Frequency of Human Disease Mutations and Spermatogonial Stem Cell Function

Abstract

Some human disease mutations enter the human population each generation as a result of de novo germline base substitutions that immediately affect children born to normal parents. In some cases the frequency of these mutations exceeds the well-documented germline mutation rate 100–1000 fold. Recent technologies have made it possible to estimate the frequency of single base disease mutations in both sperm and testes from normal men. The evidence confirms that, although unaffected, the men have high enough frequencies of these mutations in semen and testis to explain the high sporadic disease incidence. The explanation for the high frequency initially was ascribed to the idea that the affected nucleotide site was a mutation hot spot with a mutation rate per cell division at that site far greater than the rate at other sites. Recent evidence rules out this hot spot model. An alternative model suggests that any of these types of rare disease mutations can confer upon a single testis stem cell a selective advantage. Over time, a disproportionate increase of mutant stem cells over the wild-type stem cells occurs that increases the disease mutation frequency in sperm. The evidence against the hot spot model and for the selection model is reviewed and the functional consequences of these disease mutations on testis stem cell proliferation is also summarized. Finally, the consequence of these mutations is considered within the context of the paternal age effect and the human genetic load.