Expression quantitative trait loci (eQTL) mapping studies have become a widely-used tool for identifying genetic variants that affect gene regulation. In these studies, gene expression levels are viewed as quantitative traits, and expression phenotypes are mapped to particular genomic loci by combining estimates of gene expression levels across individuals with genome-wide genotyping data. Recent eQTL studies in humans, as well as in other species, have revealed substantial variation in gene expression levels within and between populations, and identified a large number of genetic factors that influence gene regulation. However, to date, all eQTL mapping studies, regardless of species, have considered variation in steady-state gene expression levels and thus could not determine the exact regulatory mechanism underlying the eQTL association. In particular, typical eQTL studies, as well as most other genome-wide studies of gene expression phenotypes, do not collect data that will allow one to distinguish between variation in transcriptional regulation and variation in RNA decay rates. In general, perhaps because transcription initiation rates are commonly assumed to be the major determinants of overall gene expression levels, RNA decay mechanisms are under-studied compared with the regulation of transcription. As a result, we know relatively little about variation in RNA decay rates across genes or between individuals, and the potential importance of such variation in determining ultimate physiological phenotypes such as human disease remains unclear. To address this issue, we propose to perform a genome-wide eQTL mapping study of RNA decay rates in HapMap lymphoblastoid cell lines (LCLs) for which genome-wide steady- state gene-expression data and genotype data are also available. The data we propose to collect will allow us to identify genetic factors underlying variation in RNA decay rates as well as to study the relative importance of variation in RNA decay rates to overall regulatory variation in gene expression levels.

Public Health Relevance

We propose to use a combination of genomic approaches to map QTLs that affect variation in RNA decay rates in order to increase our understanding of regulatory mechanisms underlying variation in overall gene expression levels.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG006123-02
Application #
8257511
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Struewing, Jeffery P
Project Start
2011-04-14
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$450,534
Indirect Cost
$160,385
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Burrows, Courtney K; Banovich, Nicholas E; Pavlovic, Bryan J et al. (2016) Genetic Variation, Not Cell Type of Origin, Underlies the Majority of Identifiable Regulatory Differences in iPSCs. PLoS Genet 12:e1005793
Bainer, Russell; Frankenberger, Casey; Rabe, Daniel et al. (2016) Gene expression in local stroma reflects breast tumor states and predicts patient outcome. Sci Rep 6:39240
Davenport, Emily R; Cusanovich, Darren A; Michelini, Katelyn et al. (2015) Genome-Wide Association Studies of the Human Gut Microbiota. PLoS One 10:e0140301
Pai, Athma A; Pritchard, Jonathan K; Gilad, Yoav (2015) The genetic and mechanistic basis for variation in gene regulation. PLoS Genet 11:e1004857
Tung, Jenny; Zhou, Xiang; Alberts, Susan C et al. (2015) The genetic architecture of gene expression levels in wild baboons. Elife 4:
van de Geijn, Bryce; McVicker, Graham; Gilad, Yoav et al. (2015) WASP: allele-specific software for robust molecular quantitative trait locus discovery. Nat Methods 12:1061-3
Davenport, Emily R; Mizrahi-Man, Orna; Michelini, Katelyn et al. (2014) Seasonal variation in human gut microbiome composition. PLoS One 9:e90731
Çalışkan, Minal; Pritchard, Jonathan K; Ober, Carole et al. (2014) The effect of freeze-thaw cycles on gene expression levels in lymphoblastoid cell lines. PLoS One 9:e107166
Gallego Romero, Irene; Pai, Athma A; Tung, Jenny et al. (2014) RNA-seq: impact of RNA degradation on transcript quantification. BMC Biol 12:42
Cusanovich, Darren A; Pavlovic, Bryan; Pritchard, Jonathan K et al. (2014) The functional consequences of variation in transcription factor binding. PLoS Genet 10:e1004226

Showing the most recent 10 out of 17 publications