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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-Alu (SVA) elements...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997352/
https://www.ncbi.nlm.nih.gov/pubmed/35332097
http://dx.doi.org/10.1101/gr.275515.121
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author 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.
author_facet 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.
author_sort van Bree, Elisabeth J.
collection PubMed
description 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.
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spelling pubmed-89973522022-04-22 A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci 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. Genome Res Research 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. Cold Spring Harbor Laboratory Press 2022-04 /pmc/articles/PMC8997352/ /pubmed/35332097 http://dx.doi.org/10.1101/gr.275515.121 Text en © 2022 van Bree et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/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/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research
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.
A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
title A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
title_full A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
title_fullStr A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
title_full_unstemmed A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
title_short A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
title_sort hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997352/
https://www.ncbi.nlm.nih.gov/pubmed/35332097
http://dx.doi.org/10.1101/gr.275515.121
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