Intellectual Merit: In isolation, a gene is an inert object - nothing more than a string of nucleotide bases. Only when placed in a cellular environment and interacting with the products of other genes can a gene become active. The first step in this activation is for the gene to be transcribed, or "expressed." This expression is essential for the proper development and physiology of an organism, and mutations that alter expression are a common source of evolutionary change. Despite their importance, there are few cases in which the mutations responsible for differences in gene expression between species have been identified, and our understanding of the molecular mechanisms and evolutionary processes that underlie regulatory evolution remain limited. This project will help close this knowledge gap by revealing the types of molecular changes responsible for the evolution of gene expression throughout the genome using the latest high-throughput sequencing technology. New computational tools will also be developed in the course of this work that will assist other researchers working on a variety of scientific questions.
Broader impacts: This project will generate DNA sequence data and bioinformatic tools that will benefit the broader scientific research community. The research will also establish a technical and conceptual foundation for understanding how organisms adapt to changing environments. The project includes activities designed to increase the participation of members of underrepresented groups in the sciences and improve undergraduate and graduate teaching in genetics, genomics, and evolution. For example, the principal investigator will teach a module on "Genetics and Genomics" at the Arizona State University Mathematical and Theoretical Biology Summer Institute that enrolls predominantly minority students; host A.P. Biology students from a high school with >85% African-American students; and serve as chair of a diversity committee at the University of Michigan that develops and oversees programs designed to increase opportunities for minority undergraduate and graduate students. Pedagogical contributions include evaluating the effectiveness of a teaching technique developed by the principal investigator, contributing teaching resources to Nature Education; and promoting strategies for active learning systems in large lecture courses at the University of Michigan.
Most cells in a multicellular organism contain the same genes, but different genes are active in different cells. A process known as gene regulation controls which genes are "turned on" or expressed in each cell and how much product is produced from that gene. Changes in the amount of gene product can alter development and/or physiology and change the properties of an organism. Such changes in gene expression have evolved within and between species and many contribute to traits unique to one individual or one species. The intellectual merit of this project was to determine the rate at which, and mechanisms by which, differences in gene expression have evolved. To do this, we focused on a group of closely related fruit flies, including the classic genetic model species Drosophila melanogaster. We used a newly developed sequencing technology to measure gene expression in different strains and species of Drosophila, examining both total and allele-specific expression for the entire genome. (Drosophila, like humans, are diploids, meaning that they have two alleles of each gene per cell.) This data allowed us to determine not only how levels of gene expression change over evolutionary time, but also to separate the contribution of different (cis- and trans-acting) regulatory mechanisms controlling gene expression. We found that cis-acting changes accumulate faster than total expression difference over time, suggesting compensatory mechanisms that maintain total gene expression in the face of changes in the mechanisms controlling expression. The data generated in the course of addressing this question also allowed us to investigate other questions, including whether or not alleles are expressed similarly in Drosophila when transmitted by mothers and fathers and how genetic variants that affect gene expression act differently in males and females. The broader impacts of this project included distribution of a software protocol that is useful to a diverse research community, novel DNA sequences that can facilitate future research, and scientific training for a group of people that are diverse in terms of educational and ethnic background. Further broader impacts resulted from activities to improve undergraduate and graduate teaching in genetics, genomics, and evolution.
