The goal of this project is to systematically survey the evolution of pre-mRNA splicing in primates, and elucidate the molecular mechanisms that created species-specific exons and splicing patterns. Alternative splicing in higher eukaryotes generates an enormous regulatory and functional diversity from a limited repertoire of protein-coding genes. It also permits a gene to evolve a new spliced isoform, while still expressing the ancestral spliced isoform. Many genes have species-specific exons and splicing patterns that arose from either small-scale sequence changes that affected essential splicing signals, or large-scale insertions or deletions. However, despite the critical role of splicing during eukaryotic genome evolution, many questions regarding how splicing changes occurred and the evolutionary significance of such changes remain largely unexplored. We propose to combine genomic, computational, and molecular approaches to study splicing changes during primate and human evolution.
The specific aims are: 1) To investigate the birth and evolution of new exons in primates, using genome alignments of vertebrate species, extensive exon-level transcriptome profiles of human genes generated by microarray and sequencing-based technologies, and molecular splicing analysis of new exons in humans and nonhuman primates. 2) To globally examine splicing differences between humans and nonhuman primates, by high-density exon junction array and RNA-seq profiling of a large panel of human and primate tissues. 3) To elucidate the mechanisms of splicing evolution in primates, via comparative analysis of splicing regulatory signals and minigene experiments. This project will improve the annotation of human and primate genomes, greatly expand the knowledge of new exons and splicing patterns that are unique to our species, and shed light on how eukaryotic genomes expand their functional repertoire via the evolution of splicing. The results of these studies will elucidate how the evolution of genomic sequences contributed to splicing differences among species. This will provide significant insight into the regulation of splicing, and how genetic variations disrupt splicing in human diseases.

Public Health Relevance

Many human diseases are caused by aberrations in pre-mRNA splicing. This project will systematically survey the evolution of splicing in primates, and elucidate how splicing patterns change as a result of genome sequence evolution. These studies will provide significant insight into how splicing is regulated, and how genetic variations disrupt splicing in human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088342-03
Application #
8248784
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Bender, Michael T
Project Start
2010-04-05
Project End
2013-01-01
Budget Start
2012-04-01
Budget End
2013-01-01
Support Year
3
Fiscal Year
2012
Total Cost
$130,910
Indirect Cost
$43,637
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Tokheim, Collin; Park, Juw Won; Xing, Yi (2014) PrimerSeq: Design and visualization of RT-PCR primers for alternative splicing using RNA-seq data. Genomics Proteomics Bioinformatics 12:105-9
Boudreau, Ryan L; Jiang, Peng; Gilmore, Brian L et al. (2014) Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81:294-305
Lackford, Brad; Yao, Chengguo; Charles, Georgette M et al. (2014) Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal. EMBO J 33:878-89
Guo, Rui; Zheng, Lijuan; Park, Juw Won et al. (2014) BS69/ZMYND11 reads and connects histone H3.3 lysine 36 trimethylation-decorated chromatin to regulated pre-mRNA processing. Mol Cell 56:298-310
Yao, Chengguo; Choi, Eun-A; Weng, Lingjie et al. (2013) Overlapping and distinct functions of CstF64 and CstF64ýý in mammalian mRNA 3' processing. RNA 19:1781-90
Heinicke, Laurie A; Nabet, Behnam; Shen, Shihao et al. (2013) The RNA binding protein RBM38 (RNPC1) regulates splicing during late erythroid differentiation. PLoS One 8:e78031
Dittmar, Kimberly A; Jiang, Peng; Park, Juw Won et al. (2012) Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol Cell Biol 32:1468-82
Shen, Shihao; Park, Juw Won; Huang, Jian et al. (2012) MATS: a Bayesian framework for flexible detection of differential alternative splicing from RNA-Seq data. Nucleic Acids Res 40:e61
Lu, Zhi-xiang; Jiang, Peng; Cai, James J et al. (2011) Context-dependent robustness to 5' splice site polymorphisms in human populations. Hum Mol Genet 20:1084-96
Liu, Song; Lin, Lan; Jiang, Peng et al. (2011) A comparison of RNA-Seq and high-density exon array for detecting differential gene expression between closely related species. Nucleic Acids Res 39:578-88

Showing the most recent 10 out of 12 publications