Huttley G A, Jakobsen I B, Wilson S R, Easteal S
John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Mol Biol Evol. 2000 Jun;17(6):929-37. doi: 10.1093/oxfordjournals.molbev.a026373.
Rates of mutation and substitution in mammals are generally greater in the germ lines of males. This is usually explained as resulting from the larger number of germ cell divisions during spermatogenesis compared with oogenesis, with the assumption made that mutations occur primarily during DNA replication. However, the rate of cell division is not the only difference between male and female germ lines, and mechanisms are known that can give rise to mutations independently of DNA replication. We investigate the possibility that there are other causes of male-biased mutation. First, we show that patterns of variation at approximately 5,200 short tandem repeat (STR) loci indicate a higher mutation rate in males. We estimate a ratio of male-to-female mutation rates of approximately 1.9. This is significantly greater than 1 and supports a greater rate of mutation in males, affecting the evolution of these loci. Second, we show that there are chromosome-specific patterns of nucleotide and dinucleotide composition in mammals that have been shaped by mutation at CpG dinucleotides. Comparable patterns occur in birds. In mammals, male germ lines are more methylated than female germ lines, and these patterns indicate that differential methylation has played a role in male-biased vertebrate evolution. However, estimates of male mutation bias obtained from both classes of mutation are substantially lower than estimates of cell division bias from anatomical data. This discrepancy, along with published data indicating slipped-strand mispairing arising at STR loci in nonreplicating DNA, suggests that a substantial percentage of mutation may occur in nonreplicating DNA.
在哺乳动物中，雄性生殖系中的突变率和替换率通常更高。这通常被解释为是由于精子发生过程中生殖细胞分裂的数量比卵子发生过程中更多，前提是假设突变主要发生在DNA复制期间。然而，细胞分裂速率并不是雄性和雌性生殖系之间的唯一差异，而且已知有一些机制可以独立于DNA复制而导致突变。我们研究了存在其他导致雄性偏向性突变的原因的可能性。首先，我们表明，在大约5200个短串联重复序列（STR）位点处的变异模式表明雄性的突变率更高。我们估计雄性与雌性突变率的比率约为1.9。这显著大于1，并支持雄性中更高的突变率，影响这些位点的进化。其次，我们表明，哺乳动物中存在由CpG二核苷酸处的突变所塑造的核苷酸和二核苷酸组成的染色体特异性模式。鸟类中也出现了类似的模式。在哺乳动物中，雄性生殖系比雌性生殖系甲基化程度更高，并且这些模式表明差异甲基化在脊椎动物雄性偏向性进化中发挥了作用。然而，从这两类突变中获得的雄性突变偏向性估计值大大低于从解剖学数据得出的细胞分裂偏向性估计值。这种差异，以及已发表的数据表明在非复制DNA中的STR位点会出现滑链错配，表明相当大比例的突变可能发生在非复制DNA中。
