A screen for deeply conserved non-coding GWAS SNPs uncovers a MIR-9-2 functional mutation associated to retinal vasculature defects in human
- Madelaine, R., Notwell, J.H., Skariah, G., Halluin, C., Chen, C.C., Bejerano, G., Mourrain, P.
- Nucleic acids research 46(7): 3517-3531 (Journal)
- Registered Authors
- Halluin, Caroline, Mourrain, Philippe
- MeSH Terms
- Conserved Sequence/genetics
- Disease Models, Animal
- Enhancer Elements, Genetic/genetics*
- Gene Expression Regulation/genetics
- Genome-Wide Association Study
- MEF2 Transcription Factors/genetics
- Polymorphism, Single Nucleotide/genetics
- Retinal Vasculitis/genetics*
- Retinal Vasculitis/pathology
- 29518216 Full text @ Nucleic Acids Res.
Madelaine, R., Notwell, J.H., Skariah, G., Halluin, C., Chen, C.C., Bejerano, G., Mourrain, P. (2018) A screen for deeply conserved non-coding GWAS SNPs uncovers a MIR-9-2 functional mutation associated to retinal vasculature defects in human. Nucleic acids research. 46(7):3517-3531.
Thousands of human disease-associated single nucleotide polymorphisms (SNPs) lie in the non-coding genome, but only a handful have been demonstrated to affect gene expression and human biology. We computationally identified risk-associated SNPs in deeply conserved non-exonic elements (CNEs) potentially contributing to 45 human diseases. We further demonstrated that human CNE1/rs17421627 associated with retinal vasculature defects showed transcriptional activity in the zebrafish retina, while introducing the risk-associated allele completely abolished CNE1 enhancer activity. Furthermore, deletion of CNE1 led to retinal vasculature defects and to a specific downregulation of microRNA-9, rather than MEF2C as predicted by the original genome-wide association studies. Consistent with these results, miR-9 depletion affects retinal vasculature formation, demonstrating MIR-9-2 as a critical gene underpinning the associated trait. Importantly, we validated that other CNEs act as transcriptional enhancers that can be disrupted by conserved non-coding SNPs. This study uncovers disease-associated non-coding mutations that are deeply conserved, providing a path for in vivo testing to reveal their cis-regulated genes and biological roles.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes