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Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes


Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors Wang, Q.; Pierce-Hoffman, E.; Cummings, B. B.; Alfoldi, J.; Francioli, L. C.; Gauthier, L. D.; Hill, A. J.; O'Donnell-Luria, A. H.; Genome Aggregation Database Production, Team; Genome Aggregation Database, Consortium; Karczewski, K. J.; MacArthur, D. G.
Responsible Garvan Author Daniel MacArthur
Publisher Name Nature Communications
Published Date 2020-05-27
Published Volume 11
Published Issue 1
Published Pages 2539
Status Published in-print
DOI 10.1038/s41467-019-12438-5
URL link to publisher's version