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| Status |
Public on Jan 17, 2022 |
| Title |
A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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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 SVA (Sine-VNTR-Alu) 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 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-associated risk loci and in the BCKDK Parkinson 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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| Overall design |
RNA and ChIP-seq analysis of CRISPR/Cas9 SVA-KO and wild type hESC-derived cortical organoids.
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| Contributor(s) |
van Bree EJ, Guimarães R, Lundberg M, Blujdea ER, Rosenkrantz JL, White FT, Poppinga J, Ferrer Raventos P, Schneider AE, Clayton I, Haussler D, Reinders MJ, Holstege H, Ewing AD, Moses C, Jacobs FM |
| Citation(s) |
35332097 |
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| Submission date |
Feb 24, 2021 |
| Last update date |
Apr 27, 2022 |
| Contact name |
Frank M.J. Jacobs |
| Organization name |
University of Amsterdam
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| Department |
Sammerdam Institute for Life Sciences
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| Lab |
Evolutionary Neurogenomics
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| Street address |
Science Park 904
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| City |
Amsterdam |
| ZIP/Postal code |
1098XH |
| Country |
Netherlands |
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| Platforms (2) |
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| Samples (39)
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| Relations |
| BioProject |
PRJNA704612 |
| SRA |
SRP307934 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE167409_CapRNA_EV_CD2AP-SVA-KO_h9coD35_SVA-KO_Counts.tsv.gz |
101.6 Kb |
(ftp)(http) |
TSV |
| GSE167409_RAW.tar |
25.8 Mb |
(http)(custom) |
TAR (of BROADPEAK, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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