Scaling accurate genetic variant discovery to tens of thousands of samples

Citations Over Time

Abstract

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.

Related Papers

• → The missing indels: an estimate of indel variation in a human genome and analysis of factors that impede detection(2015)61 cited
• → Patterns of Insertion and Deletion in Mammalian Genomes(2007)56 cited
• → The pattern of insertion/deletion polymorphism in Arabidopsis thaliana(2008)29 cited
• → Genetic structure and relationships among 11 cattle populations using indel markers(2018)1 cited
• → Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function(2023)18 cited