To what extent changes in gene expression regulation drive the evolutionary innovations of life is an important unresolved question. In particular, the role of cis-regulation has been contentious. While some contend that changes in cis-regulation are responsible for the majority of morphological adaptations, others point out that only a few such cases have been demonstrated. The paucity of examples of adaptive regulatory divergence (cis-acting or otherwise) may be due in large part to the fact that no method for identifying such cases from genome-scale data has yet been developed. We have recently developed the first such method, which is based on analysis of genome-scale catalogs of regulatory differences between any pair of strains or species. We have demonstrated its ability to detect genes and even entire functional groups/pathways that have been subject to positive selection for changes in gene expression. What is now most needed is additional data from which to detect the signature of positive selection, as well as methods to pinpoint and functionally characterize the individual nucleotide changes responsible for these adaptations. Saccharomyces budding yeast represents an ideal model in which to study these questions. The end result of this work, in addition to a greatly increased understanding of how regulatory evolution occurs at the molecular level, will be a comprehensive catalog of cis-regulatory changes in yeast, as well as the first collection of strains (from any species) differing only by single adaptive mutations. We believe that this collection of results and resources will transform yeast into the leading model organism for studying gene expression adaptation.

Public Health Relevance

The subject of this project-the evolution of gene expression-is of great importance to biomedicine. For example, a general understanding of mechanisms of gene expression evolution could be applied to pathogens to help understand the rapid emergence of drug resistant strains and other evolutionary dynamics that occur at scales ranging from a single host infection to global epidemics. Indeed, one yeast strain we propose to study (YJM789) is pathogenic in immunocompromised humans. In addition, a deeper understanding of human gene expression evolution will be essential for elucidating the molecular mechanisms underlying human-specific phenotypes, including many disease phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097171-03
Application #
8602838
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2012-02-05
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$268,470
Indirect Cost
$97,470
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Artieri, Carlo G; Fraser, Hunter B (2014) Evolution at two levels of gene expression in yeast. Genome Res 24:411-21
Domman, Daryl; Collingro, Astrid; Lagkouvardos, Ilias et al. (2014) Massive expansion of Ubiquitination-related gene families within the Chlamydiae. Mol Biol Evol 31:2890-904
Artieri, Carlo G; Fraser, Hunter B (2014) Transcript length mediates developmental timing of gene expression across Drosophila. Mol Biol Evol 31:2879-89
Chang, Jessica; Zhou, Yiqi; Hu, Xiaoli et al. (2013) The molecular mechanism of a cis-regulatory adaptation in yeast. PLoS Genet 9:e1003813
Fraser, Hunter B (2013) Cell-cycle regulated transcription associates with DNA replication timing in yeast and human. Genome Biol 14:R111
Fraser, Hunter B (2013) Gene expression drives local adaptation in humans. Genome Res 23:1089-96
Smith, Justin D; McManus, Kimberly F; Fraser, Hunter B (2013) A novel test for selection on cis-regulatory elements reveals positive and negative selection acting on mammalian transcriptional enhancers. Mol Biol Evol 30:2509-18