Germline mutation rates in young adults predict longevity and reproductive lifespan

Abstract

Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. 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). Fertility analyses were restricted to women whose age at last birth (ALB) was ≥ 30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.

Figure 1

The frequency or rate of mutations in the germ cells of young adults increases with age and can vary more than 2-fold between sex- and age- matched individuals. Germline mutation rates were measured as (#germline autosomal mutations)/(#diploid autosomal callable base pairs). The single data point plotted for each of the 61 Generation I males (squares) and 61 Generation I females (circles) is derived from de novo mutations discovered in a single one of their offspring. After adjusting for the effects of parental age, the mutation rate of each individual was assigned to a quartile of Age-Adjusted Mutation Rate (AAMR), with each quartile indicated by one of the four colors in the graph. Differences between Generation I individuals in their germline mutation rates are unlikely to be due to differences in the presence or absence or degree of progression of various terminal illnesses, since all Generation I subjects survived more than 20 years past the age at which they transmitted these germ cell mutations to their offspring. Furthermore, it is unlikely that any of the mutations analyzed here are strongly deleterious, since all Generation II individuals in whom the de novo mutations were identified are known to have reached maturity and had several children of their own. (Adapted from Sasani et al., Fig. 2a).

Figure 2

Predicted survival curves by quartiles of age-adjusted germline mutation rates. Parental age and birth year were fixed to their median values (25 years and 1912, respectively) based on the fitted model in Table 1. (a) both sexes combined, all-cause mortality; (b) males only, all-cause mortality; (c) females only, non-cardiovascular disease (non-CVD) mortality. AAMRs: age-adjusted mutation rates, with quartiles color-coded as in Fig. 1.

Figure 3

Estimating the age when germline mutation accumulation rates are established. The germline mutation rates plotted in Fig. 1 are again plotted here, but with the x and y axes flipped. Analyzed in this way, the y intercepts of the linear regression lines, when mutation counts would be zero, provide approximate lower bounds for the ages when the observed mutation accumulation rates (slopes of the regression lines) were established: about 14 years for males (panel a) and 18 years for females (panel b). Germline mutation rate = (#germline autosomal mutations)/(#diploid autosomal callable base pairs).

Figure 4

Effects of age at menarche on germline mutation rates in 20 Generation I women. Top panel: linear regression of age at menarche vs. AAMR showing that older ages at menarche are associated with lower AAMRs, Pearson correlation coefficient r = −0.418, p value = 0.021. Bottom panel: box plot of age at menarche by two categories of AAMRs, <50th percentile (<0.0095) and ≥50th percentile (≥0.0095), showing that the mean age at menarche for women in the bottom half for AAMRs (13.3 years) was significantly higher than the mean age at menarche for women in the top half for AAMRs (12.4 years), by a two-tail t test (p  =  0.0276). Diamonds mark the mean ages of menarche.