TY - JOUR
T1 - A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci
AU - van Bree, Elisabeth J.
AU - Guimarães, Rita L. F. P.
AU - Lundberg, Mischa
AU - Blujdea, Elena R.
AU - Rosenkrantz, Jimi L.
AU - White, Fred T. G.
AU - Poppinga, Josse
AU - Ferrer-Raventós, Paula
AU - Schneider, Anne-Fleur E.
AU - Clayton, Isabella
AU - Haussler, David
AU - Reinders, Marcel J. T.
AU - Holstege, Henne
AU - Ewing, Adam D.
AU - Moses, Colette
AU - Jacobs, Frank M. J.
N1 - Funding Information:
This work was supported by a Human Frontier Science Program (HFSP) Career Development Award (CDA00030/2016C) to F.M.J.J. and a European Research Council (ERC) starting grant (ERC-2016-stG-716035) to F.M.J.J. and a grant from Alzheimer Nederland (WE.03-2018-07) to F.M.J.J., H.H., and M.J.T.R. We thank Lindsay Payer and Kathleen Burns for helpful discussions and advice about the project; Evan Eichler, Tobias Marschall, Peter Audano, and Marc Bonder for helpful discussion about SV-eQTL analysis; the National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center for gDNA; Gonzalo Congrains Sotomayor for technical assistance with FACS; Cindy Wagemans for technical support during gDNA isolation of SVA KO lines; Sophie Imhof and Elias Brandorff for providing the BIN1-SVA reference plasmid; Sol Katzman for EP300 ChIP-data processing; Wim de Leeuw for technical support with bioinformatics; MAD: Dutch Genomics Service & Support Provider of the University of Amsterdam for sequencing; and the Evolutionary Neurogenomics Group and others at the Swammerdam Institute for Life Sciences (SILS) for helpful discussions.
Funding Information:
This work was supported by a Human Frontier Science Program (HFSP) Career Development Award (CDA00030/2016C) to F.M.J.J. and a European Research Council (ERC) starting grant (ERC-2016-stG-716035) to F.M.J.J. and a grant from Alzheimer Nederland (WE.03-2018-07) to F.M.J.J., H.H., and M.J.T.R. We thank Lindsay Payer and Kathleen Burns for helpful discussions and advice about the project; Evan Eichler, Tobias Marschall, Peter Audano, and Marc Bonder for helpful discussion about SV-eQTL analysis; the National Institute of Neurological Disorders and Stroke (NINDS) Human Genetics Resource Center for gDNA; Gonzalo Congrains Sotomayor for technical assistance with FACS; Cindy Wagemans for technical support during gDNA isolation of SVA KO lines; Sophie Imhof and Elias Brandorff for providing the BIN1-SVA reference plasmid; Sol Katzman for EP300 ChIP-data processing; Wim de Leeuw for technical support with bioin-formatics; MAD: Dutch Genomics Service & Support Provider of the University of Amsterdam for sequencing; and the Evolutionary Neurogenomics Group and others at the Swammerdam Institute for Life Sciences (SILS) for helpful discussions.
Publisher Copyright:
© 2022 van Bree et al.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85128488168&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35332097
U2 - 10.1101/gr.275515.121
DO - 10.1101/gr.275515.121
M3 - Article
C2 - 35332097
SN - 1088-9051
VL - 32
SP - 656
EP - 670
JO - Genome Research
JF - Genome Research
IS - 4
ER -