Functional annotation of rare structural variation in the human brain
-
Published:2020-06-12
Issue:1
Volume:11
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Han LideORCID, Zhao XuefangORCID, Benton Mary LaurenORCID, Perumal Thaneer, Collins Ryan L.ORCID, Hoffman Gabriel E.ORCID, Johnson Jessica S., Sloofman Laura, Wang Harold Z., Stone Matthew R., Akbarian Schahram, Bendl Jaroslav, Breen Michael, Brennand Kristen J., Brown Leanne, Browne Andrew, Buxbaum Joseph D., Charney Alexander, Chess Andrew, Couto Lizette, Crawford Greg, Devillers Olivia, Devlin Bernie, Dobbyn Amanda, Domenici Enrico, Filosi Michele, Flatow Elie, Francoeur Nancy, Fullard John, Gil Sergio Espeso, Girdhar Kiran, Gulyás-Kovács Attila, Gur Raquel, Hahn Chang-Gyu, Haroutunian Vahram, Hauberg Mads Engel, Huckins Laura, Jacobov Rivky, Jiang Yan, Johnson Jessica S., Kassim Bibi, Kim Yungil, Klei Lambertus, Kramer Robin, Lauria Mario, Lehner Thomas, Lewis David A., Lipska Barbara K., Montgomery Kelsey, Park Royce, Rosenbluh Chaggai, Roussos Panos, Ruderfer Douglas M., Senthil Geetha, Shah Hardik R., Sloofman Laura, Song Lingyun, Stahl Eli, Sullivan Patrick, Visintainer Roberto, Wang Jiebiao, Wang Ying-Chih, Wiseman Jennifer, Xia Eva, Zhang Wen, Zharovsky Elizabeth, Brennand Kristen J.ORCID, Brand Harrison, Sieberts Solveig K.ORCID, Marenco Stefano, Peters Mette A., Lipska Barbara K., Roussos PanosORCID, Capra John A.ORCID, Talkowski MichaelORCID, Ruderfer Douglas M.ORCID,
Abstract
AbstractStructural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs.
Funder
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference50 articles.
1. Stankiewicz, P. & Lupski, J. R. Structural variation in the human genome and its role in disease. Annu. Rev. Med. 61, 437–455 (2010). 2. Sudmant, P. H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75–81 (2015). 3. Weischenfeldt, J., Symmons, O., Spitz, F. & Korbel, J. O. Phenotypic impact of genomic structural variation: insights from and for human disease. Nat. Rev. Genet. 14, 125–138 (2013). 4. CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). 5. Glessner, J. T. et al. Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders. Genome Med. 9, 106 (2017).
Cited by
30 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|