Journal
ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, VOL 17
Volume 17, Issue -, Pages 219-243Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-genom-083115-022656
Keywords
mutation frequency; mutational load; selective advantage; computational analysis; asymmetric and symmetric cell divisions
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Funding
- NIGMS NIH HHS [R01 GM036745] Funding Source: Medline
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Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.
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