Somatic mutations in autism spectrum disorder - PROJECT SUMMARY / ABSTRACT This NIH K08 proposal describes a four-year career development training program in autism spectrum disorder (ASD) genomics research. With this research program, Dr. Mo will develop expertise in human genetics, analysis of next-generation sequencing data, and interpretation of somatic variants in non-neoplastic tissue. These skills complement Dr. Mo’s prior research and clinical training and ideally position her to transition to an independent investigator position studying somatic mutations in ASD. Dr. Mo’s mentor for this proposal is Dr. Christopher A. Walsh, a Professor of Neurology at Harvard Medical School, an HHMI Investigator at Boston Children’s Hospital, and a leader in the genetics of human neurological diseases. With over 25 years of mentorship experience, Dr. Walsh has an established track record of mentoring trainees to successful academic careers in biomedical research. Dr. Mo will be supported by a scientific advisory team and collaborators with complementary expertise in autism genetics, computational genomics, genotype-phenotype correlations of somatic mutations, and career mentorship. The institutional resources available at Boston Children’s Hospital, which is affiliated with Harvard Medical School, are world- class and provide an ideal environment to foster the development of a physician-scientist career. The primary scientific objective of the proposed research plan is to study the role of somatic (post- zygotic) variants in ASD. Dr. Mo’s central hypothesis is that somatic variants contribute to ASD risk. Dr. Mo provides pilot data indicating that somatic single nucleotide variants (sSNVs) are increased in gene exons in ASD probands compared to controls, particularly in highly constrained genes with loss-of-function intolerance. Furthermore, Dr. Mo shows that sSNVs in non-coding gene regulatory regions can be efficiently detected using ATAC-seq, which allows the detection of non-coding sSNVs in larger sample sizes than previously possible using whole genome sequencing. To achieve the research objective, a combination of whole exome sequencing, ATAC-seq, whole genome sequencing, amplicon sequencing, and computational analysis will be used. These strategies will systemically examine two independent, but related, aims: (1) the burden of sSNVs in functionally-relevant genes in ASD compared to neurotypical individuals; and (2) the distribution of sSNVs in non-coding gene regulatory regions in postmortem human brain neurons from ASD and neurotypical individuals. Findings from this study may improve our understanding of the genetic architecture and mechanisms of ASD as well as the genetic diagnosis of ASD in clinical practice.
