2022 Theses Doctoral

Scouring genomes and evolutionary trees for the origins of sex-biased germline mutation

Wu, Felix

Mammals receive more germline mutations from fathers than mothers. While the paternal bias in mutation has historically been attributed to errors in DNA replication during spermatogenesis, evidence suggests that in humans mutational mechanisms independent from cell division may play a more prominent role. Understanding how the ratio of paternal-to-maternal mutations, 𝛼, varies across animals differing in their gametogenic development, physiologies, and habitats can provide unique insights into the processes by which mutation arises in male and female germlines. To these ends, this thesis examines features of paternal mutation bias in dozens of amniote species using a combination of sequencing and evolutionary approaches.

A direct way of measuring the strength of paternal mutation bias involves sequencing pedigrees of related individuals and detecting mutations arising in a single generation. In Chapter 2, we applied this approach to measure 𝛼 in olive baboons (Papio anubis) and humans. Strikingly, we estimated that in baboons 𝛼 = 4.5, similar to humans, despite baboons experiencing far fewer spermatogenic cell divisions than humans. A model of mutation based on cell division differences in the two species failed to explain this observation. Our results provide added evidence for non-replicative processes driving paternal bias in mutation and suggest that these causes are likely shared across mammals.

In Chapter 3, we expanded our analysis to survey 𝛼 across 42 amniote species. We estimated 𝛼 from putatively neutral substitution rates of sex chromosomes and autosomes and found that in mammals, 𝛼 ranges up to 4 and correlates with generation times. In contrast, birds and snakes harbor a stable 𝛼 of roughly 2. These results are well predicted by modeling sex bias in mutation as a product of an early developmental phase when mutation occurs equally in both parents and a late phase after sexual differentiation when the male germline is more mutagenic. That the paternal mutation bias is widespread and occupies a narrow range of values suggests that it is caused by endogenous damage sources that are similar across species.

Through a combination of pedigree sequencing and evolutionary techniques, this work demonstrates how a comparative approach across diverse taxa can shed light on the origins of sex-bias in germline mutation.