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

Wang, Qingbo ; Groop, Leif LU ; Haiman, C ; Melander, Olle LU orcid ; Nilsson, Peter M LU and MacArthur, Daniel G (2020) In Nature Communications 11.
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,... (More)
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 (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
11
article number
2539
publisher
Nature Publishing Group
external identifiers
  • scopus:85085576031
ISSN
2041-1723
DOI
10.1038/s41467-019-12438-5
language
English
LU publication?
yes
id
0ca9995c-aa77-4782-bed8-6f7680b00ba7
date added to LUP
2022-03-29 11:53:57
date last changed
2024-04-10 09:33:26
@article{0ca9995c-aa77-4782-bed8-6f7680b00ba7,
  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}},
  author       = {{Wang, Qingbo and Groop, Leif and Haiman, C and Melander, Olle and Nilsson, Peter M and MacArthur, Daniel G}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-12438-5}},
  doi          = {{10.1038/s41467-019-12438-5}},
  volume       = {{11}},
  year         = {{2020}},
}