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 #
5R01GM088342-06
Application #
8643793
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Bender, Michael T
Project Start
2010-04-05
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$289,674
Indirect Cost
$101,574
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ji, Xinjun; Park, Juw Won; Bahrami-Samani, Emad et al. (2016) αCP binding to a cytosine-rich subset of polypyrimidine tracts drives a novel pathway of cassette exon splicing in the mammalian transcriptome. Nucleic Acids Res 44:2283-97
Shen, Shihao; Wang, Yuanyuan; Wang, Chengyang et al. (2016) SURVIV for survival analysis of mRNA isoform variation. Nat Commun 7:11548
Damianov, Andrey; Ying, Yi; Lin, Chia-Ho et al. (2016) Rbfox Proteins Regulate Splicing as Part of a Large Multiprotein Complex LASR. Cell 165:606-19
Yang, Yueqin; Park, Juw Won; Bebee, Thomas W et al. (2016) Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition. Mol Cell Biol 36:1704-19
Molinie, Benoit; Wang, Jinkai; Lim, Kok Seong et al. (2016) m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome. Nat Methods 13:692-8
Lin, Lan; Jiang, Peng; Park, Juw Won et al. (2016) The contribution of Alu exons to the human proteome. Genome Biol 17:15
Cieply, Benjamin; Park, Juw Won; Nakauka-Ddamba, Angela et al. (2016) Multiphasic and Dynamic Changes in Alternative Splicing during Induction of Pluripotency Are Coordinated by Numerous RNA-Binding Proteins. Cell Rep 15:247-55
Park, Juw Won; Jung, Sungbo; Rouchka, Eric C et al. (2016) rMAPS: RNA map analysis and plotting server for alternative exon regulation. Nucleic Acids Res 44:W333-8
Wang, Jinkai; Lu, Zhi-xiang; Tokheim, Collin J et al. (2015) Species-specific exon loss in human transcriptomes. Mol Biol Evol 32:481-94
Stein, Shayna; Lu, Zhi-Xiang; Bahrami-Samani, Emad et al. (2015) Discover hidden splicing variations by mapping personal transcriptomes to personal genomes. Nucleic Acids Res 43:10612-22

Showing the most recent 10 out of 28 publications