Heritable differences in gene expression are common and contribute to phenotypic diversity between species, between individuals of the same species, and sometimes even between cells of the same individual. This diversity includes """"""""normal"""""""" variation among healthy individuals as well as """"""""abnormal"""""""" variation causing disease. Despite their importance, the genetic changes responsible for difference in gene expression and the evolutionary processes that affect them are not well understood. One reason for this is that little is known about the mutational input for regulatory variation, upon which selection and drift act to produce patterns of regulatory polymorphism and divergence in the wild. This project will help fill this knowledge gap by (1) collecting and characterizing new mutations affecting activity of a focal gene, (2) identifying and characterizing genetic variants segregating as polymorphisms within a species, and (3) comparing properties of these mutations with fitness and between the sets of mutations and polymorphisms. These properties will include: the type of mutation (coding or noncoding), effect size, network position, dominance, and pleiotropy. Using this information, diverse hypotheses will be tested about the effects of these mutational properties on the evolutionary fate of new regulatory mutations. This work will advance our understanding of the molecular mechanisms underlying regulatory (and presumably phenotypic) differences, as well as provide an empirical foundation for developing more realistic models of regulatory evolution in the future.
This project examines the properties of mutations that affect gene expression and how they relate to fitness. This information will help us understand how phenotypes change between species, between individuals and between cells within an individual. This includes phenotypic changes that can cause a healthy cell to become cancerous.
|Metzger, Brian P H; Duveau, Fabien; Yuan, David C et al. (2016) Contrasting Frequencies and Effects of cis- and trans-Regulatory Mutations Affecting Gene Expression. Mol Biol Evol 33:1131-46|
|Metzger, Brian P H; Yuan, David C; Gruber, Jonathan D et al. (2015) Selection on noise constrains variation in a eukaryotic promoter. Nature 521:344-7|
|Coolon, Joseph D; Stevenson, Kraig R; McManus, C Joel et al. (2015) Molecular Mechanisms and Evolutionary Processes Contributing to Accelerated Divergence of Gene Expression on the Drosophila X Chromosome. Mol Biol Evol 32:2605-15|
|Duveau, Fabien; Metzger, Brian P H; Gruber, Jonathan D et al. (2014) Mapping small effect mutations in Saccharomyces cerevisiae: impacts of experimental design and mutational properties. G3 (Bethesda) 4:1205-16|