Sattar Khoshkhoo

The human brain is a mosaic structure with significant genetic diversity arising from post-zygotic (i.e., somatic) genetic variation. The overarching mission of our lab is to examine how this somatic variation contributes to both typical and pathological brain development. While mutations can occur throughout the genome, genetic variation in the human brain is non-random. We have previously demonstrated that focal epilepsies and neurodegenerative conditions strongly implicate somatic variation in canonical oncogenic signaling pathways. For example, activating Ras-MAPK mutations present in a small fraction of hippocampal cells contribute to circuit hyperexcitability and epilepsy, however, the mechanisms driving cellular and circuit dysfunction remain unknown. Interestingly, we have also discovered that pathogenic somatic variation exists in the neurotypical human brain, raising broader questions about the developmental origins and functional consequences of these somatic mutations.

To address these questions, we employ a range of approaches, from direct investigation of human brain tissue to the use of cell lines and model systems. For instance, we use novel single-cell and single-molecule DNA and RNA sequencing to identify new mutations, genes, and pathways implicated in neurologic diseases. We then leverage protein biochemistry, massively parallel reporter assays, and high-throughput electrophysiology and calcium/voltage imaging to examine their functional consequences. Although the primary aim of our lab is to contribute to the development of novel treatments for neuropsychiatric diseases, we strive to achieve this goal through rigorous science grounded in cutting-edge genetics, genomics, and systems neurobiological approaches.