Review
Male-driven evolution

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Abstract

The strength of male-driven evolution – that is, the magnitude of the sex ratio of mutation rate – has been a controversial issue, particularly in primates. While earlier studies estimated the male-to-female ratio (α) of mutation rate to be about 4–6 in higher primates, two recent studies claimed that α is only about 2 in humans. However, a more recent comparison of mutation rates between a noncoding fragment on Y and a homologous region on chromosome 3 gave an estimate of α = 5.3, reinstating strong male-driven evolution in hominoids. Several studies investigated variation in mutation rates among genomic regions that may not be related to sex differences and found strong evidence for such variation. The causes for regional variation in mutation rate are not clear but GC content and recombination are two possible causes. Thus, while the strong male-driven evolution in higher primates suggests that errors during DNA replication in the germ cells are the major source of mutation, the contribution of some replication-independent factors such as recombination may also be important.

Introduction

Almost 70 years ago, Haldane [1] proposed that the male mutation rate in humans is much higher than the female mutation rate because the male germline goes through many more rounds of cell divisions (DNA replications) per generation than does the female germline. Under this hypothesis, mutations arise mainly in males, so that evolution is ‘male-driven’ [2]. Although a higher mutation rate in males than in females has been well accepted, the magnitude of the male-to-female ratio (α) of mutation rate remains a point of contention. Knowing the magnitude of α is important because it is related to the issue of whether DNA replication errors are the major source of mutation 3., 4., which has been a subject of heated debate for the past several decades. Clearly, resolving these issues has implications for understanding the mechanism of mutagenesis and for the generation-time effect hypothesis, which postulates a faster molecular clock for organisms with a short generation time than for ones with a long generation time. In this article, we review studies on male-driven evolution in mammals and birds in the past decade and discuss factors that may affect the sex ratio of mutation rate. Note that mutation here refers to point (substitution) mutation; we are not concerned here with deletion or insertion mutation, which seem to have a mechanism of mutagenesis different from that of point mutation.

Section snippets

Estimating α from new or recently produced mutations

Dramatic advances in DNA technology have allowed the inference of the origin of a new or recently-produced mutation. When the origins of many mutations are inferred, α can be estimated as the ratio of the number of point mutations of paternal origin to that of maternal origin. This direct approach has replaced the indirect methods for estimating α from incidents of X-linked diseases [1]. Application of the direct approach to 119 families of haemophilia A (an X-linked recessive disease) led to

Evolutionary approach

In addition to the drawbacks mentioned above, the direct method may not be applicable to non-human organisms. As an alternative, Miyata et al. [2] proposed to estimate α from the mutation rates of the two sex chromosomes or of a sex chromosome and an autosome (or autosomes). Let Y, X, and A be the mutation rates for a Y-linked sequence, an X-linked sequence, and an autosomal sequence, respectively. Noting that in a population all Y-linked sequences are derived from the fathers, whereas

Methylation effects

In mammalian cells, DNA methylation occurs mostly at the C residue of CpG dinucleotides and a methylated C residue is easily transformed to a T through deamination, which creates a C→T transitional mutation. If the C→T transition occurs on the antisense strand of DNA, it is reflected as a G→A transition on the sense strand. As methylation occurs at a considerably higher rate in sperm DNA than in oocyte DNA [16], it increases the frequency of the paternal origin of mutation. For example, in Rett

Regional effects

The possibility that mutation rate may vary among genomic regions was first proposed, on the basis of very limited data, by Filipski [18] and Wolfe et al. [19]. Support for this hypothesis came from a study that detected substantial variation in both mutation rate and pattern among three primate arginosuccinate synthetase processed pseudogenes located in different regions of the genome [20]. Later, in a comparison of human and mouse genes, Matassi et al. [21] found that synonymous substitution

Conclusions and future directions

The above survey of studies that used the method of Miyata et al. [2] to estimate α suggests that it is between 5 and 6 for hominoids (humans and apes) (Table 2). The α value (∼11) estimated from the direct method (Table 1) was considerably higher for two reasons. First, it included the effect of methylation. Second, it referred to humans only; α is expected to be higher in humans than in apes because it increases with generation time. There is indeed a positive correlation between α and

Acknowledgements

This study was supported by grants from the National Institutes of Health.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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