Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Significance Harvey rat sarcoma viral oncogene homolog ( HRAS ) occupies an important place in medical history, because it was the first gene in which acquired mutations that led to activation of a normal protein were associated with cancer, making it the prototype of the now canonical oncogene mechanism. Here, we explore what happens when similar HRAS mutations occur in male germ cells, an issue of practical importance because the mutations cause a serious congenital disorder, Costello syndrome, if transmitted to offspring. We provide evidence that the mutant germ cells are positively selected, leading to an increased burden of the mutations as men age. Although there are many parallels between this germline process and classical oncogenesis, there are interesting differences of detail, which are explored in this paper.