A paternal bias in germline mutation is widespread in amniotes and can arise independently of cell divisions

Abstract

In humans and other mammals, germline mutations are more likely to arise in fathers than in mothers. Although this sex bias has long been attributed to DNA replication errors in spermatogenesis, recent evidence from humans points to the importance of mutagenic processes that do not depend on cell division, calling into question our understanding of this basic phenomenon. Here, we infer the ratio of paternal-to-maternal mutations, α, in 42 species of amniotes, from putatively neutral substitution rates of sex chromosomes and autosomes. Despite marked differences in gametogenesis, physiologies and environments across species, fathers consistently contribute more mutations than mothers in all the species examined, including mammals, birds and reptiles. In mammals, α is as high as 4 and correlates with generation times; in birds and snakes, α appears more stable around 2. These observations can be explained by a simple model, in which mutations accrue at equal rates in both sexes during early development and at a higher rate in the male germline after sexual differentiation, with a conserved paternal-to-maternal ratio across species. Thus, α may reflect the relative contributions of two or more developmental phases to total germline mutations, and is expected to depend on generation time even if mutations do not track cell divisions.

De novo Mutations in Domestic Cat are Consistent with an Effect of Reproductive Longevity on Both the Rate and Spectrum of Mutations

“…We found 93 mutations were of paternal origin, whereas 31 were of maternal origin, consistent with a male mutation bias (binomial P = 2.2 × 10 −8 ; Wilson Sayres and Makova 2011 ; Ségurel et al 2014 ). The proportion of male-biased cat mutations (75%) is consistent with the proportion found in humans (80.4%; Jónsson et al 2017 ) and other mammals ( de Manuel et al 2022 ). These phased mutations also show a parental age effect: more mutations were transmitted from older parents, significantly so for older fathers (Poisson regression of read-phased mutations, paternal P = 0.032; supplementary fig.…”

De novomutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations

“…We found 93 mutations were of paternal origin while 31 were of maternal origin, consistent with a male mutation bias (binomial p = 2.2 × 10 -8 ; Wilson Sayres and Makova 2011; Ségurel et al 2014). The proportion of male-biased cat mutations (75%) is consistent with the proportion found in humans (80.4%; Jónsson et al 2017) and other mammals (de Manuel et al 2022). These phased mutations also show a parental age effect: more mutations were transmitted from older parents, significantly so for older fathers (Poisson regression of read-phased mutations, paternal p = 0.032; Fig.…”

Hibernation shows no apparent effect on germline mutation rates in grizzly bears

“…Although continued male germline replication is an obvious correlate of many of the coarse patterns of mutation accumulation, data from whole-genome sequencing has also uncovered multiple finegrained patterns that do not fit with this hypothesis. A simple model in which some aspect of mutation repair differs between males and females across most of their lifespan would fit the general trends equally well, and do much to explain several seemingly paradoxical patterns (Gao et al 2019; de Manuel et al 2022). Further investigation of underlying mutational mechanisms may help to add further detail to this newer model.…”

“…One obvious explanation is that an increasing mutation rate with age and a male bias in mutation are not driven by continuing mitosis during male spermatogenesis. As mentioned in the Introduction (also see de Manuel et al 2022), there are several patterns from whole-genome sequencing studies that do not appear consistent with the classical role attributed to male germline replication. Although continued male germline replication is an obvious correlate of many of the coarse patterns of mutation accumulation, data from whole-genome sequencing has also uncovered multiple finegrained patterns that do not fit with this hypothesis.…”

“…Despite the general acceptance of the male germline replication model of mutation accumulation, several patterns from whole-genome sequencing studies have emerged that do not fit easily within this paradigm. Here we mention four of these patterns (see de Manuel et al 2022 for further discussion). 1) Spermatogenic cycle length is not predictive of mutation rates: non-human primates with shorter seminiferous epithelial cycle lengths do not show a faster rate of mutation accumulation per year (Wang et al 2020; Wu et al 2020).…”