A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
- Elisabeth J. van Bree1,8,
- Rita L.F.P. Guimarães1,2,3,8,
- Mischa Lundberg4,
- Elena R. Blujdea1,
- Jimi L. Rosenkrantz1,
- Fred T.G. White1,
- Josse Poppinga1,
- Paula Ferrer-Raventós1,
- Anne-Fleur E. Schneider1,
- Isabella Clayton1,
- David Haussler5,
- Marcel J.T. Reinders6,
- Henne Holstege2,3,6,7,
- Adam D. Ewing4,
- Colette Moses1 and
- Frank M.J. Jacobs1,7
- 1Evolutionary Neurogenomics, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands;
- 2Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands;
- 3Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands;
- 4Mater Research Institute—University of Queensland, Woolloongabba, QLD 4102, Australia;
- 5UC Santa Cruz Genomics Institute, and Howard Hughes Medical Institute, UC Santa Cruz, Santa Cruz, California 95064, USA;
- 6Delft Bioinformatics Lab, Delft University of Technology, 2628 XE Delft, The Netherlands;
- 7Amsterdam Neuroscience, Complex Trait Genetics, University of Amsterdam, Amsterdam, The Netherlands
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↵8 These authors contributed equally to this work.
Abstract
Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR-Alu (SVA) elements, a class of great ape-specific transposable elements with gene-regulatory roles, which represents a major source of structural variability in the human population. We highlight the presence of structurally variable SVAs (SV-SVAs) in neurological disease–associated loci, and we further associate SV-SVAs to disease-associated SNPs and differential gene expression using luciferase assays and expression quantitative trait loci data. Finally, we genetically deleted SV-SVAs in the BIN1 and CD2AP Alzheimer's disease–associated risk loci and in the BCKDK Parkinson's disease–associated risk locus and assessed multiple aspects of their gene-regulatory influence in a human neuronal context. Together, this study reveals a novel layer of genetic variation in transposable elements that may contribute to identification of the structural variants that are the actual drivers of disease associations of GWAS loci.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.275515.121.
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Freely available online through the Genome Research Open Access option.
- Received March 14, 2021.
- Accepted January 28, 2022.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
