{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T19:34:59Z","timestamp":1785526499807,"version":"3.56.0"},"reference-count":50,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"31","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32470646"],"award-info":[{"award-number":["32470646"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key Research and Development Program of China","award":["2024YFA1802500"],"award-info":[{"award-number":["2024YFA1802500"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,7,31]]},"abstract":"<jats:p>\n                    Germline mutations play a pivotal role in evolution and are the primary cause of hereditary diseases in humans. Although interpopulation and interspecific variations in the mutation rate and spectrum are observed, their underlying genetic basis is still unclear. In this study, we explore the genetic regulation of germline mutation rates using one of the largest publicly available datasets derived from parent-offspring whole-genome sequencing. We first showed that germline mutation rates are strongly correlated between siblings, suggesting the influence of heritable factors. We then performed a genome-wide association study (GWAS), identifying 14 loci significantly associated with mutation rates, Notably, a lead single-nucleotide polymorphism (SNP) in the\n                    <jats:italic toggle=\"yes\">NHEJ1<\/jats:italic>\n                    gene, critical for DNA repair, was linked to a 27% increase in maternal mutation rates and a significant shift toward A-to-T mutations only in females. This mutator allele is particularly prevalent in East Asian populations, where a similar shift in the A-to-T mutation spectrum has been observed. Evolutionary analysis suggests that this allele likely emerged in the common ancestor of humans and the\n                    <jats:italic toggle=\"yes\">Pan<\/jats:italic>\n                    genus. Furthermore, the genotype at the lead SNP position in\n                    <jats:italic toggle=\"yes\">Pan<\/jats:italic>\n                    species is also the same as the human mutator allele, supporting the potential role for this allele to explain the accelerated A-to-T mutations observed in the human-\n                    <jats:italic toggle=\"yes\">Pan<\/jats:italic>\n                    lineage. Together, these results indicate that genetic variants, particularly in DNA repair pathways, contribute to variation in mutation rates and spectra across individuals and populations, with a notable sex-specific effect.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed2571","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:58:34Z","timestamp":1785520714000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A\n                    <i>NHEJ1<\/i>\n                    mutator allele influencing germline mutation rates sex-specifically in humans"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2878-8437","authenticated-orcid":true,"given":"Kun","family":"Wu","sequence":"first","affiliation":[{"name":"Center for Evolutionary &amp; Organismal Biology, Department of Pharmacy, Center for Regeneration and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, International School of Medicine, and International Institutes of Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4355-7015","authenticated-orcid":true,"given":"Jiuhong","family":"Nan","sequence":"additional","affiliation":[{"name":"Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 311121, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1075-8185","authenticated-orcid":true,"given":"Haoxuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Evolutionary &amp; Organismal Biology, Department of Pharmacy, Center for Regeneration and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, International School of Medicine, and International Institutes of Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Zhejiang-Denmark Joint Laboratory of Regeneration and Aging Medicine, Yiwu 322000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3295"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21062"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-1878(200012)22:12<1057::AID-BIES3>3.0.CO;2-W"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.104"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24364-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.24284"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418652112"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08922-2"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/evlett\/qrad027"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1186802"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/em.22087"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00648-7"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39248-0"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.06.005"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1619655114"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0016672300010284"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2010.05.003"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/gbe\/evr066"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-59750-x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1901259116"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3469"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24018"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat6576"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0107-y"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11396"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3597"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.271809.120"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2507"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702620104"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm579"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn957"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.05.052"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06045-0"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-019-5572-x"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2146"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.116.197145"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10231"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00297-8"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.7.1731"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-024-05703-y"},{"key":"e_1_3_2_43_2","first-page":"11.10.1","article-title":"From FastQ data to high-confidence variant calls: The genome analysis toolkit best practices pipeline","volume":"43","author":"Van der Auwera G. 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