作者
Bo Zhou,Joseph G. Arthur,Hanmin Guo,Taeyoung Kim,Yi‐Ling Huang,Reenal Pattni,Tao Wang,Soumya Kundu,Jay X. J. Luo,HoJoon Lee,Daniel Nachun,Carolin Purmann,Emma Monte,Annika K. Weimer,Pingping Qu,Minyi Shi,Lixia Jiang,Xinqiong Yang,John F. Fullard,Jaroslav Bendl,Kiran Girdhar,Minsu Kim,Xi Chen,William J. Greenleaf,Laramie E. Duncan,Hanlee P. Ji,Xiang Zhu,Giltae Song,Stephen B. Montgomery,Dean Palejev,Heinrich zu Dohna,Panos Roussos,Anshul Kundaje,Joachim Hallmayer,M Snyder,Winghing Wong,Alexander E. Urban
摘要
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 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. 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.