTmは少なくとも82℃である、請求項36から46のいずれか1つに記載の組成物。
- 前記ポリヌクレオチドブロッカーのTmは80~90℃である、請求項36から46のいずれか1つに記載の組成物。
- 核酸ハイブリダイゼーションのための方法であって、
複数のゲノムインサートを含む、アダプタでライゲートされた試料核酸ライブラリを提供する工程と、
前記アダプタでライゲートされた試料核酸ライブラリを、請求項36から53のいずれか1つに記載の組成物の存在下で少なくとも5000のポリヌクレオチドプローブを含むプローブライブラリと接触させる工程と、
プローブの少なくとも一部を前記ゲノムインサートにハイブリダイズする工程と
を含む、方法。 - 前記試料核酸ライブラリが少なくとも100万の固有ゲノムインサートを含む、請求項54に記載の方法。
- 前記ゲノムインサートの少なくとも一部はヒトDNAを含む、請求項54に記載の方法。
- 濃縮された試料核酸ライブラリを生成する工程をさらに含む、請求項54に記載の方法。
- 前記濃縮された試料核酸ライブラリを配列決定する工程をさらに含む、請求項57に記載の方法。
- 前記試料核酸ライブラリは、次世代シーケンシングのために構成されるアダプタを含む、請求項54から58のいずれか1つに記載の方法。
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