A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci

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- (SVA) elements, a...

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Bibliographic Details
Published in:Genome research 2022-04, Vol.32 (4), p.656-670
Main Authors: van Bree, Elisabeth J, Guimarães, Rita L F P, Lundberg, Mischa, Blujdea, Elena R, Rosenkrantz, Jimi L, White, Fred T G, Poppinga, Josse, Ferrer-Raventós, Paula, Schneider, Anne-Fleur E, Clayton, Isabella, Haussler, David, Reinders, Marcel J T, Holstege, Henne, Ewing, Adam D, Moses, Colette, Jacobs, Frank M J
Format: Article
Language:English
Subjects:
Alu Elements
Alzheimer's disease
DNA Transposable Elements - genetics
Gene expression
Gene regulation
Genetic diversity
Genetic Predisposition to Disease
Genetic Variation
Genome, Human
Genome-wide association studies
Genome-Wide Association Study
Genomes
Humans
Movement disorders
Neurodegenerative diseases
Neurological diseases
Parkinson's disease
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Single-nucleotide polymorphism
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Summary: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- (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 and Alzheimer's disease-associated risk loci and in the 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.
ISSN:1088-9051
1549-5469
DOI:10.1101/gr.275515.121