title: 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.
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Grace X Y
authors.initials: GX
authors.lastname: Zheng
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.
authors.forename: Billy T
authors.initials: BT
authors.lastname: Lau
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schnall-Levin
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Mirna
authors.initials: M
authors.lastname: Jarosz
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Bell
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hindson
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Sofia
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authors.lastname: Kyriazopoulou-Panagiotopoulou
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Masquelier
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Landon
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authors.lastname: Merrill
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Terry
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Patrice A
authors.initials: PA
authors.lastname: Mudivarti
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Wyatt
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Bharadwaj
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Makarewicz
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Belgrader
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Andrew D
authors.initials: AD
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authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.lastname: Lowe
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0002-3231-7163
authors.initials: P
authors.lastname: Marks
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.initials: GM
authors.lastname: Vurens
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.lastname: Hardenbol
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Birch
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Short
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.initials: KP
authors.lastname: Bjornson
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Pranav
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authors.lastname: Patel
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.
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authors.initials: ES
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authors.affiliation: Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
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authors.initials: C
authors.lastname: Wood
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.initials: GK
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authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.initials: D
authors.lastname: Stafford
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.initials: JP
authors.lastname: Delaney
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
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authors.initials: I
authors.lastname: Wu
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Ordonez
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Grimes
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Greer
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Josephine Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Kamila
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authors.lastname: Belhocine
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Giorda
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Heaton
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: McDermott
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: Bent
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Meschi
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Nikola O
authors.initials: NO
authors.lastname: Kondov
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Wilson
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bernate
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Gauby
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Kindwall
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Bermejo
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Adrian N
authors.initials: AN
authors.lastname: Fehr
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Chan
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Saxonov
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Ness
authors.affiliation: 10X Genomics, Pleasanton, California, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Hindson
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.|Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Hanlee P
authors.initials: HP
authors.lastname: Ji
mesh_terms: D004247:DNA / Q000235:genetics; D015894:Genome, Human; D056914:Genomic Structural Variation; D005854:Germ Cells; D006239:Haplotypes / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009690:Nucleic Acid Conformation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D004247:DNA
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