Grant: Project Grant

Susceptibility or resistance to most common diseases is determined by the type of genes we inherit in our parent's DNA. The DNA is 99.9% identical between any two unrelated individuals and it is the 0.1% that determines differences between individuals. These inherited small variants modify the DNA, the blueprint that determines how our body is built and how it functions. The DNA encodes proteins, the building blocks of the body. The variants sometimes change the protein itself but, more often, what varies among individuals is how much of the protein will be expressed, when and under what stimulus. This is done in many cases by modulating transcription of DNA into RNA. RNA carries the DNA instructions to the ribosomes, the cell's protein-production factory. In 1997, our lab discovered one of the first such effects, of a variant of the insulin gene in type 1 diabetes and now thousands of such effects are known. A much less-well studied level at which genetic variants can determine protein production is the translation of RNA variants into protein. Proteins are much harder to study than RNA but we have developed a method that quantifies how much RNA is associated with ribosomes as an indirect but powerful way of identify proteins whose production is affected by variants in the RNA sequence, and validated it in a small number of subjects. We now propose to apply this method to a much larger sample of individuals to discover all common variants that affect association of RNA with ribosomes. The method will then be validated by using targeted protein quantification using targeted methods of modern proteomics. Significance: Thousands of variants are known to affect susceptibility to various diseases but, to translate this into understanding of disease and therapeutic targets, we need to define the mechanism of the genetic effect.