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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.

Original publication

DOI

10.1038/s41467-019-12438-5

Type

Journal article

Journal

Nature communications

Publication Date

27/05/2020

Volume

11

Addresses

Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

Keywords

Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Humans, DNA Mutational Analysis, CpG Islands, Mutation, Genome, Human, Databases, Genetic, Genetic Variation, Exome