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Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss


One of the most interesting opportunities in comparative genomics is to compare not only genome sequences but additional phenomena, such as alternative splicing, using orthologous genes in different genomes to find similarities and differences between organisms1,2. Recently, genomics studies have suggested that 40–60% of human genes are alternatively spliced3,4,5,6,7,8 and have catalogued up to 30,000 alternative splice relationships in human genes9. Here we report an analysis of 9,434 orthologous genes in human and mouse, which indicates that alternative splicing is associated with a large increase in frequency of recent exon creation and/or loss. Whereas most exons in the mouse and human genomes are strongly conserved in both genomes, exons that are only included in alternative splice forms (as opposed to the constitutive or major transcript form) are mostly not conserved and thus are the product of recent exon creation or loss events. A similar comparison of orthologous exons in rat and human validates this pattern. Although this says nothing about the complex question of adaptive benefit, it does indicate that alternative splicing in these genomes has been associated with increased evolutionary change.

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Figure 1: Gene structure and alternative splicing of human–mouse ortholog pairs.
Figure 2: Comparison of alternative splicing levels in human versus mouse for orthologous exons.
Figure 3: Exon inclusion levels versus evolutionary conservation of orthologous exons in human and mouse.
Figure 4: Exon inclusion levels versus evolutionary conservation of orthologous exons in human and rat.


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We wish to thank D. Black and M. Ares for discussions developing the hypothesis that alternative splicing can facilitate evolutionary tunneling and C. Brunk, G. Chanfreau, J. Lake, A. Resch, Y. Xing, Q. Xu and L. Zipursky for their discussions and comments on this work. C.J.L. was supported by grants from the US National Institutes of Health and U.S. Department of Energy. B.M. was supported by an IGERT award from the National Science Foundation.

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Correspondence to Christopher J Lee.

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Modrek, B., Lee, C. Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss. Nat Genet 34, 177–180 (2003).

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