title: Global analysis of alternative splicing differences between humans and chimpanzees.
abstract: 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.
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto, Terrence Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario M5S 3E1, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Calarco
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
authors.forename: Mario
authors.initials: M
authors.lastname: Cáceres
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Calarco
authors.forename: Xinshu
authors.initials: X
authors.lastname: Xiao
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.forename: Christopher
authors.initials: C
authors.lastname: Lee
authors.forename: Todd M
authors.initials: TM
authors.lastname: Preuss
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D019143:Evolution, Molecular; D005091:Exons; D020224:Expressed Sequence Tags / Q000737:chemistry; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D007527:Isoenzymes / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D002679:Pan troglodytes / Q000235:genetics*; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics; D013045:Species Specificity; D014162:Transfection
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; C492569:GSTO2 protein, human; D005982:Glutathione Transferase