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

Qingbo Wang, Emma Pierce-Hoffman, Beryl B. Cummings, Jessica Alföldi, Laurent C. Francioli, Laura D. Gauthier, Andrew J. Hill, Anne H. O’Donnell-Luria, Konrad J. Karczewski and Daniel G. MacArthur ()
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Qingbo Wang: The Broad Institute of MIT and Harvard
Emma Pierce-Hoffman: The Broad Institute of MIT and Harvard
Beryl B. Cummings: The Broad Institute of MIT and Harvard
Jessica Alföldi: The Broad Institute of MIT and Harvard
Laurent C. Francioli: The Broad Institute of MIT and Harvard
Laura D. Gauthier: The Broad Institute of MIT and Harvard
Andrew J. Hill: The Broad Institute of MIT and Harvard
Anne H. O’Donnell-Luria: The Broad Institute of MIT and Harvard
Konrad J. Karczewski: The Broad Institute of MIT and Harvard
Daniel G. MacArthur: The Broad Institute of MIT and Harvard

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-12438-5

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