The origins, patterns and implications of human spontaneous mutation

The germline mutation rate in human males, especially older males, is generally much higher than in females, mainly because in males there are many more germ-cell divisions. However, there are some exceptions and many variations. Base substitutions, insertion–deletions, repeat expansions and chromosomal changes each follow different rules. Evidence from evolutionary sequence data indicates that the overall rate of deleterious mutation may be high enough to have a large effect on human well-being. But there are ways in which the impact of deleterious mutations can be mitigated.Key PointsGermline base substitution mutations occur more frequently in males than in females, especially in older males. The main explanation for the sex and age effect is that a much larger number of germline divisions occurs in the male than in the female, and continues throughout male adulthood. Point mutations at some loci occur almost exclusively in males, whereas others have a smaller excess, roughly ten times more than in females. Which is more typical remains to be determined. For mutations other than point mutations, sex biases in the mutation rate are very variable. However, small deletions are more frequent in females. The total rate of new deleterious mutations for all genes is estimated to be about three per zygote. This value is uncertain, but it is likely that the number is greater than one. It is suggested that quasi-truncation selection is the principal explanation for how the population can rid itself of a large number of mutations with a relatively low fitness cost. Since this form of selection is effective only with sexual reproduction, perhaps the fact that humans reproduce sexually has made it possible to have such a long life cycle.