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

Author

Listed:
  • Qingbo Wang

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Emma Pierce-Hoffman

    (The Broad Institute of MIT and Harvard)

  • Beryl B. Cummings

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Jessica Alföldi

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Laurent C. Francioli

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Laura D. Gauthier

    (The Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Andrew J. Hill

    (The Broad Institute of MIT and Harvard
    University of Washington)

  • Anne H. O’Donnell-Luria

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Konrad J. Karczewski

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Daniel G. MacArthur

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Garvan Institute of Medical Research, and UNSW Sydney
    Murdoch Children’s Research Institute)

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.

Suggested Citation

  • 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 & Daniel G. MacArth, 2020. "Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-12438-5
    DOI: 10.1038/s41467-019-12438-5
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    Cited by:

    1. Naser Ansari-Pour & Yonglan Zheng & Toshio F. Yoshimatsu & Ayodele Sanni & Mustapha Ajani & Jean-Baptiste Reynier & Avraam Tapinos & Jason J. Pitt & Stefan Dentro & Anna Woodard & Padma Sheila Rajagop, 2021. "Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Chao Yang & Zhenzhen Ma & Keshan Wang & Xingxiao Dong & Meiyu Huang & Yaqiu Li & Xiagu Zhu & Ju Li & Zhihui Cheng & Changhao Bi & Xueli Zhang, 2023. "HMGN1 enhances CRISPR-directed dual-function A-to-G and C-to-G base editing," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Hangxing Jia & Shengjun Tan & Yingao Cai & Yanyan Guo & Jieyu Shen & Yaqiong Zhang & Huijing Ma & Qingzhu Zhang & Jinfeng Chen & Gexia Qiao & Jue Ruan & Yong E. Zhang, 2024. "Low-input PacBio sequencing generates high-quality individual fly genomes and characterizes mutational processes," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Wenan Chen & Shuoguo Wang & Saima Sultana Tithi & David W. Ellison & Daniel J. Schaid & Gang Wu, 2022. "A rare variant analysis framework using public genotype summary counts to prioritize disease-predisposition genes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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