Mapping and characterization of structural variation in 17,795 deeply sequenced human genomes
Haley J Abel,
David E. Larson,
Krishna L Kanchi,
Ryan M. Layer,
Benjamin M. Neale,
William J Salerno,
NHGRI Centers for Common Disease Genomics,
Tara C Matise,
Donna M. Muzny,
Michael C. Zody,
Eric S Lander,
Susan K Dutcher,
Nathan O. Stitziel,
Ira M Hall
Posted 31 Dec 2018
bioRxiv DOI: 10.1101/508515
Posted 31 Dec 2018
A 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.
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