Disease genetics: SNPs and the structural deficit


tion studies is vast, yet it is rarely straightforward to identify the functional connection between a variant and a disorder. A genome-wide scan of non-coding SNPs now links several disease variants to alterations in mRNA conformation. The authors devised an improved assay for determining the effect of a variant on the stability of an RNA molecule: rather than looking to see whether the variant affects the (single) RNA structure that has the minimum free energy, the new algorithm explores the probability that a variant affects any of the many possible base-pairing interactions. The algorithm detects any discrepancy between the base-pairing potential of an RNA in the presence of the wild-type and variant SNP, and assigns a score to sequences based on how severely the variant affects the conformation of the entire UTR. This approach was applied to 524 non-coding SNPs found in the Human Gene Mutation Database, which records the results of human disease association studies. The variants mapped to 350 UTRs, and 206 of these fell in the 5′ UTR. After excluding SNPs that have potential functions in alternative splicing, transcription or translation, the authors narrowed down the list to the 10% of SNPs that had the most marked structural consequences, and analysed further the 20 SNPs that affected 6 diseases, including retinoblastoma and β-thalassaemia. Previous work on some of these SNPs had shown that, in general, they affect translational efficiency, mRNA stability, and protein binding but do not affect expression levels. They also have a stronger influence on the stability of the mature RNA than the pre-mRNA. On top of these studies, the authors now show that the variants map to known RNA functional elements, such as internal ribosome entry sites (IREs) and upstream ORFs. In hyperferritinemia cataract syndrome, for example, all four disease-associated SNPs cause alternative conformations in which the IRE is not formed. The structural rearrangements seen in the diseases studied resemble those seen in bacterial riboswitches. In humans, however, the conformational changes are irreversible — that is, the UTRs are stuck in a pathologically variant form. As well as designing a new tool (SNPFold) for functionally annotating non-coding SNPs, this study highlights a new class of therapeutic targets. Tanita Casci

DOI: 10.1038/nrg2871

Cite this paper

@article{Casci2010DiseaseGS, title={Disease genetics: SNPs and the structural deficit}, author={Tanita Casci}, journal={Nature Reviews Genetics}, year={2010}, volume={11}, pages={669-669} }