Haplotype-resolved genome sequencing of a Gujarati Indian individual

Haplotype-resolved genome sequencing of a Gujarati Indian individual

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Jacob O Kitzman,
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Alexandra P MacKenzie,
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Andrew Adey,
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Joseph B Hiatt,
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Rupali P Patwardhan,
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Peter H Sudmant,
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Sarah B Ng,
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Can Alkan,
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Ruolan Qiu,
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Evan E Eichler
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& Jay Shendure

Haplotype information is essential to the complete description and interpretation of genomes1, genetic diversity2 and genetic ancestry3. Although individual human genome sequencing is increasingly routine4, nearly all such genomes are unresolved with respect to haplotype. Here we combine the throughput of massively parallel sequencing5 with the contiguity information provided by large-insert cloning6 to experimentally determine the haplotype-resolved genome of a South Asian individual. A single fosmid library was split into a modest number of pools, each providing ~3% physical coverage of the diploid genome. Sequencing of each pool yielded reads overwhelmingly derived from only one homologous chromosome at any given location. These data were combined with whole-genome shotgun sequence to directly phase 94% of ascertained heterozygous single nucleotide polymorphisms (SNPs) into long haplotype blocks (N50 of 386 kilobases (kbp)). This method also facilitates the analysis of structural variation, for example, to anchor novel insertions7, 8 to specific locations and haplotypes.http://www.nature.com