De novo mutations (DNMs) originating during gametogenesis (when the sperm and oocyte are formed) are an important source of genetic variation. The process of gametogenesis is quite different between males and females. The sperm produced by a 20-year-old male has gone through ~190 cell divisions (mitoses), whereas this number increases to ~650 cell divisions by the age of 40 years. To the contrary, eggs do not replicate after birth. These sex-specific differences in germline biology are likely to explain the 3:1 excess of paternally-derived DNMs observed in the children. However, maternal and paternal DNMs do increase in number with parental age by a different mutational mechanism, and these DNMs show sex-specific mutational patterns.
Authors [see attached article] used a data set of 7,216 autosomal DNMs (i.e. those not on the X- or Y-chromosome) with resolved parent-of-origin from whole-genome sequencing (WGS) of 816 parent–offspring trios to investigate differences between maternally- and paternally-derived DNMs and studied the underlying mutational mechanisms. Their results demonstrate that the number of DNMs in offspring increases––not only with paternal age, but also with maternal age––and that some genomic regions show enrichment for maternally-derived DNMs. Authors identified parent-of-origin-specific mutation signatures that become more pronounced with increased parental age, pointing to the different mutational mechanisms in spermatogenesis and oogenesis.
Finally, authors discovered DNMs––that are spatially clustered––to have a unique mutational signature with no significant differences between parental alleles, suggesting a different mutational mechanism. These findings provide insights into the molecular mechanisms that underlie mutagenesis and are relevant to disease and evolution in humans.
Nat Genetics Aug 2o16; 48: 935–939 & News-N-Views editorial pp 823–824