Functional interrogation of somatic mosaicism in neurodevelopmental disorders

The National Institute of Mental Health awarded Yale University $157,388 on July 1, 2026, under the Mental Health Research Grants program (CFDA 93.242) to functionally characterize somatic mosaic variants in the brains of patients with schizophrenia and autism and determine their causal roles in neurodevelopmental disease.

The funded work applies massively parallel reporter assays, CRISPR technology, and human induced pluripotent stem cell-derived neural progenitor cells and post-mitotic neurons to create a functional catalog of expression-modulated somatic mosaic variants in a developmental and cell-type-specific manner. The investigator will compare somatic and germline genetic architectures across neurodevelopmental disorder cases and controls, addressing major gaps in understanding how thousands of clonal somatic mutations discovered in patient brains relate to disease manifestation, incomplete penetrance, and variable expressivity. The research leverages state-of-the-art functional genomic technologies and bioinformatic pipelines to systematically characterize all brain non-coding somatic mosaic variants discovered to date.

Performance occurs in New Haven, Connecticut. The award period runs July 1, 2026, through June 30, 2027. This is a Project Grant, a competitive fellowship-track award supporting postdoctoral researcher training and development under NIMH's core research mission to transform understanding and treatment of mental illnesses through basic and clinical research.

Abstract

Somatic mosaicism, the genomic differences among the billions of cells in the human brain, may explain the incomplete penetrance and variable expressivity in highly heritable neurodevelopmental disorders. Thousands of clonal somatic mosaic variants (smvs) in subpopulations of neurons have been discovered in brains of schizophrenia and autism patients, necessitating an urgent, unmet demand to determine if these diverse somatic mutations have a causal role in disease. Major challenges include (1) the inability of using conventional statistical methods for common variants to associate disease status with risk variant, (2) the vast space of non-coding candidates with unknown function, and (3) the unresolved relevant cell types and developmental stages linking mutations to phenotypes. Just as integrating high-throughput genomic-, crispr, and stem cell-based technologies resulted in significant progress in understanding germline risk variants, they represent a novel approach to uniquely address the major challenges in the field of somatic mosaicism. As a CO-mentored computational and experimental biologist, i will leverage state-of-the-art functional genomic technologies and bioinformatic pipelines to systematically characterize all brain non-coding smvs discovered to date, resolving their causal roles in neurodevelopmental disorders. From all smvs identified in case and control brains, i will first create a functional catalog of expression-modulated smvs in a developmental- and cell-type-specific manner by applying massively parallel reporter assays in human induced pluripotent stem cells (hipscs)-derived neural progenitor cells (npcs) and post-mitotic neurons. By doing so, i will be able to interrogate whether differences in patterns of expression-modulated smvs exist between cases and controls. Second, i will compare the somatic and germline genetic architectures across neurodevelopmental disorders, determining whether somatic mutations act via the same pathways as germline mutations, or affect genes relevant to diseases, indicating a causal role. By simultaneously uncovering the downstream transcriptomic profiles of hundreds of regulatory elements harboring smvs with crispr screen, i will be able to pinpoint putative disease-causal smvs. Finally, i will validate the phenotypic impact of putative causal smvs in physiologically complex and relevant models including 3D brain organoids and "mosaicism-in-a-dish", testing both cell-autonomous and non-autonomous mechanisms of smvs. Overall, this work, representing a novel application of scalable functional genomic technologies to smvs, provides a framework to identify smvs with putative causal effects in neurodevelopmental diseases, advancing our understanding of a poorly understood disease mechanism. This fellowship will provide me with training encompassing computational genomics, stem cell models and broadly applicable phenotyping techniques, setting a foundation for me to launch an independent research program distinct from my mentors', querying somatic mosaicism's impact into novel cell types, contexts and diseases towards discovering novel therapeutic targets.