Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
By Qingbo S. Wang, Emma Pierce-Hoffman, Beryl B. Cummings, Jessica Alföldi, L. Francioli, Laura D. Gauthier, Andrew J. Hill, Anne H. O'Donnell-Luria, Irina M. Armean, Eric Banks and 150 more. 2020
126 citations recorded by the source corpus.
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. 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.
Subfields: Genetics, Molecular Biology
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Citations in the corpus
- Variant interpretation using population databases: lessons from gnomAD (2021, background): “MNVs that occur within a codon are annotated in gnomAD v2 data to aid interpretation of their combined effect (Wang et al., 2020).”