Naturally-occurring polymorphisms can affect gene expression and thereby underlie human diseases and other important phenotypic traits. A deeper understanding of cis-regulatory variafion will also facilitate the design of better algorithms for predicting cis-regulatory sites and help us elucidate the impact of changes in gene regulafion on morphological evolution. Previously, we analyzed polymorphisms in human and Drosophila microRNA sites and yeast transcription factor binding sites and their relafion to changes in gene expression between individuals in a species, Here we propose to extend this work to cis-regulatory sites that mediate post-transcripfional control via binding of RNA-binding proteins in S. cerevisiae. We use S. cerevisiae as a model system because it offers experimental tractability, arguably the best studied Eukaryofic gene regulatory network and mulfiple sequenced strains. RNA processing is a fundamental cellular process and factors involved in these pathways are conserved in higher Eukaryotes.
Our specific aims for the ROO phase are (1) We will collect the best possible set of motifs for yeast RNA-binding proteins from the literature and by analyzing recent RNA immunoprecipitation (RIP-chip) data and microarray data following knock-out of various RNA-binding proteins. We will test exisfing motif finding tools and try to extend them using regression and conservation techniques, (2) We will predict cis-regulatory sites for RNA binding proteins by combining comparative and populafion genomics data in yeast. We will experimentally validate a subset of the predictions using standard site-directed mutagenesis and qPCR techniques. (3) We will use the recentiy available Digital Gene Expression ? Tag Profiling kit from lllumina to annotate 3'end isoforms In the BY and RM strains and two environmental conditions to help us predict the cis-regulatory sites in Aim 2. If there is at least one gene that is differenfially polyadenylated between BY and RM, we will map cis- and trans- regulators of alternative polyadenylation using either the well-studied BY/RM segregant lines or a panel of recently sequenced wild isolates. Our long-term goal is to use computafional and experimental approaches to link sequence polymorphisms and gene expression changes to morphological change.

Public Health Relevance

Many human diseases are partly caused by the aberrant regulation of genes. Identifying the genefic mutations responsible forthe changes in control ofthese genes is the first step towards diagnosing and curing these diseases. The aim of this project is to develop and validate computafional methods that can eventually be used to create a comprehensive catalogue of gene regulatory variation in the human genome.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Transition Award (R00)
Project #
4R00HG004515-02
Application #
7908044
Study Section
Special Emphasis Panel (NSS)
Program Officer
Good, Peter J
Project Start
2008-09-28
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$248,968
Indirect Cost
Name
Rutgers University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Diao, Liyang; Marcais, Antoine; Norton, Scott et al. (2014) MixMir: microRNA motif discovery from gene expression data using mixed linear models. Nucleic Acids Res 42:e135
Song, Jimin; Liu, Jixia; Schnakenberg, Sandra L et al. (2014) Variation in piRNA and transposable element content in strains of Drosophila melanogaster. Genome Biol Evol 6:2786-98
Tomar, Parul; Bhatia, Aatish; Ramdas, Shweta et al. (2013) Sporulation genes associated with sporulation efficiency in natural isolates of yeast. PLoS One 8:e69765
Diao, Liyang; Chen, Kevin C (2012) Local ancestry corrects for population structure in Saccharomyces cerevisiae genome-wide association studies. Genetics 192:1503-11
Kumar, M Senthil; Chen, Kevin C (2012) Evolution of animal Piwi-interacting RNAs and prokaryotic CRISPRs. Brief Funct Genomics 11:277-88
Gould, David W; Lukic, Sergio; Chen, Kevin C (2012) Selective constraint on copy number variation in human piwi-interacting RNA Loci. PLoS One 7:e46611
Yang, Jr-Shiuan; Phillips, Michael D; Betel, Doron et al. (2011) Widespread regulatory activity of vertebrate microRNA* species. RNA 17:312-26
Lukic, Sergio; Hey, Jody; Chen, Kevin (2011) Non-equilibrium allele frequency spectra via spectral methods. Theor Popul Biol 79:203-19
Lukic, Sergio; Chen, Kevin (2011) Human piRNAs are under selection in Africans and repress transposable elements. Mol Biol Evol 28:3061-7

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