Male-driven evolution of DNA sequences

Abstract

It is commonly believed that the mutation rate is much higher in the human male germ line than in the female germ line because the number of germ-cell divisions per generation is much larger in males than in females. But direct estimation of mutation rates is difficult, relying mainly on sex-linked genetic diseases, so the ratio (alpha m) of male to female mutation rates is not clear. It has been noted that if alpha m is very large, then the rate of synonymous substitution in X-linked genes should be only 2/3 of that in autosomal genes, and comparison of human and rodent genes supported this prediction. As the number of X-linked genes used in the study was small and the X-linked and autosomal sequences were non-homologous, and given that the synonymous rate varies among genes, we sequenced the last intron (approximately 1 kb) of the Y-linked and X-linked zinc-finger-protein genes (ZFY and ZFX) in humans, orang-utans, baboons and squirrel monkeys. The ratio Y/X of the substitution rate in the Y-linked intron to that in the X-linked intron is approximately 2.3, which is close to that estimated from synonymous rates in the ZFY and ZFX genes and implies alpha m approximately 6. This estimate of alpha m supports the view that the evolution of DNA sequences in higher primates is male-driven. It is, however, much lower than the previous estimate and therefore raises a number of issues.

Human mutation—blame (mostly) men

“…The new α m estimate of 5.2 carries a large 95% confidence interval (2.44 to ∞), but it should be noted that it is similar to that obtained in previous comparisons of homologous X-Y genes 10 . If we accept a significant male bias in human mutation rate, it would suggest that a large proportion of germline mutations derive from replication-associated processes (replication errors, for example), a conclusion that can be drawn from the fact that the number of germline cell divisions in spermatogenesis vastly exceeds that in oogenesis 13 .…”

“…1a), the rate of presumably neutral substitutions in primate comparisons is higher on Y than on X. The observed rate differences correspond to an α m of approximately 4-6, which suggests a rather distinct male bias in hominoids 10 . However, these data were recently challenged in a study by Bohossian et al 3 , who suggested that α m is only 1.7, using data from a large region transposed from X to Y after the human lineage split with chimpanzees (Fig.…”

Recent progress in the genetics of incontinentia pigmenti (Bloch-Sulzberger syndrome)

“…Because the male child inherits the maternal X chromosome, and the affected heterozygous female does not transmit the mutant gene, because of the genetic lethality, the highly mutated paternal X chromosome may explain the exclusive occurrence of X-linked dominant disorders in females. In support of this hypothesis is the observation that there is a striking difference in mutation rates between males and females (Shimmin et al 1993;Vogel 1977;Vogel and Rothenberg 1975). However, a recent report (Roberts et al 1998) suggests that IP in a newborn male infant is maternally transmitted, which, again, contradicts the above de-novo germline mutation theory.…”

Meiotic recombination counteracts male-biased mutation (male-driven evolution)

“…Importantly, the values for K Y or K Z were substantially higher than for K X or K W in almost all of the regions, although K Z was equal to K W in the Sox3 coding sequence. Next, we estimated the male-to-female rate ratio (a) and the 95% CI of the formula as described in the Introduction section [2,3]. We found that all of the a values for the five regions, except for the Sox3 coding sequences in the ZW group, were greater than 1, indicating male-biased mutations.…”