TY - JOUR
T1 - Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
AU - Genome Aggregation Database Production Team
AU - Genome Aggregation Database Consortium
AU - Wang, Qingbo
AU - Pierce-Hoffman, Emma
AU - Cummings, Beryl B.
AU - Alföldi, Jessica
AU - Francioli, Laurent C.
AU - Gauthier, Laura D.
AU - Hill, Andrew J.
AU - O’Donnell-Luria, Anne H.
AU - Armean, Irina M.
AU - Banks, Eric
AU - Bergelson, Louis
AU - Cibulskis, Kristian
AU - Collins, Ryan L.
AU - Connolly, Kristen M.
AU - Covarrubias, Miguel
AU - Daly, Mark J.
AU - Donnelly, Stacey
AU - Farjoun, Yossi
AU - Ferriera, Steven
AU - Gabriel, Stacey
AU - Gentry, Jeff
AU - Gupta, Namrata
AU - Jeandet, Thibault
AU - Kaplan, Diane
AU - Laricchia, Kristen M.
AU - Llanwarne, Christopher
AU - Minikel, Eric V.
AU - Munshi, Ruchi
AU - Neale, Benjamin M.
AU - Novod, Sam
AU - Petrillo, Nikelle
AU - Poterba, Timothy
AU - Roazen, David
AU - Ruano-Rubio, Valentin
AU - Saltzman, Andrea
AU - Samocha, Kaitlin E.
AU - Schleicher, Molly
AU - Seed, Cotton
AU - Solomonson, Matthew
AU - Soto, Jose
AU - Tiao, Grace
AU - Tibbetts, Kathleen
AU - Tolonen, Charlotte
AU - Vittal, Christopher
AU - Wade, Gordon
AU - Wang, Arcturus
AU - Ware, James S.
AU - Watts, Nicholas A.
AU - Weersma, Rinse K.
AU - Karczewski, Konrad J.
AU - MacArthur, Daniel G.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85085576031
U2 - 10.1038/s41467-019-12438-5
DO - 10.1038/s41467-019-12438-5
M3 - Article
C2 - 32461613
AN - SCOPUS:85085576031
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
M1 - 2539
ER -