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    De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population

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    Author
    Kessler, M.D.
    Loesch, D.P.
    Perry, J.A.
    O'Connell, J.R.
    Mitchell, B.D.
    National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Consortium
    TOPMed Population Genetics Working Group
    O'Connor, T.D.
    Date
    2020
    Journal
    Proceedings of the National Academy of Sciences of the United States of America
    Publisher
    National Academy of Sciences
    Type
    Article
    
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    See at
    https://doi.org/10.1073/pnas.1902766117
    Abstract
    De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment. Copyright 2020 the Author(s).
    Keyword
    Amish
    de novo mutations
    diversity
    mutation rate
    recombination
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85079020940&doi=10.1073%2fpnas.1902766117&partnerID=40&md5=02a62308f5bbe35a696b8ffb710f65c7; http://hdl.handle.net/10713/12018
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.1902766117
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