IP Library › Granted Patent US 12,247,252
Granted Patent B2
US 12,247,252 · App. 17/815,815 · Granted Mar 11, 2025

Method of improved sequencing by strand identification

Inventors: Malek Faham (Burlingame, CA); Shengrong Lin (Fremont, CA); Ling Fung Tang (San Francisco, CA); Yontao Lu (Sunnyvale, CA); Zhaohui Sun (Albany, CA); Yingyu Wang (Mountain View, CA); Li Weng (Fremont, CA)
Assignee: ACCURAGEN HOLDINGS LIMITED
C12Q1/6869C12Q1/6827C12Q1/6858C40B50/06C12Q2521/501C12Q2535/139C12Q2537/143
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Quick Facts
Patent No.
US 12,247,252
App. No.
17/815,815
Granted
Mar 11, 2025
Kind
B2
Abstract

In some aspects, the present disclosure provides methods for identifying sequence variants, as well as methods of determining copy number of a genetic locus in a sample. Systems and kits for performing methods of the disclosure, as well as compositions produced by or useful in methods of the disclosure are also provided. In some embodiments, methods comprise extending 3′ ends of polynucleotides by adding one or more pre-determined nucleotides. In some embodiments, methods comprise use of a strand-tagging sequence.

Claims (16)

1. A method of identifying complementary strands in a nucleic acid sample comprising a plurality of double-stranded polynucleotides, each double-stranded polynucleotide of the plurality comprising a first complementary strand and a second complementary strand, each having a 5′ end and a 3′ end, the method comprising:

(a) modifying a polynucleotide sequence of at least one of a first complementary strand and a second complementary strand of individual double-stranded polynucleotides by adding one or more predetermined nucleotides in a base by base manner to the 3′ end of at least one of the first complementary strand and the second complementary strand to yield a plurality of modified double-stranded polynucleotides;

(b) sequencing said plurality of modified double-stranded polynucleotides or a derivative thereof to yield a plurality of sequencing reads; and

(c) identifying from said plurality of sequencing reads, a given first complementary strand and a given second complementary strand as originating from a common double-stranded polynucleotide based on (i) sequences of the 5′ ends, (ii) sequences 3′ ends adjacent to the one or more predetermined nucleotides, and (iii) sequences of the one or more predetermined nucleotides.

2. The method of claim 1 , wherein modifying a polynucleotide sequence further comprises attaching a polynucleotide having a predefined polynucleotide sequence to a 5′ end, a 3′ end, or both 5′ and 3′ ends of at least one of the first complementary strand and the second complementary strand or altering at least one nucleotide of the polynucleotide sequence.

3. The method of claim 1 , wherein modifying the polynucleotide sequence comprises altering at least one nucleotide of the polynucleotide sequence, and altering at least one nucleotide of the polynucleotide sequence is effected by treatment with bisulfite.

4. The method of claim 1 , further comprising identifying two first complementary strands or two second complementary strands as originating from different double-stranded polynucleotides based on extension of the respective 3′ ends by a different number of predetermined nucleotides.

5. A method of identifying a sequence variant in a nucleic acid sample comprising a plurality of double-stranded polynucleotides, each double-stranded polynucleotide of the plurality comprising a first complementary strand and a second complementary strand, each having a 5′ end and a 3′ end, the method comprising:

(a) modifying a polynucleotide sequence of at least one of a first complementary strand and a second complementary strand of individual double-stranded polynucleotides by adding one or more predetermined nucleotides in a base by base manner to the 3′ end of at least one of the first complementary strand and the second complementary strand;

(b) sequencing a plurality of first complementary strands and a plurality of second complementary strands, or amplification products thereof, to yield a plurality of sequencing reads;

(c) identifying from the plurality of sequencing reads, a given first complementary strand and a given second complementary strand as originating from a common double-stranded polynucleotide based on (i) sequences of the respective 3′ end and 5′ ends adjacent to the one or more predetermined nucleotides, and (ii) sequences of the one or more predetermined nucleotides;

(d) comparing polynucleotide sequences of the given first complementary strand and the given second complementary strand originating from the common double-stranded polynucleotide; and

(e) calling a sequence difference in the given first complementary strand relative to a reference sequence as the sequence variant only when the given second complementary strand originating from the common double-stranded polynucleotide comprises a complement of the sequence difference.

6. The method of claim 5 , wherein modifying a polynucleotide sequence further comprises attaching a polynucleotide having a predefined polynucleotide sequence to a 5′ end, a 3′ end, or both 5′ and 3′ ends of at least one of the first complementary strand and the second complementary strand or altering at least one nucleotide of the polynucleotide sequence.

7. The method of claim 5 , wherein modifying the polynucleotide sequence comprises altering at least one nucleotide of the polynucleotide sequence, and altering at least one nucleotide of the polynucleotide sequence is effected by treatment with bisulfite.

8. The method of claim 5 , further comprising joining an adaptor polynucleotide to the 3′ end of: (i) one or both strands of the double-stranded polynucleotides; or (ii) the extended polynucleotides.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 23, 2025
From: ACCURAGEN HOLDINGS LIMITED
To: ACCUSCAN SCIENCES INC.
Reel/Frame 074035/0680 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 20, 2023
From: FAHAM, MALEK; LIN, SHENGRONG; TANG, LING FUNG; LU, YONTAO; SUN, ZHAOHUI; WANG, YINGYU; WENG, LI
To: ACCURAGEN HOLDINGS LIMITED
Reel/Frame 062444/0562 →
Continuity (4)
Continuation 16301707
Provisional Application 62506390 · May 15, 2017
Provisional Application 62337296 · May 16, 2016
Related Publication 20230167493A1 · Jun 1, 2023
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