Figure 6. | Splicing repression allows the gradual emergence of new Alu-exons in primate evolution

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Splicing repression allows the gradual emergence of new Alu-exons in primate evolution

Figure 6.

Affiliation details

UCL Institute of Neurology, United Kingdom; MRC-Laboratory of Molecular Biology, United Kingdom; Institute de Biologie de l’ENS (IBENS), CNRS UMR 8197, France; University College London Genetics Institute, United Kingdom; Goethe University Frankfurt, Germany; Institute of Molecular Biology (IMB), Germany
Figure 6.
Download figureOpen in new tabFigure 6. Repressive elements co-evolve with splice site sequences at cryptic exons.

Alignment within primate genomes of Alu elements that contain human Alu-exon reveals a tight coupling between repressive U-tracts and the variation of 3' splice site strength. (A) As the strength of 3' splice sites increases, the repressive U-tracts are lengthened, which recruits hnRNPC to prevent splicing of Alu-exons. Hence, the splice site sequence and the repressive U-tract undergo an evolutionary dynamic that we refer to as regulatory co-evolution. Splice site sequences without a nearby repressive element are depleted, likely due to strong negative selection. Selection pressure for long U-tracts decreased for as-yet unknown reasons at the more ancient Alu-exons (those that contain a splice site in a distant primate species, or their sequence diverges from the Alu consensus), and these exons are less repressed by hnRNPC and have an increased incidence of tissue-specific splicing. At this stage, abundance of the Alu-exon isoform is determined also by its ability to trigger NMD, and likely other factors such as tissue-specific splicing factors. (B) Based on the variation of the 3' splice sites between primate species, we characterised three evolutionary groups of Alu-exons. Most human Alu-exons have stronger 3' splice sites in human compared to New World monkeys, and these exons also have longer repressive U-tracts in human. These exons are split according to the evolutionary trajectory of their 3' splice site sequence into emerging, evolving or stable 3' splice sites. The most ancient Alu-exons, which have a strong and stable 3' splice site, lack any trend towards longer U-tracts. This demonstrates that tight coupling between positive and negative splicing elements establishes a balanced regulatory environment at the newly emerging exons.