Genetic variation in protein synthesis and abundance
Final Report Abstract
Phenotypic differences among individuals for many traits (e.g. many common diseases) are influenced by genetic differences and it is important to understand precisely how these differences in DNA sequence affect the organism. During my DFG research fellowship, I examined “regulatory variants” that influence the expression of genes. I conducted two projects aimed at better understanding how genetic differences influence gene expression. I worked with the yeast Saccharomyces cerevisiae, a single-celled fungus that shares many key aspects of cell biology with humans. In the first project I developed a novel approach to identify genetic loci that influence protein levels. Because this method uses millions of genetically different yeast cells it has very high statistical power to identify the underlying loci. I made several observations. First, contrary to what had been reported earlier, most loci that affect the mRNA level of a given gene do also affect the corresponding protein. Second, the genetic influences on protein expression are substantially more complex than previously known: a typical gene is influenced by up to dozens of different sites in the genome. In turn, some of these sites influence the expression of more than half of the genes I studied. In the second project, I studied how genetic differences between yeast strains influence “translation”, i.e. the production of proteins from mRNA molecules. I found that the translation of hundreds of genes is affected by these genetic differences. For most genes, these effects are subtle so that differences in mRNA levels are a good approximation of differences in protein production. This work has provided important insights into how genetic variation influences protein production and abundance. Unraveling the details of the considerable genetic complexity this work has revealed is a crucial challenge for future work.
Publications
- Genetic influences on translation in yeast. PLoS Genetics; bioRxiv Preprint (2014)
Albert FW, Muzzey D, Weissman J, and Kruglyak L
(See online at https://doi.org/10.1371/journal.pgen.1004692) - Genetics of single-cell protein abundance variation in large yeast populations. Nature, (2014) 506: 494-497
Albert FW, Treusch S, Shockley AH, Bloom JS, and Kruglyak L
(See online at https://doi.org/10.1038/nature12904)
