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ZFIN ID: ZDB-PUB-180309-7
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.
Date: 2018
Source: Nucleic acids research   46(7): 3517-3531 (Journal)
Registered Authors: Halluin, Caroline, Mourrain, Philippe
Keywords: none
MeSH Terms:
  • Alleles
  • Animals
  • Conserved Sequence/genetics
  • Disease Models, Animal
  • Enhancer Elements, Genetic/genetics*
  • Gene Expression Regulation/genetics
  • Genome-Wide Association Study
  • Humans
  • MEF2 Transcription Factors/genetics
  • MicroRNAs/genetics*
  • Mutation
  • Polymorphism, Single Nucleotide/genetics
  • Retina/metabolism
  • Retina/pathology
  • Retinal Vasculitis/genetics*
  • Retinal Vasculitis/pathology
  • Zebrafish/genetics
PubMed: 29518216 Full text @ Nucleic Acids Res.
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.