Understanding what determines the frequency and pattern of human germline mutations

Abstract

Recent technological advances have made it possible to directly measure the frequency of rare nucleotide substitution mutations in human germline DNA. Semen is an ideal source of genetic material as a single sample can contain over 10⁸ sperm. Some human nucleotides have mutation frequencies that are orders of magnitude greater than the genome average and, at least in some disease-causing examples, there is evidence that this increased frequency is not due to more frequent mutation. Rather, a selective advantage conferred on the male germline cells by the mutation has been suggested; other diseases may also achieve high frequencies in the population owing to germline selection. The indirect method of studying nucleotide substitution mutations by comparing aligned sequences in different species has found that the mutation rate varies across the genome. Many genomic factors such as coding versus non-coding sequence, base identity, GC content, recombination rate, and proximity to insertions or deletions are correlated with this rate, although it is likely that no single factor can explain all the variation. Both interspecific sequence comparisons and analysis of parental origins of human disease mutations in families suggest that nucleotide substitutions occur more frequently in males than females. Recent studies have shown that mutations at CpG sites are significantly more male-biased if the CpG sites are in CpG islands. Human disease mutations increase in frequency with the father's age; this has long been thought to result from the life-long divisions of the male germ cells. In some cases, new evidence suggests that selection of germ cells carrying the new mutation can explain the age-dependent increase.