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Haplotyping germline and cancer genomes with high-throughput linked-read sequencing.


ABSTRACT: Haplotyping of human chromosomes is a prerequisite for cataloguing the full repertoire of genetic variation. We present a microfluidics-based, linked-read sequencing technology that can phase and haplotype germline and cancer genomes using nanograms of input DNA. This high-throughput platform prepares barcoded libraries for short-read sequencing and computationally reconstructs long-range haplotype and structural variant information. We generate haplotype blocks in a nuclear trio that are concordant with expected inheritance patterns and phase a set of structural variants. We also resolve the structure of the EML4-ALK gene fusion in the NCI-H2228 cancer cell line using phased exome sequencing. Finally, we assign genetic aberrations to specific megabase-scale haplotypes generated from whole-genome sequencing of a primary colorectal adenocarcinoma. This approach resolves haplotype information using up to 100 times less genomic DNA than some methods and enables the accurate detection of structural variants.

SUBMITTER: Zheng GX 

PROVIDER: S-EPMC4786454 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Haplotyping germline and cancer genomes with high-throughput linked-read sequencing.

Zheng Grace X Y GX   Lau Billy T BT   Schnall-Levin Michael M   Jarosz Mirna M   Bell John M JM   Hindson Christopher M CM   Kyriazopoulou-Panagiotopoulou Sofia S   Masquelier Donald A DA   Merrill Landon L   Terry Jessica M JM   Mudivarti Patrice A PA   Wyatt Paul W PW   Bharadwaj Rajiv R   Makarewicz Anthony J AJ   Li Yuan Y   Belgrader Phillip P   Price Andrew D AD   Lowe Adam J AJ   Marks Patrick P   Vurens Gerard M GM   Hardenbol Paul P   Montesclaros Luz L   Luo Melissa M   Greenfield Lawrence L   Wong Alexander A   Birch David E DE   Short Steven W SW   Bjornson Keith P KP   Patel Pranav P   Hopmans Erik S ES   Wood Christina C   Kaur Sukhvinder S   Lockwood Glenn K GK   Stafford David D   Delaney Joshua P JP   Wu Indira I   Ordonez Heather S HS   Grimes Susan M SM   Greer Stephanie S   Lee Josephine Y JY   Belhocine Kamila K   Giorda Kristina M KM   Heaton William H WH   McDermott Geoffrey P GP   Bent Zachary W ZW   Meschi Francesca F   Kondov Nikola O NO   Wilson Ryan R   Bernate Jorge A JA   Gauby Shawn S   Kindwall Alex A   Bermejo Clara C   Fehr Adrian N AN   Chan Adrian A   Saxonov Serge S   Ness Kevin D KD   Hindson Benjamin J BJ   Ji Hanlee P HP  

Nature biotechnology 20160201 3


Haplotyping of human chromosomes is a prerequisite for cataloguing the full repertoire of genetic variation. We present a microfluidics-based, linked-read sequencing technology that can phase and haplotype germline and cancer genomes using nanograms of input DNA. This high-throughput platform prepares barcoded libraries for short-read sequencing and computationally reconstructs long-range haplotype and structural variant information. We generate haplotype blocks in a nuclear trio that are concor  ...[more]

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