Striking differences in patterns of germline mutation between mice and humans

Abstract

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.

Moderate nucleotide diversity in the Atlantic herring is associated with a low mutation rate

“…Our finding of a high degree of parental mosaicism for the detected de novo mutations is consistent with several recent studies indicating that the early cleavage cell divisions in the germ-line are particularly mutation-prone (Harland et al, 2016; Rahbari et al, 2016; Ségurel et al, 2014). A high rate of de novo mutations at early germ-cell divisions has also been reported for Drosophila (Gao et al, 2014).…”

“…About half of the de novo mutations were present in two or more offspring, indicating that they occurred during early germ cell divisions. Assuming that the number of cell divisions from zygote to mature sperm or egg is similar in Atlantic herring to the one in mammalian species, we can conclude from a recent simulation study (Harland et al, 2016) that it would be highly unlikely to observe such a high rate of parental mosaicism unless a large fraction of the de novo mutations occurred during early germ cell divisions. Further, the incidence of parental mosaicism differed significantly between the two families included in this study (Table 2; p=0.01, Fisher’s exact test).…”

“…Currently, the number of studies using any of the methods outlined above remains small, and the available data is somewhat biased towards unicellular organisms (Dettman et al, 2016; Dillon et al, 2015; Farlow et al, 2015; Lee et al, 2012; Ness et al, 2012; Zhu et al, 2014), insects (Keightley et al, 2014, 2015, 2009) and mammals (Harland et al, 2016; Kong et al, 2012; Uchimura et al, 2015; Venn et al, 2014), while including a single plant (Ossowski et al, 2010) and one bird (Smeds et al, 2016). In all, this leaves large sections of the tree of life essentially unexplored.…”

Mutations beget more mutations – The baseline mutation rate and runaway accumulation

“…In general, short-living animals have a much higher baseline rate (Welch, et al 2008;Thomas, et al 2010;Wilson Sayres, et al 2011). For example, the per year mutation rate in mice is 10 times higher than in humans (Lindsay, et al 2018). Even among hominoids, the slight delay in the age of reproduction (~ age 29) may have contributed to the much lower baseline rate in humans than in other apes (age 19-25) (Langergraber, et al 2012).…”

“…4d). This age-dependency could explain why the mutation rate per year in mice is 10 times higher than in humans (Lindsay, et al 2018). Furthermore, there is a negative correlation between generation time and per year mutation rate.…”