To date the majority of expression analysis has focused on the total amount of transcript. However, emerging evidence underlies the importance of understanding the allele specific transcript in cases of human disease. Human diseases are complex traits and understanding the nature of genetic variation underlying such complexity is one of the great challenges before the scientific community. Incorporating a basic understanding of the allele-specific nature of expression will allows us to address fundamental questions about quantitative inheritance in novel ways. Understanding quantitative inheritance at for allele specific transcription will help us understand and effectively model complex human disease. Since little is known about the mechanisms underlying allele specific expression, we need to begin with basic questions about the conditions under which allelic expression varies. What is the quantitative nature of such allele specific expression? Is it additive? Or is there evidence for dominance variation? Is allele specific expression caused by cis effects? trans effects? or the interaction between cis and trans effects? Drosophila is a model organism perfectly suited to understanding these basic questions. Full genome sequences for five divergent lines of D. simulans are readily available, chromosomal content can be manipulated in order to test experimentally the impact of specific alleles on transcription. In this proposal we seek to understand the basis for allele specific expression. We will accomplish this goal by i) developing a high density microarray platform that will allow us to assay allele specific expression in D. simulans ii) developing analytic tools that facilitate modeling of allele specific expression iii) examining the impact of maternal effects, dose response, additivity, and dominance on allele specific expression in a reciprocal reference mating design iv)Partitioning cis and trans variation from the interactions by developing a set of X chromosome substitution lines, and 3rd chromosome introgression lines and combining these into X substitution/ 3rd chromosome introgression lines. The immediate objective of this work is to understand how specific alleles are expressed, how that expression is influenced by cis and trans effects, and how classic quantitative genetics concepts of additivity and dominance are related to cis and trans effects. The long term objective is to understand how genetic variation contributes to complex, quantitative phenotypes such as human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM077618-03S1
Application #
7884921
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
2009-09-01
Project End
2012-01-31
Budget Start
2009-09-01
Budget End
2012-01-31
Support Year
3
Fiscal Year
2009
Total Cost
$387,696
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Graze, Rita M; McIntyre, Lauren M; Morse, Alison M et al. (2014) What the X has to do with it: differences in regulatory variability between the sexes in Drosophila simulans. Genome Biol Evol 6:818-29
Hall, David W; Wayne, Marta L (2013) Ohno's ""peril of hemizygosity"" revisited: gene loss, dosage compensation, and mutation. Genome Biol Evol 5:1-15
Graze, R M; Novelo, L L; Amin, V et al. (2012) Allelic imbalance in Drosophila hybrid heads: exons, isoforms, and evolution. Mol Biol Evol 29:1521-32
Tarone, A M; McIntyre, L M; Harshman, L G et al. (2012) Genetic variation in the Yolk protein expression network of Drosophila melanogaster: sex-biased negative correlations with longevity. Heredity (Edinb) 109:226-34
Wayne, Marta L; Pienaar, Jason; Telonis-Scott, Marina et al. (2011) Expression of defense genes in Drosophila evolves under a different selective regime from expression of other genes. Evolution 65:1068-78
Yang, Jie; Casella, George; McIntyre, Lauren M (2011) Generalized shrinkage F-like statistics for testing an interaction term in gene expression analysis in the presence of heteroscedasticity. BMC Bioinformatics 12:427
McIntyre, Lauren M; Lopiano, Kenneth K; Morse, Alison M et al. (2011) RNA-seq: technical variability and sampling. BMC Genomics 12:293
Verhoeven, Koen J F; Casella, George; McIntyre, Lauren M (2010) Epistasis: obstacle or advantage for mapping complex traits? PLoS One 5:e12264
Telonis-Scott, Marina; Kopp, Artyom; Wayne, Marta L et al. (2009) Sex-specific splicing in Drosophila: widespread occurrence, tissue specificity and evolutionary conservation. Genetics 181:421-34
Graze, Rita M; McIntyre, Lauren M; Main, Bradley J et al. (2009) Regulatory divergence in Drosophila melanogaster and D. simulans, a genomewide analysis of allele-specific expression. Genetics 183:547-61, 1SI-21SI

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