Massively parallel quantification of the regulatory effects of noncoding genetic variation in a human cohort
Open accessAbstract
We report a novel high-throughput method to empirically quantify individual-specific regulatory element activity at the population scale. The approach combines targeted DNA capture with a high-throughput reporter gene expression assay. As demonstration, we measured the activity of more than 100 putative regulatory elements from 95 individuals in a single experiment. In agreement with previous reports, we found that most genetic variants have weak effects on distal regulatory element activity. Because haplotypes are typically maintained within but not between assayed regulatory elements, the approach can be used to identify causal regulatory haplotypes that likely contribute to human phenotypes. Finally, we demonstrate the utility of the method to functionally fine map causal regulatory variants in regions of high linkage disequilibrium identified by expression quantitative trait loci (eQTL) analyses.
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MPRAs have been applied to assess biochemically annotated candidate enhancers, candidate enhancers harbouring variants that potentially mediate eQTLs, and even scans of the entire human genome.
“MPRAs have been applied to assess biochemically annotated candidate enhancers77,176-178, candidate enhancers harbouring variants that potentially mediate eQTLs179-182, and even scans of the entire human genome108,183.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [181]
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- Authors
- Vockley, C. M., Guo, C., Majoros, W. H., Nodzenski, M., Scholtens, D. M., Hayes, M. G., Lowe, W. L., & Reddy, T. E.
- Affiliations
- Duke University (US)
- Northwestern University (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-06-17
- Volume
- 25
- Issue
- 8
- Pages
- 1206-1214
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC4510004
- OpenAlex
- W2107596936
- Cited by
- 99
- References
- 54
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 9 · 2023: 4 · 2022: 9 · 2021: 8 · 2020: 15 · 2019: 11 · 2018: 8 · 2017: 11 · 2016: 14 · 2015: 2
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK099820, DK097534)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- distal regulatory elements, haplotypes, expression quantitative trait loci, linkage disequilibrium, fine mapping, human phenotypes
- MeSH terms
- Haplotypes, Humans, Regulatory Sequences, Nucleic Acid, Genetic Variation, Genome, Human, Computational Biology, Quantitative Trait Loci, High-Throughput Nucleotide Sequencing, Patient-Specific Modeling
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