Haplotype-resolved whole-genome sequencing by contiguity-preserving transposition and combinatorial indexing

被引：131

作者：

Amini, Sasan ^{[1
]}

Pushkarev, Dmitry ^{[1
]}

Christiansen, Lena ^{[1
]}

Kostem, Emrah ^{[1
]}

Royce, Tom ^{[1
]}

Turk, Casey ^{[1
]}

Pignatelli, Natasha ^{[1
]}

Adey, Andrew ^{[2
]}

Kitzman, Jacob O. ^{[2
]}

Vijayan, Kandaswamy ^{[1
]}

Ronaghi, Mostafa ^{[1
]}

Shendure, Jay ^{[2
]}

Gunderson, Kevin L. ^{[1
]}

Steemers, Frank J. ^{[1
]}

机构：

[1] Illumina Inc, Adv Res Grp, San Diego, CA 92122 USA

[2] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 12期

基金：

美国国家科学基金会;

关键词：

PHASE; ALGORITHMS; LIBRARIES; DESIGN;

D O I：

10.1038/ng.3119

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Haplotype-resolved genome sequencing enables the accurate interpretation of medically relevant genetic variation, deep inferences regarding population history and non-invasive prediction of fetal genomes. We describe an approach for genome-wide haplotyping based on contiguity-preserving transposition (CPT-seq) and combinatorial indexing. Tn5 transposition is used to modify DNA with adaptor and index sequences while preserving contiguity. After DNA dilution and compartmentalization, the transposase is removed, resolving the DNA into individually indexed libraries. The libraries in each compartment, enriched for neighboring genomic elements, are further indexed via PCR. Combinatorial 96-plex indexing at both the transposition and PCR stage enables the construction of phased synthetic reads from each of the nearly 10,000 'virtual compartments'. We demonstrate the feasibility of this method by assembling >95% of the heterozygous variants in a human genome into long, accurate haplotype blocks (N50 = 1.4-2.3 Mb). The rapid, scalable and cost-effective workflow could enable haplotype resolution to become routine in human genome sequencing.

引用

页码：1343 / 1349

页数：7

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