JPWO2019157445A5 - - Google Patents

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JPWO2019157445A5
JPWO2019157445A5 JP2020542878A JP2020542878A JPWO2019157445A5 JP WO2019157445 A5 JPWO2019157445 A5 JP WO2019157445A5 JP 2020542878 A JP2020542878 A JP 2020542878A JP 2020542878 A JP2020542878 A JP 2020542878A JP WO2019157445 A5 JPWO2019157445 A5 JP WO2019157445A5
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nucleotides
nucleic acid
flow cell
amplification primer
target
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JP7372927B6 (en
JP7372927B2 (en
JP2021512631A (en
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Claims (21)

組織試料からの少なくとも１つの細胞内の少なくとも１つの標的検体の存在量を空間的に検出する方法であって、以下：
（１）組織試料中の少なくとも１つの細胞内の少なくとも１つの標的検体を、少なくとも３つのプローブと接触させ、それにより前記少なくとも１つの標的検体上に前記プローブをタイリングする工程であって、
ここで前記プローブのそれぞれは：
前記少なくとも１つの標的検体に結合する標的結合ドメイン；および
一本鎖識別子オリゴヌクレオチド
を含み、
ここで前記一本鎖識別子オリゴヌクレオチドは、
前記標的結合ドメインに結合した標的検体を識別する固有の核酸配列、
固有の分子識別子を含む核酸配列、
第１の増幅プライマー結合部位、および
第２の増幅プライマー結合部位
を含み、
ここで前記プローブのそれぞれが、前記一本鎖識別子オリゴヌクレオチドと前記標的結合ドメインとの間に光切断性リンカーを含む、工程；
（２）前記光切断性リンカーを切断することができる十分な波長の光で前記組織試料の位置を励起し、それにより前記一本鎖識別子オリゴヌクレオチドを解放させる工程；
（３）工程（２）で励起された前記組織試料の前記位置から、解放された前記一本鎖識別子オリゴヌクレオチドを採取する工程；
（４）採取された前記一本鎖識別子オリゴヌクレオチドを増幅する工程であって、ここで採取された前記一本鎖識別子オリゴヌクレオチドを増幅することが、ＰＣＲを実施することを含み、ここで前記ＰＣＲを実施することは、第１の増幅プライマー及び第２の増幅プライマーを含み、
ここで前記第１の増幅プライマーは：
第１のフローセル結合部位；
前記識別子オリゴヌクレオチドが解放された前記組織試料の前記特定の位置を識別する第１の核酸配列；および
前記第２の増幅プライマー結合部位に相補的な核酸配列
を含み；
ここで前記第２の増幅プライマーは：
第２のフローセル結合部位；
前記識別子オリゴヌクレオチドが解放された前記試料の前記特定の位置を識別する第２の核酸配列；および
前記第１の増幅プライマー結合部位に相補的な核酸配列
を含む、工程；および
（５）工程（４）で生成された前記増幅産物を配列決定して解放された前記一本鎖識別子オリゴヌクレオチドを識別し、それにより組織試料中の前記少なくとも１つの細胞内の前記少なくとも１つの標的検体の存在量を空間的に検出する工程
を含む、方法。 A method for spatially detecting the abundance of at least one target sample in at least one cell from a tissue sample, the following:
(1) In the step of contacting at least one target sample in at least one cell in a tissue sample with at least three probes , thereby tiling the probe on the at least one target sample . There,
Where each of the probes is:
A target binding domain that binds to at least one target specimen; and
Single-stranded identifier oligonucleotide
Including
Here, the single-stranded identifier oligonucleotide is
A unique nucleic acid sequence that identifies a target sample bound to the target binding domain,
Nucleic acid sequence containing a unique molecular identifier,
Includes a first amplification primer binding site and a second amplification primer binding site.
Here, each of the probes comprises a photocleavable linker between the single-stranded identifier oligonucleotide and the target binding domain ;
(2) A step of exciting the position of the tissue sample with light of sufficient wavelength to cleave the photocleavable linker , thereby releasing the single-stranded identifier oligonucleotide ;
(3) A step of collecting the released single-stranded identifier oligonucleotide from the position of the tissue sample excited in the step (2) ;
(4) In the step of amplifying the collected single- stranded identifier oligonucleotide, amplifying the single-stranded identifier oligonucleotide collected here includes carrying out PCR, and here. Performing the PCR comprises a first amplification primer and a second amplification primer.
