PROJECT SUMMARY Somatic post-zygotic mutations are increasingly recognized as a cause of neurologic disorders ranging from epilepsy to autism to neurodegeneration. Somatic mutations accumulate with each cell division during fetal life, a developmental process of not yet fully defined scale and mechanism, hampering interpretation of disease states. The first part of this study implements a clinically applicable somatic-aware algorithm to identify early somatic mutations that lead to epilepsy and brain malformations. The latter aspect applies cutting-edge single- cell DNA technology to human fetal brain in order to define the rates and mechanisms driving accumulation of somatic mutations in neurons during normal development. The insights from this study have the potential to impact the detection and diagnosis of somatic disorders in clinical practice, and defines the scope of normal brain developmental mosaicism in neurons to serve as a framework for future studies of neurological disease. The candidate’s career goal is to become an independent physician-scientist contributing to the understanding of genetic and functional implications of post-zygotic mutations in childhood neurological disorders. The candidate trained clinically in child neurogenetics with deep research experience, including in cellular and molecular biology and statistical analysis, acquired in the cancer field. During the mentored training period, the candidate will prioritize activities to transition skills from a cancer background to human genetics and neuroscience: specifically working with primary human postmortem tissue, single cell analytical methods, and evaluating genotype-phenotype relationships in somatic disorders, and additionally, preparing for a transition to independence. The candidate will be mentored by Dr. Christopher Walsh, a renowned neurobiologist who has mentored dozens of successful independent investigators and will be supported by an advisory team with expertise in epilepsy, neuroscience, and bioinformatics. The proposed research and training plan will take place in the laboratory of Dr. Walsh at Boston Children’s Hospital (BCH), which is affiliated with Harvard Medical School and Howard Hughes Medical Institute, embedded within a world-class life sciences community of the Boston- Cambridge area. The candidate will benefit from both the outstanding resources and intellectual community of this tremendous network in addition to the close-knit communities within the BCH Department of Neurology and Division of Genetics.