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Detection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders

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Oct 07, 2024 version files 736.32 MB

Abstract

Complex structural variations (cxSVs) are often overlooked in genome analyses due to detection challenges. We developed ARC-SV, a probabilistic and machine-learning-based method that enables accurate detection and reconstruction of cxSVs from standard whole-genome sequencing datasets. By applying ARC-SV across 4,262 genomes representing all continental populations, we identified cxSVs as a significant source of natural human genetic variation. The 4,262 individual genomes are sourced from the 1000 Genomes Project, the Human Genome Diversity Project, and the Simons Genome Diversity Project. We also applied ARC-SV to Neanderthal genomes, a number of benchmarking genomes including CHM13-T2T, HG002, HuRef, PG1, and HepG2 (cancer) as well as 119 postmortem brain (79 from ComminMind Consortium and 40 from the National Institute of Mental Health Human Brain Collection Core). Most brain samples are from donors with major psychiatric disorders. The high-confidence cxSV calls for all samples (including dot plot visualizations) are compiled into Dataset S1. ARC-SV. The high-confidence simple SV calls produced by ARC-SV for all samples are also included and compiled into Dataset S2. In our study (Zhou et al, Cell 2024), our analysis of these Datasets revealed that rare cxSVs have a propensity to occur in neural genes and loci that underwent rapid human-specific evolution, including those regulating corticogenesis. By performing single-nucleus multiomics in postmortem brains, we discovered cxSVs associated with differential gene expression and chromatin accessibility across various brain regions and cell types. Additionally, cxSVs detected in brains of psychiatric cases are enriched for linkage with psychiatric GWAS risk alleles detected in the same brains. Furthermore, our analysis revealed significantly decreased brain-region- and cell-type-specific expression of cxSV genes, specifically for psychiatric cases, implicating cxSVs in the molecular etiology of major neuropsychiatric disorders.