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Global analysis of alternative splicing differences between humans and chimpanzees

¹ Banting and Best Department of Medical Research, University of Toronto, Terrence Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario M5S 3E1, Canada; ² Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; ³ Molecular Biology Institute, Center for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA; ⁴ Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine and Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, Iowa, 52242, USA; ⁵ Division of Neuroscience and Center for Behavioral Neuroscience, Yerkes National Primate Research Center, and Department of Pathology, Emory University, Atlanta, Georgia 30329, USA; ⁶ Genes and Disease Program, Center for Genomic Regulation (CRG-UPF), 08003 Barcelona, Spain; ⁷ Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Alternative splicing is a powerful mechanism affording extensive proteomic and regulatory diversity from a limited repertoire of genes. However, the extent to which alternative splicing has contributed to the evolution of primate species-specific characteristics has not been assessed previously. Using comparative genomics and quantitative microarray profiling, we performed the first global analysis of alternative splicing differences between humans and chimpanzees. Surprisingly, 6%–8% of profiled orthologous exons display pronounced splicing level differences in the corresponding tissues from the two species. Little overlap is observed between the genes associated with alternative splicing differences and the genes that display steady-state transcript level differences, indicating that these layers of regulation have evolved rapidly to affect distinct subsets of genes in humans and chimpanzees. The alternative splicing differences we detected are predicted to affect diverse functions including gene expression, signal transduction, cell death, immune defense, and susceptibility to diseases. Differences in expression at the protein level of the major splice variant of Glutathione S-transferase omega-2 (GSTO2), which functions in the protection against oxidative stress and is associated with human aging-related diseases, suggests that this enzyme is less active in human cells compared with chimpanzee cells. The results of this study thus support an important role for alternative splicing in establishing differences between humans and chimpanzees.

[Keywords: Alternative splicing; gene regulation; microarray profiling; primate evolution]]

Received August 20, 2007; revised version accepted September 18, 2007.

⁹ Corresponding authors.

E-MAIL b.blencowe{at}utoronto.ca; FAX (416) 978-8287.

¹⁰ E-MAIL tpreuss{at}emory.edu; FAX (404) 727-8070.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1606907

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