Brian J. O’Roak’s team at Oregon Health and Science University in Portland has been exploring genetic mutations that are difficult to identify using conventional means, and what role these mutations might play in neurodevelopmental disorders. In a previous study, O’Roak and his colleagues sequenced the protein-coding regions of the genome, or ‘exomes,’ in more than 200 families that have a single child affected with autism¹.

In doing so, the researchers unexpectedly identified several genetic mutations that appeared to be present in only a fraction of the child’s DNA, meaning the child’s cells are a mixture of non-mutated and mutated cells. These somatic mosaic mutations have been studied extensively in cancer, in which they play a significant role. However, for technical reasons, this class of mutations has been largely unstudied in other disorders, including autism. New evidence suggests that these mutations may explain a significant fraction of unsolved genetic risk but it is unknown how frequently they might occur in early development.

O’Roak and his team devised a computational and experimental framework for detecting low-level mosaicism and applied these techniques in other disorders². Using these methods, they are performing a systematic evaluation of the role of somatic mosaic mutations in human development and autism risk.

They plan to first examine the rates of somatic mosaic mutations in affected and unaffected children and their parents in exome data from a large family-based sample, the Simons Simplex Collection. They will then evaluate a cohort that is potentially enriched for these types of mutations: identical-twin pairs. Approximately half of these twin pairs share an autism diagnosis, and in the other half, only one twin has autism. The researchers plan to look in depth for mutations that have occurred before and after identical twins separate into two developing embryos and the role they might play in autism risk.