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      Scaling accurate genetic variant discovery to tens of thousands of samples

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          Abstract

          Comprehensive disease gene discovery in both common and rare diseases will require the efficient and accurate detection of all classes of genetic variation across tens to hundreds of thousands of human samples. We describe here a novel assembly-based approach to variant calling, the GATK HaplotypeCaller (HC) and Reference Confidence Model (RCM), that determines genotype likelihoods independently per-sample but performs joint calling across all samples within a project simultaneously. We show by calling over 90,000 samples from the Exome Aggregation Consortium (ExAC) that, in contrast to other algorithms, the HC-RCM scales efficiently to very large sample sizes without loss in accuracy; and that the accuracy of indel variant calling is superior in comparison to other algorithms. More importantly, the HC-RCM produces a fully squared-off matrix of genotypes across all samples at every genomic position being investigated. The HC- RCM is a novel, scalable, assembly-based algorithm with abundant applications for population genetics and clinical studies.

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          Author and article information

          Journal
          bioRxiv
          November 14 2017
          Article
          10.1101/201178
          a6297dc4-558c-45c4-ae25-0b94dddd78d5
          © 2017
          History

          Human biology,Genetics
          Human biology, Genetics

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