Proper organismal function requires fine-tuned regulation of gene expression, yet variation exists within and between species. This variation can take the form of multiple disease states in humans as well as phenotypic differences between species. Despite its importance, regulatory evolution is not yet well understood. Previous studies have shown that regulatory divergence is governed by changes in cis- and trans-regulatory elements that affect the level of expression of genes. cis-regulatory changes have effects on allele-specific expression, while trans-regulatory variation contributes to the expression of both alleles in a diploid cell. The effects of cis- and trans-regulatory elements can be disentangled using measures of allele-specific gene expression. This proposal aims to address questions such as: What are the relative contributions of cis- and trans-regulatory changes to divergent gene expression? Do the relative contributions of cis- and trans-regulatory changes vary with divergence time? Are different functional classes affected more often by changes in cis- or trans-regulatory elements? To address these questions, we propose a novel strategy for distinguishing cis- and trans-regulatory effects on variable gene expression genome-wide. Using high- throughput sequencing, we will measure allele-specific expression in pairs of inbred strains from the same and different species. Alelle-specific expression will also be determined in F1 hybrids produced by crossing pairs of these strains. New computational tools have been developed to analyze the enormous amount of data produced by the massively parallel sequencing, and these tools will be made available to the broader research community. Allele-specific measurements of gene expression will be used to compare the relative contribution of cis- and trans-regulatory variants among crosses. We will also make allele-specific transgenes and use them for functional tests of cis- regulatory divergence. Finally, we will test the hypothesis that cis-regulatory changes accumulate faster than trans-regulatory changes over time, using the whole transcriptome of strains/species with divergence times ranging from 10,000-7 million years ago.

Public Health Relevance

Relevance: Proper gene regulation can mean the difference between healthy and disease states in humans. Determining the contributions that different regulatory variants make to differences in gene expression is an important step towards understanding the relationship between genotypes and phenotypes. The conclusions drawn with the proposed study of Drosophila regulatory variation can then be used as a model for human variation in gene expression regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM089009-01A1
Application #
7911134
Study Section
Special Emphasis Panel (ZRG1-F08-E (20))
Program Officer
Bender, Michael T
Project Start
2010-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$47,606
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Andrade López, J M; Lanno, S M; Auerbach, J M et al. (2017) Genetic basis of octanoic acid resistance in Drosophila sechellia: functional analysis of a fine-mapped region. Mol Ecol 26:1148-1160
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
Meiklejohn, Colin D; Coolon, Joseph D; Hartl, Daniel L et al. (2014) The roles of cis- and trans-regulation in the evolution of regulatory incompatibilities and sexually dimorphic gene expression. Genome Res 24:84-95
Coolon, Joseph D; McManus, C Joel; Stevenson, Kraig R et al. (2014) Tempo and mode of regulatory evolution in Drosophila. Genome Res 24:797-808
Coolon, Joseph D; Jones, Kenneth L; Todd, Timothy C et al. (2013) Long-term nitrogen amendment alters the diversity and assemblage of soil bacterial communities in tallgrass prairie. PLoS One 8:e67884
Coolon, Joseph D; Webb, William; Wittkopp, Patricia J (2013) Sex-specific effects of cis-regulatory variants in Drosophila melanogaster. Genetics 195:1419-22
Stevenson, Kraig R; Coolon, Joseph D; Wittkopp, Patricia J (2013) Sources of bias in measures of allele-specific expression derived from RNA-sequence data aligned to a single reference genome. BMC Genomics 14:536
Coolon, Joseph D; Stevenson, Kraig R; McManus, C Joel et al. (2012) Genomic imprinting absent in Drosophila melanogaster adult females. Cell Rep 2:69-75