2/3 Schizophrenia Genetics and Brain Somatic Mosaicism

点击翻译按钮获取中文摘要

Abstract The goal of our collaborative U01 parent grant (5U01MH106892) at the University of Michigan (UM), entitled “2/3 Schizophrenia Genetics and Brain Somatic Mosaicism,” is to discover and characterize somatic mosaicism (i.e., single nucleotide variants (SNVs), mobile genetic element insertions, and copy number variants (CNVs)) in post-mortem brain tissue from neurotypical and schizophrenic individuals. Somatic mosaicism is the occurrence of two (or more) genomes in an individual who is derived from a single zygote. Members of the NIMH-supported Brain Somatic Mosaicism Network (BSMN) are characterizing mosaic variation in other neuropsychiatric disorders with a common goal of assessing the role of somatic mosaicism across diseases including bipolar disorder, schizophrenia, autism spectrum disorder, epilepsy, and Tourette syndrome. We propose three Capstone projects to map the full spectrum of somatic variation in human brain and characterize the contributions of mosaic variants to neuropsychiatric disease risk. These Capstones can advance the mission of the BSMN to both achieve greater power of discovery of somatic mutations by combining and harmonizing deep coverage whole genome sequencing data that has been generated across BSMN nodes and placing the identified somatic variants in the context of neurodevelopment and disease. To integrate the multi-dimensional BSMN data, as well as data from other consortia, administrative supplements are requested to conduct three Capstone projects, which will also complement ongoing efforts of the Data Coordinating Center (DCC) and data analytic core (DAC). We expect these Capstone projects to increase the profile of the BSMN by creating an unprecedented data resource of somatic mosaic variants across development and diseases that will be widely available to the scientific community. The enhanced power provided by the combined analyses of the BSMN will provide foundational knowledge that will guide future work, and lead to new insight into brain somatic mosaicism. The specific aims of the Michigan/Virginia site are: Aim 1 (Capstone 1, Goal 2b), to leverage the power of 10X Genomics linked read (i.e., extended haplotype) data and enhance computational strategies to identify and validate somatic SNVs and mobile genetic element insertions in neurotypical and schizophrenia brain samples; and Aim 2 (Capstone 3, Goal 4), to exploit 10X Genomics linked-read (i.e., extended DNA haplotype) and single cell sequencing data to identify and validate copy number variants (CNVs) in neurotypical and neuropsychiatric disease brain samples. We posit that the use of 10X Genomics technology represents a transformative technology that will allow a robust platform to identify and validate SNV, mobile genetic element, and CNV somatic mosaicism in both healthy and neuropsychiatric disease brain samples.