Summary 11 12Little is known about differences in germline mutation processes between 13 extant mammals. We analysed genome sequences of mouse and human 14 pedigrees to investigate mutational differences between these species. We found 15 that while the generational mutation rate in mice is 40% of that in humans, the 16 annual mutation rate is 16 times higher, and the mutation rate per cell division is 17 two-fold higher. We classified mutations into four temporal strata reflecting the 18 timing of the mutation within the lineage from zygote to gamete. The earliest 19 embryonic cell divisions are the most mutagenic in both species, but these 20 earliest mutations account for a much higher proportion of all mutations in mice 21 (~25%) than in humans (~5%). We observed a strong sex bias in the number of 22 mutations arising in subsequent cell divisions in the early embryo in mice, but not 23 in humans. Finally, we reconstructed partial genealogies of murine parental 24 gametes that suggest markedly unequal contributions from founding primordial 25 germ cells.

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