De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population.
Michael D Kessler,
Douglas P. Loesch,
James A Perry,
Nancy L. Heard-Costa,
Brian E. Cade,
Juan C. Celedón,
Manuel E. Soto-Quiros,
Scott T Weiss,
Susan S. Redline,
Andrew D Johnson,
James G Wilson,
Deborah A. Nickerson,
Sharon R Browning,
Jeffrey R O'Connell,
Trans-Omics for Precision Medicine (TOPMed), TOPMed Population Genetics Working Group,
Timothy D. O’Connor
Posted 19 Feb 2019
bioRxiv DOI: 10.1101/553214 (published DOI: 10.1073/pnas.1902766117)
Posted 19 Feb 2019
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 directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, 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, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.
- Downloaded 806 times
- Download rankings, all-time:
- Site-wide: 53,196
- In genetics: 2,090
- Year to date:
- Site-wide: 150,395
- Since beginning of last month:
- Site-wide: 90,233
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!