Abstracts (first author)
What is advantageous for the germline may be bad for the soma; the impact of germline selection on the mutational load in humans
Some new germline mutations that arise in the testis may confer a selective advantage to the mutated germ cell relative to non-mutated cells. Theoretically, if a new mutation provided a germline selective advantage it could increase the frequency at which the mutated allele was introduced into the population by orders of magnitude even though, much to the species detriment, it reduced the fitness of the individuals that inherited it. We have shown examples of positive germline selection for three human disease mutations that arise sporadically each generation at frequencies ranging from 1/2,000 to 1/70,000 births. These sporadic disease cases occur at rates 100-1,000 times greater than would be expected based on what we know about genome average mutation rates. Using a testis dissection/mutation detection approach along with mathematical modeling we have shown that the high frequency of these de novo disease mutations cannot be explained by hyper-mutation at the disease-causing sites. Instead, our data are consistent with the idea that the newly mutated germline stem cells have a proliferative advantage over non-mutated stem cells resulting in germline mosaicism. Plausible molecular mechanisms can explain the selective advantage for each of the three disease mutations. Others previously suggested that alleles conferring a selective advantage in the germline may be disadvantageous in the adult and might lead to “mitotic drive” systems that increase the mutational load of a population. The three disease mutations we examined may be realizations of this idea.