Modeling Reciprocal Genomic Disorders in Neuronal Cells and Cerebral Organoids

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Abstract The proposed research and training program will prepare Dr. Xander Nuttle to become an independent investigator focused on human genetics and neurodevelopmental genomics. Dr. Nuttle obtained a Ph.D. in Genome Sciences, investigating genes specifically duplicated along the human lineage, and has dedicated his postdoctoral training to the development of innovative methods of genome engineering in relation to human reciprocal genomic disorders (RGDs). He now seeks to develop new expertise in functional genomics by leveraging emerging stem-cell, single-cell, organoid, and genome engineering technologies to characterize mutations linked to neurodevelopmental disorders. The training program consists of two phases: two years acquiring new skills primarily through mentored research, followed by three years establishing an independent laboratory. The research plan incorporates both experimental and computational approaches, modeling RGDs in neuronal cells and cerebral organoids to gain insights into mechanisms of pathogenesis. Dr. Michael Talkowski, Associate Professor of Neurology at the Center for Genomic Medicine (CGM) at Massachusetts General Hospital (MGH), will serve as the primary mentor. Dr. Kevin Eggan, Professor of Stem Cell and Regenerative Biology at Harvard University, will provide complementary expertise as a co-mentor. The mentor and co-mentor are world leaders in psychiatric genetics, functional genomics, and cellular disease modeling. To supplement their mentorship, a team of investigators at various career stages will provide Dr. Nuttle with targeted training and career development advice. The CGM at MGH, Harvard, and the Broad Institute form a highly collaborative environment ideally positioned to support Dr. Nuttle’s transition to independence. Here, he will have access to abundant resources and tools and a wealth of diverse scientific and clinical expertise. RGDs are among the most common genetic subtypes of autism spectrum disorder, schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, and intellectual disability. All RGDs involve recurrent deletions and duplications of particular genomic segments, yet the molecular details of how these dosage changes confer disease are not well understood. To address this challenge, we will (1) examine transcriptional signatures and neurite dynamics in RGD neuronal cellular models; (2) generate and characterize RGD cerebral organoid models; and (3) integrate high-throughput genome engineering with cellular modeling to identify driver genes underlying RGD-associated neurite phenotypes. This research will immerse Dr. Nuttle in several cutting-edge fields, giving him the opportunity to learn functional genomics, single-cell analysis, and brain organoid modeling. With these skills in hand, he will be able to functionally characterize genetic variation affecting neurodevelopment and be well-positioned to launch a productive independent research program.