The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra
Abstract De novo germline mutation is an important factor in the evolution of allelic diversity and disease predisposition in a population. Here, we study the influence of genetically-inferred ancestry and environmental factors on de novo mutation rates and spectra. Using a genetically diverse sampl...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59750-x |
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| author | O. Isaac Garcia-Salinas Seongwon Hwang Qin Qin Huang Rashesh Sanghvi Daniel S. Malawsky Joanna Kaplanis Matthew D. C. Neville Felix R. Day Raheleh Rahbari Aylwyn Scally Hilary C. Martin |
| author_facet | O. Isaac Garcia-Salinas Seongwon Hwang Qin Qin Huang Rashesh Sanghvi Daniel S. Malawsky Joanna Kaplanis Matthew D. C. Neville Felix R. Day Raheleh Rahbari Aylwyn Scally Hilary C. Martin |
| author_sort | O. Isaac Garcia-Salinas |
| collection | DOAJ |
| description | Abstract De novo germline mutation is an important factor in the evolution of allelic diversity and disease predisposition in a population. Here, we study the influence of genetically-inferred ancestry and environmental factors on de novo mutation rates and spectra. Using a genetically diverse sample of ~10 K whole-genome sequenced trios, one of the largest de novo mutation catalogues to date, we found that genetically-inferred ancestry is associated with modest but significant changes in both germline mutation rate and spectra across continental populations. These effects may be due to genetic or environmental factors correlated with ancestry. We find epidemiological evidence that cigarette smoking is significantly associated with increased de novo mutation rate, but it does not mediate the observed ancestry effects. Investigation of several other potential mutagenic factors using Mendelian randomisation showed no consistent effects, except for age at menopause, where factors increasing this corresponded to a reduction in de novo mutation rate. Overall, our study sheds light on factors influencing de novo mutation rates and spectra. |
| format | Article |
| id | doaj-art-b67871a7a58849148a6698ea337bc26b |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b67871a7a58849148a6698ea337bc26b2025-08-20T02:25:17ZengNature PortfolioNature Communications2041-17232025-05-011611910.1038/s41467-025-59750-xThe impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectraO. Isaac Garcia-Salinas0Seongwon Hwang1Qin Qin Huang2Rashesh Sanghvi3Daniel S. Malawsky4Joanna Kaplanis5Matthew D. C. Neville6Felix R. Day7Raheleh Rahbari8Aylwyn Scally9Hilary C. Martin10Wellcome Sanger Institute, Wellcome Genome CampusDepartment of Genetics, University of CambridgeWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusGenomics EnglandWellcome Sanger Institute, Wellcome Genome CampusMRC Epidemiology Unit, Box 285 Institute of Metabolic Science, University of Cambridge School of Clinical MedicineWellcome Sanger Institute, Wellcome Genome CampusDepartment of Genetics, University of CambridgeWellcome Sanger Institute, Wellcome Genome CampusAbstract De novo germline mutation is an important factor in the evolution of allelic diversity and disease predisposition in a population. Here, we study the influence of genetically-inferred ancestry and environmental factors on de novo mutation rates and spectra. Using a genetically diverse sample of ~10 K whole-genome sequenced trios, one of the largest de novo mutation catalogues to date, we found that genetically-inferred ancestry is associated with modest but significant changes in both germline mutation rate and spectra across continental populations. These effects may be due to genetic or environmental factors correlated with ancestry. We find epidemiological evidence that cigarette smoking is significantly associated with increased de novo mutation rate, but it does not mediate the observed ancestry effects. Investigation of several other potential mutagenic factors using Mendelian randomisation showed no consistent effects, except for age at menopause, where factors increasing this corresponded to a reduction in de novo mutation rate. Overall, our study sheds light on factors influencing de novo mutation rates and spectra.https://doi.org/10.1038/s41467-025-59750-x |
| spellingShingle | O. Isaac Garcia-Salinas Seongwon Hwang Qin Qin Huang Rashesh Sanghvi Daniel S. Malawsky Joanna Kaplanis Matthew D. C. Neville Felix R. Day Raheleh Rahbari Aylwyn Scally Hilary C. Martin The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra Nature Communications |
| title | The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra |
| title_full | The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra |
| title_fullStr | The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra |
| title_full_unstemmed | The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra |
| title_short | The impact of ancestral, genetic, and environmental influences on germline de novo mutation rates and spectra |
| title_sort | impact of ancestral genetic and environmental influences on germline de novo mutation rates and spectra |
| url | https://doi.org/10.1038/s41467-025-59750-x |
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