Approved Research

Epistatic interactions of regulatory and relatively frequent putative damaging variants in the healthy population

Lay summary

One of the biggest limitations of the current genetic clinical diagnostics is the interpretation of coding genetic variants (single "letter" variations in the DNA code with a potential impact on causing a disease). Some variants seem to have a pathogenic potential (according to experimental evidence) but are present in healthy individuals. Are these putative damaging variants actually associated with a disease? If so, why are they so relatively frequent in the healthy population? The answer might be still found in the DNA but outside of the current comfort zone. Despite active research in this field, we still do not know what is the function of 99% of our DNA. Experimental results indicate that some special variants called expression Quantitative Loci (eQTLs) regulate gene expression and, by consequence, the quantity of the proteins produced by the cell. Maybe these "regulatory" variants might modulate the effect of pathogenic variants either in a protective or in a harmful way. This 24 months project aims to develop a statistical method for the identification of significant combinations of regulatory and pathogenic variants and to provide a list of clinically relevant regulatory variants to be included in daily genetic testing. The outcome of this project will be important to improve the diagnostics of rare genetic diseases and help the comprehension of the unknown part of the genome.