SUMMARYBACKGROUNDAnalysis of sequenced genomes from large three-generation families allows de novo mutations identified in Generation II individuals to be attributed to each of their parents’ germlines in Generation I. Because germline mutations increase with age, we hypothesized that they directly limit the duration of childbearing in women, and if correlated with mutation accumulation in somatic tissues, also reflect systemic aging in both sexes. Here we test whether the germline mutation rates of Generation I individuals when they were young adults predict their remaining survival, as well as the women’s reproductive lifespans.METHODSGermline autosomal mutation counts in 122 Generation I individuals (61 women, 61 men) from 41 three-generation Utah CEPH families were converted to germline mutation rates by normalizing each subject’s number of mutations to the callable portion of their genome. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Cancer Registry, and Utah Genetic Reference Project. Fertility analyses were restricted to the 53 women whose age at last birth (ALB) was at least 30 years, the approximate age when the decline in female fertility begins. Cox proportional hazard regression models were used to test the association of age-adjusted mutation rates (AAMRs) with aging-related outcomes. Linear regression analysis was used to estimate the age when adult germline mutation accumulation rates are established.FINDINGSQuartiles of increasing AAMRs were associated with increasing all-cause mortality rates in both sexes combined (test for trend, p=0.009); subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21-3.56; p=0.008; median survival difference = 4.7 years). Women with higher AAMRs had significantly fewer live births and a younger ALB. The analyses also indicate that adult germline mutation accumulation rates are established in adolescence, and that later menarche in women may delay mutation accumulation.INTERPRETATIONParental-age-adjusted germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic aging. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair genes’ expression levels are known to begin their lifelong decline.FUNDINGNIH R01AG038797 and R21AG054962 (to R.M.C.); University of Utah Program in Personalized Health (to H.D.M.); NIH T32GM007464 (to T.A.S.); NIH R01AG022095 (to K.R.S.); NIH R01HG006693, R01HG009141, and R01GM124355 (to A.R.Q.); NIH GM118335 and GM059290 (to L.B.J.); NIH P30CA2014 (to the Utah Population Database, a.k.a. the UPDB); National Center for Research Resources Public Health Services grant M01RR00064 (to the Huntsman General Clinical Research Center, University of Utah); National Center for Advancing Translational Sciences NIH grant UL1TR002538 (to the University of Utah’s Center for Clinical and Translational Science); Howard Hughes Medical Institute funding (to Ray White); gifts from the W.M. Keck Foundation (to Stephen M. Prescott and M.F.L.) and from the George S. and Delores Doré Eccles Foundation (to the University of Utah) that supported the Utah Genetic Reference Project (UGRP). Sequencing of the CEPH samples was funded by the Utah Genome Project, the George S. and Dolores Doré Eccles Foundation, and the H.A. and Edna Benning Foundation. We thank the Pedigree and Population Resource of the Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the UPDB.
Distinct mutation accumulation rates among tissues determine the variation in cancer risk