BioProject

For autosomal dominant diseases, if an affected child is born to unaffected parents it must be due to a new mutation in one of the parent’s germlines. More...

For autosomal dominant diseases, if an affected child is born to unaffected parents it must be due to a new mutation in one of the parent’s germlines. For some diseases, the frequency of such new cases is orders of magnitude greater than expected based on the small number of causal mutations. Examples include Apert syndrome, achondroplasia, MEN2B, Noonan syndrome, and Rett syndrome. These diseases share four characteristics leading to the acronym RAMP: Recurrent mutations, Autosomal dominant, Male biased (new mutation is almost always in the father’s germline), and Paternal age effect (older fathers are more likely to have affected children than younger fathers). One possibility is that these disease mutations are mutation hotspots, another is that these mutations are positively selected for in the male germline. The hotspot hypothesis predicts that the mutations will be spatially uniform, while germline selection predicts that they will be clustered. We have studied the spatial distribution of disease mutations in testes from normal donors and found that they were strongly clustered, supporting the germline selection hypothesis. We are continuing our work studying germline selection, in particular, studying the feasibility of using the Safe Sequencing System to measure extremely rare mutation frequencies. Less...