期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 5, 页码 2560-2569出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1902766117
关键词
de novo mutations; Amish; mutation rate; recombination; diversity
资金
- National Heart, Lung, and Blood Institute (NHLBI)
- NIH [T32CA154274, T32HL007698]
- Center for Health Related Informatics and Bioimaging at the University of Maryland School of Medicine
- NIH Genomic Commons Award [OT3 OD025459-01]
- NHLBI Trans-Omics for Precision Medicine Program High-performance Grant [U01 HL137181-01]
- National Human Genome Research Institute Genomic Innovator Grant [1 R35 HG010692-01]
- American Thoracic Society Foundation [K01-HL135405]
- Framingham Heart Study Grant [HHSN268201500001]
- [R01 HL121007]
- [R01 AG18728]
- [U01 HL072515]
- [1P01HL132825-01]
- [R01-HL113338]
- [3R01HL121007.-01S1]
- [3R01HL104608-04S1]
- [3R01HL098433-05S1]
- [3R37HL066289-13S1]
- [3R01HL092577-06S1]
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 DNM5 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 DNM5 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 DNM5. Finally, we calculated near-zero estimates of narrow sense heritability (h(2)), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
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