Since replication error during cell division has been seen as a major source of mutation, the usually higher number of cell division in spermatogenesis than in oogenesis means that, everything else being equal, more mutations will be generated in the male than in the female germ line. The concept of male-biased mutation builds upon the mechanistic basis of mutation. This expectation derives from what now seems to be a widespread phenomenon among higher organisms, the rate of germ line mutation is typically higher in spermatogenesis than in oogenesis-in other words, the mutation rate is male biased ( Vogel & Motulsky 1997 Hurst & Ellegren 1998 Li et al. While the necessary technology is not yet available to allow such an endeavour, we can make one particular prediction when it comes to the relative contribution from mothers and fathers: we expect to see most mutations originating from our father's germ cells. If we were able to identify all de novo mutations that our parents provided us with, we would have the possibility to directly measure the rate of mutation per generation. Moreover, the rate of mutation must be taken into account in order to infer the type and the intensity of selection in DNA sequences in the analyses of divergence data. For instance, in the absence of selection, the rate of molecular evolution and the level of standing genetic variation are directly governed by the rate of mutation. However, mutation is not a homogenous process that occurs at a constant rate among lineages or within genomes, and variation in the rate and pattern of germ line mutation are therefore key factors in many aspects of evolutionary and population genetics. Mutational events are likely to arise in all cells of an organism but only those originating in germ cells are transmitted to subsequent generations, and thus are relevant to evolution.
Mutations constitute the ultimate source of genetic novelty required for evolution by natural selection. Male-biased mutation has implications for important aspects of evolutionary biology such as mate choice in relation to mutation load, sexual selection and the maintenance of genetic diversity despite strong directional selection, the tendency for a disproportionate large role of the X (Z) chromosome in post-zygotic isolation, and the evolution of sex. Another life-history correlate is sexual selection: when there is intense sperm competition among males, increased sperm production will be associated with a larger number of mitotic cell divisions in spermatogenesis and hence an increase in α m. The male mutation bias is positively correlated with the relative excess of cell divisions in the male compared to the female germ line, as evidenced by a generation time effect: in mammals, α m is estimated at approximately 4–6 in primates, approximately 3 in carnivores and approximately 2 in small rodents. For instance, assuming that a neutral sequence is analysed, that rate heterogeneity owing to other factors is cancelled out by the investigation of many loci and that the effect of ancestral polymorphism is properly taken into account, the male-to-female mutation rate ratio, α m, can be solved from the observed difference in rate of X and Y chromosome divergence. The concept of male-biased mutation has been thoroughly analysed in recent years using an evolutionary approach, in which sequence divergence of autosomes and/or sex chromosomes are compared to allow inference about the relative contribution of mothers and fathers in the accumulation of mutations. Haldane was the first to connect this association of replication and mutation to the difference in the number of cell divisions in oogenesis (low) and spermatogenesis (usually high), and the resulting sex difference in the rate of mutation.
One facet of mutation rate variation is the propensity for genetic change to correlate with the number of germ cell divisions, reflecting the replication-dependent origin of many mutations. Mutation has traditionally been considered a random process, but this paradigm is challenged by recent evidence of divergence rate heterogeneity in different genomic regions.
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