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Stitziel, Nathan

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Stitziel

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Stitziel, Nathan

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    Mapping and Characterization of Structural Variation in 17,795 Human Genomes
    (Cold Spring Harbor Laboratory, 2020-05-27) Abel, Haley J.; Larson, David E.; Regier, Allison A.; Chiang, Colby; Das, Indraniel; Kanchi, Krishna L.; Layer, Ryan M.; Neale, Benjamin; Salerno, William J.; Reeves, Catherine; Buyske, Steven; Matise, Tara C.; Muzny, Donna M.; Zody, Michael; Lander, Eric; Dutcher, Susan K.; Stitziel, Nathan; Hall, Ira M.
    ABSTRACTA key goal of whole genome sequencing (WGS) for human genetics studies is to interrogate all forms of variation, including single nucleotide variants (SNV), small insertion/deletion (indel) variants and structural variants (SV). However, tools and resources for the study of SV have lagged behind those for smaller variants. Here, we used a cloud-based pipeline to map and characterize SV in 17,795 deeply sequenced human genomes from common disease trait mapping studies. We publicly release site-frequency information to create the largest WGS-based SV resource to date. On average, individuals carry 2.9 rare SVs that alter coding regions, which affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Based on a computational model, we estimate that SVs account for 17.2% of rare alleles genome-wide whose predicted deleterious effects are equivalent to loss-of-function (LoF) coding alleles; ~90% of such SVs are non-coding deletions (mean 19.1 per genome). We report 158,991 ultra-rare SVs and show that ~2% of individuals carry ultra-rare megabase-scale SVs, nearly half of which are balanced and/or complex rearrangements. Finally, we exploit this resource to infer the dosage sensitivity of genes and non-coding elements, revealing strong trends related to regulatory element class, conservation and cell-type specificity. This work will help guide SV analysis and interpretation in the era of WGS.