Somatic mosaicism, or the emergence of variations in the sequence or structure of the genome of somatic cells, has been detected in both healthy individuals and individuals with various diseases, particularly cancer. It has been suggested that somatic variations play a major role in driving neuronal diversity and genome evolution. However, the extent to which mosaicism occurs in normal development, and its significance in brain disorders, has only recently begun to be investigated.

In the current project, Flora Vaccarino and Alexej Abyzov aim to assess the role of somatic mosaicism in autism spectrum disorder (ASD). Preliminary data from Vaccarino’s and Abyzov’s groups, along with other recent results, suggest the likely occurrence of hundreds of somatic single nucleotide variations per neuron. This raises the possibility that mosaic variants in the brain could play a major role in the etiology of neurodevelopmental disorders such as ASD.

Vaccarino and Abyzov hypothesize that individuals with ASD have an increased predisposition to somatic mutations in neuronal cells compared to unaffected individuals. In support of this idea, past genetic analyses of individuals with ASD indicate an increased incidence of de novo variants, with mosaicism even being detected in the proband’s blood in some studies¹. It is possible that other post-zygotic variants are also present in ASD probands but have remained undetected thus far either because they are absent in the blood or because they are present only in a subpopulation of cells.

Currently, there are no estimates of the extent to which somatic mutations occur in ASD, and the Vaccarino and Abyzov laboratories aim to address this issue. Vaccarino and colleagues recently carried out an extensive genomic, transcriptomic and cellular characterization of induced pluripotent stem cell (iPSC)-derived telencephalic organoids from four individuals with ASD and four unaffected first-degree family members recruited in part from the Simons Simplex Collection (SSC)². Using this model, the researchers plan to study somatic mosaicism across the genomes of three individuals with ASD and three unaffected individuals. The studies will focus on the analysis of stem cells (single cells isolated from iPSCs), brain progenitor cells and terminally differentiated neurons (by analysis of single cells isolated from organoids). The frequency, type and functional relevance of variants will be compared between cases and controls and stratified across genomic features, gene expression states and epigenomic states.

This project provides an experimental system for an unbiased assessment of the extent of somatic mosaicism in cells derived from individuals with ASD, and will help provide a greater understanding of the array of genetic contributions leading to this complex disorder.