Rotem Sorek ^{1, 2, 5}, Galit Lev-Maor ^{1, 5}, Mika Reznik ^{1, 5}, Tal Dagan ³, Frida Belinky ³, Dan Graur ⁴, and Gil Ast ^{1, @}

¹Department of Human Genetics and Molecular Medicine, Tel Aviv University, Ramat Aviv 69978, Israel
² Compugen, 72 Pinchas Rosen Street, Tel Aviv 69512, Israel
³ Department of Zoology, Tel Aviv University, Ramat Aviv 69978, Israel
⁴ Department of Biology and Biochemistry, University of Houston, Houston, TX 77204 USA
⁵These authors contributed equally to this work

^@ Correspondence: Gil Ast;   +972-3-640-6893 (phone);   +972-3-640-9900 (fax)
    gilast@post.tau.ac.il

Alu exonization, which is an evolutionary pathway that creates primate-specific transcriptomic diversity, is a powerful tool for studying alternative-splicing regulation. Through bioinformatic analyses combined with experimental methodology, we identified the mutational changes needed to create functional 5' splice sites in Alu. We revealed a complex mechanism by which the sequence composition of the 5' splice site and its base pairing with the small nuclear RNA U1 govern alternative splicing. We show that in Alu-derived GC introns the strength of the base pairing between U1 snRNA and the 5' splice site controls the skipping/inclusion ratio of
alternative splicing. Based on these findings, we identified 7810 Alus within the human genome that are prone to exonization. Mutations in these Alus may cause genetic disorders or contribute to human-specific protein diversity.

1. Allen TA, Von Kaenel S, Goodrich JA, and Kugel JF, "The SINE-encoded mouse B2 RNA represses mRNA transcription in response to heat shock", Nature Structural and Molecular Biology, Published online: 08 August 2004; | doi:10.1038/nsmb813

2. Espinoza CA, Allen TA, Hieb AR, Kugel JF, and Goodrich JA, "B2 RNA binds directly to RNA polymerase II to repress transcript synthesis",  Nature Structural and Molecular Biology, Published online: 08 August 2004; | doi:10.1038/nsmb812

3. Ferrigno O, Virolle T, Djabari Z, Ortonne J-P, White RJ, and Aberdam D, "Transposable B2 SINE elements can provide mobile RNA polymerase II promoters", Nature Genetics, vol. 28,  no. 1, pp. 77-81 (May, 2001). (doi:10.1038/88306 ).

4. Otieno AC, Carter AB, Hedges DJ, Walker JA, Ray DA, Garber RK, Anders BA, Stoilova N, Laborde ME, Fowlkes JD, Huang CH, Perodeau B, and Batzer MA, "Analysis of the Human Alu Ya-lineage", J. Mol. Biol., vol. 342, no. 1: pp. 109-18, (September 3, 2004).

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