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

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

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)6687-6706.e25
JournalCell
Volume187
Issue number23
DOIs
StatePublished - 14 Nov 2024

Keywords

  • ARC-SV
  • GTEx
  • PsychENCODE
  • complex structural variation
  • cxSVs
  • human evolution
  • population genetics
  • psychiatric genetics
  • single-cell multiomics
  • structural variation

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