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

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Genome Aggregation Database Prod T , Genome Aggregation Database Consor , Wang , Q , Pierce-Hoffman , E , Cummings , B B , MacArthur , D G , Groop , L , Färkkilä , M , Palotie , A , Remes , A M , Ripatti , S , Salomaa , V , Soininen , H , Suvisaari , J , Tuomi , T , Vartiainen , E & Wessman , M 2020 , ' Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes ' , Nature Communications , vol. 11 , no. 1 , 2539 . https://doi.org/10.1038/s41467-019-12438-5

Title: Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
Author: Genome Aggregation Database Prod T; Genome Aggregation Database Consor; Wang, Qingbo; Pierce-Hoffman, Emma; Cummings, Beryl B.; MacArthur, Daniel G.; Groop, Leif; Färkkilä, Martti; Palotie, Aarno; Remes, Anne M.; Ripatti, Samuli; Salomaa, Veikko; Soininen, Hilkka; Suvisaari, Jaana; Tuomi, Tiinamaija; Vartiainen, Erkki; Wessman, Maija
Other contributor: University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland





















Date: 2020-05-27
Language: eng
Number of pages: 13
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-019-12438-5
URI: http://hdl.handle.net/10138/325078
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 2bp 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. Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.
Subject: DNA-POLYMERASE-ZETA
DE-NOVO MUTATIONS
WHOLE-GENOME
FRAMEWORK
SLIPPAGE
ELEMENTS
REPEATS
SIGNATURES
EVOLUTION
PATTERNS
1184 Genetics, developmental biology, physiology
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