Here, the first amplification primer is:
First flow cell binding site;
A first nucleic acid sequence that identifies the particular location of the tissue sample from which the identifier oligonucleotide has been released;
Nucleic acid sequence complementary to the second amplification primer binding site
Including;
Here, the second amplification primer is:
Second flow cell binding site;
A second nucleic acid sequence that identifies the particular position of the sample from which the identifier oligonucleotide has been released; and
Nucleic acid sequence complementary to the first amplification primer binding site
And (5) the single-stranded identifier oligonucleotide released by sequencing the amplification product produced in step (4), thereby identifying the at least one of said in a tissue sample. A method comprising the step of spatially detecting the abundance of the at least one target sample in a cell. 工程（１）が、組織試料中の少なくとも１つの細胞内の前記少なくとも１つの標的検体を少なくとも５つのプローブと接触させることを含む、請求項１に記載の方法。 The method of claim 1, wherein step (1) comprises contacting the at least one target sample in at least one cell in a tissue sample with at least five probes. 前記フローセル結合部位のうちの少なくとも１つは、配列決定に適するフローセルアダプター配列を含む、請求項１または２に記載の方法。 The method of claim 1 or 2 , wherein at least one of the flow cell binding sites comprises a flow cell adapter sequence suitable for sequencing. 前記フローセル結合部位のうちの少なくとも１つは、Ｐ５フローセルアダプター配列を含み、ここで前記Ｐ５フローセルアダプター配列は配列番号３に記載の配列を含む、請求項１～３のいずれか１項に記載の方法。 The P5 flow cell adapter sequence comprises the P5 flow cell adapter sequence, wherein the P5 flow cell adapter sequence comprises the sequence set forth in SEQ ID NO: 3, according to any one of claims 1 to 3 . Method. 前記フローセル結合部位のうちの少なくとも１つは、Ｐ７フローセルアダプター配列を含み、前記Ｐ７フローセルアダプター配列は配列番号４に記載の配列を含む、請求項１～４のいずれか１項に記載の方法。 The method according to any one of claims 1 to 4 , wherein at least one of the flow cell binding sites comprises a P7 flow cell adapter sequence, wherein the P7 flow cell adapter sequence comprises the sequence set forth in SEQ ID NO: 4. 前記フローセル結合部位のうちの少なくとも１つは、１５～４０ヌクレオチドを含む、請求項１～５のいずれか１項に記載の方法。 The method of any one of claims 1-5, wherein at least one of the flow cell binding sites comprises 15-40 nucleotides. 前記フローセル結合部位のうちの少なくとも１つは、２９ヌクレオチドを含む、請求項６に記載の方法。 The method of claim 6, wherein at least one of the flow cell binding sites comprises 29 nucleotides. 前記フローセル結合部位のうちの少なくとも１つは、２４ヌクレオチドを含む、請求項６に記載の方法。 The method of claim 6, wherein at least one of the flow cell binding sites comprises 24 nucleotides. 前記標的結合ドメインに結合した前記標的検体を識別する前記固有の核酸配列は、５ヌクレオチド～２５ヌクレオチドを含む、請求項１～８のいずれか１項に記載の方法。 The method according to any one of claims 1 to 8, wherein the unique nucleic acid sequence that identifies the target sample bound to the target binding domain comprises 5 nucleotides to 25 nucleotides. 前記標的結合ドメインに結合した前記標的検体を識別する前記核酸配列は、１２ヌクレオチドを含む、請求項１～９のいずれか１項に記載の方法。 The method according to any one of claims 1 to 9, wherein the nucleic acid sequence that identifies the target sample bound to the target binding domain comprises 12 nucleotides. 前記増幅プライマー結合部位のうちの少なくとも１つは、１０～４０ヌクレオチドを含む、請求項１～１０のいずれか１項に記載の方法。 The method according to any one of claims 1 to 10, wherein at least one of the amplification primer binding sites comprises 10 to 40 nucleotides. 前記増幅プライマー結合部位のうちの少なくとも１つは、３４ヌクレオチドを含む、請求項１１に記載の方法。 11. The method of claim 11, wherein at least one of the amplification primer binding sites comprises 34 nucleotides. 前記増幅プライマー結合部位のうちの少なくとも１つは、３３ヌクレオチドを含む、請求項１１に記載の方法。 11. The method of claim 11, wherein at least one of the amplification primer binding sites comprises 33 nucleotides. 前記増幅プライマー結合部位のうちの少なくとも１つはｉ７配列を含み、ここで前記ｉ７配列は配列番号１に記載の配列を含む、請求項１～１３のいずれか１項に記載の方法。 The method according to any one of claims 1 to 13 , wherein at least one of the amplification primer binding sites comprises an i7 sequence, wherein the i7 sequence comprises the sequence set forth in SEQ ID NO: 1. 前記増幅プライマー結合部位のうちの少なくとも１つはｉ５配列を含み、ここで前記ｉ５配列は配列番号２に記載の配列を含む、請求項１～１４のいずれか１項に記載の方法。 The method according to any one of claims 1 to 14 , wherein at least one of the amplification primer binding sites comprises an i5 sequence, wherein the i5 sequence comprises the sequence set forth in SEQ ID NO: 2. 前記識別子オリゴヌクレオチドが解放された前記組織試料の前記特定の位置を識別する前記核酸配列のうちの少なくとも１つは、１～２０ヌクレオチドを含む、請求項１～１５のいずれか１項に記載の方法。 The expression according to any one of claims 1 to 15, wherein at least one of the nucleic acid sequences identifying the particular position of the tissue sample from which the identifier oligonucleotide has been released comprises 1 to 20 nucleotides. the method of. 前記識別子オリゴヌクレオチドが解放された前記組織試料の前記特定の位置を識別する前記核酸配列のうちの少なくとも１つは、８ヌクレオチドを含む、請求項１６に記載の方法。 16. The method of claim 16, wherein at least one of the nucleic acid sequences identifying the particular location of the tissue sample from which the identifier oligonucleotide has been released comprises 8 nucleotides. 固有の分子識別子を含む前記核酸配列は、５～２０ヌクレオチドを含む、請求項１～１７のいずれか１項に記載の方法。 The method according to any one of claims 1 to 17, wherein the nucleic acid sequence containing a unique molecular identifier comprises 5 to 20 nucleotides. 固有の分子識別子を含む前記核酸配列は、１４ヌクレオチドを含む、請求項１８に記載の方法。 18. The method of claim 18, wherein the nucleic acid sequence comprising a unique molecular identifier comprises 14 nucleotides. 前記標的結合ドメインは、１０ヌクレオチド～７０ヌクレオチドを含む、請求項１～１９のいずれか１項に記載の方法。 The method according to any one of claims 1 to 19, wherein the target binding domain comprises 10 nucleotides to 70 nucleotides. 前記標的結合ドメインは、３５ヌクレオチド～５０ヌクレオチドを含む、請求項２０に記載の方法。 The method of claim 20, wherein the target binding domain comprises 35 to 50 nucleotides.
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