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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Bender, Michael T
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Zhang, Zijun; Park, Eddie; Lin, Lan et al. (2018) A panoramic view of RNA modifications: exploring new frontiers. Genome Biol 19:11
Park, Eddie; Pan, Zhicheng; Zhang, Zijun et al. (2018) The Expanding Landscape of Alternative Splicing Variation in Human Populations. Am J Hum Genet 102:11-26
Zhou, Chan; Molinie, Benoit; Daneshvar, Kaveh et al. (2017) Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs. Cell Rep 20:2262-2276
Zhang, Zijun; Xing, Yi (2017) CLIP-seq analysis of multi-mapped reads discovers novel functional RNA regulatory sites in the human transcriptome. Nucleic Acids Res 45:9260-9271
Park, Eddie; Guo, Jiguang; Shen, Shihao et al. (2017) Population and allelic variation of A-to-I RNA editing in human transcriptomes. Genome Biol 18:143
Lin, Lan; Jiang, Peng; Park, Juw Won et al. (2016) The contribution of Alu exons to the human proteome. Genome Biol 17:15
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
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
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
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

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