ATAV: a comprehensive platform for population-scale genomic analyses

Abstract

We present ATAV, an analysis platform for large-scale whole-exome and whole-genome sequencing projects. ATAV stores variant and coverage data for all samples in a centralized database, which is then efficiently queried by ATAV to support diagnostic analyses for trios and singletons, as well as rare-variant collapsing analyses for finding disease associations in complex diseases. Runtime logs ensure full reproducibility and the modularized ATAV framework makes it extensible to continuous development of new functions. In recent years ATAV has not only been helpful for identifying disease-causing variants for a range of diseases, but has also enabled the discovery of novel genes by rare-variant collapsing on datasets containing more than 20,000 samples. Analyses to date have been performed on more than 110,000 sequenced individuals demonstrating that the framework is robust to large-scale studies. Availability and implementation:ATAV is open source, cross-platform compatible, and is available under the MIT license at https://github.com/igm-team/atav

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

“…43,44 Finally, variants were annotated with ClinEff 45 and custom annotations, including Genome Aggregation Database (gnomAD) v.2.1 frequencies, 20 regional-intolerance metrics, 31,32 in silico filters, 46 and ClinVar (as of 10/20/2020) 38,39 clinical annotation, were added via the IGM's in-house analysis tool for annotated variants (ATAV) platform. 47…”

Challenges associated with diagnostic exome sequencing in liver diseases

“…We focused on variants that were predicted to have at least moderate to strong biological effects toward protein function and excluded those in intergenic and promoter regions. We used stringent quality filters and removed potential technical false-positive insertions and deletions (indels) using ATAV as previously described [29,31]. We excluded variants failing quality cutoffs in gnomAD or those identified as sequencing artifacts through a comparison of in-house control sequencing data.…”

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19

“…Variants were called according to the Genome Analysis Toolkit (GATK - Broad Institute, Boston, MA, USA) Best Practices recommendations v3.6 6,7 . Finally, variants were annotated with ClinEff 8 and the IGM’s in-house ATAV 9 (https://github.com/igm-team/atav) was used to add custom annotations including gnomAD v2.1 frequencies 10 and clinical annotations provided by the Human Gene Mutation Database (HGMD) 11 , ClinVar 12,13 , and Online Mendelian Inheritance in Man (OMIM). A centralized database was used to store variant and per site coverage data for all samples enabling well controlled analyses without the need of generating jointly called VCF files (see Ren et al 2020 9 for details).…”

“…Finally, variants were annotated with ClinEff 8 and the IGM’s in-house ATAV 9 (https://github.com/igm-team/atav) was used to add custom annotations including gnomAD v2.1 frequencies 10 and clinical annotations provided by the Human Gene Mutation Database (HGMD) 11 , ClinVar 12,13 , and Online Mendelian Inheritance in Man (OMIM). A centralized database was used to store variant and per site coverage data for all samples enabling well controlled analyses without the need of generating jointly called VCF files (see Ren et al 2020 9 for details). For each patient, we performed ancestry classification into one of the six major ancestry groups (European, African, Latino, East Asian, South Asian and Middle Eastern) using a neural network trained on a set of 1000 Genomes samples with known ancestry labels.…”