Evolution and distribution of RNA polymerase II regulatory sites from RNA polymerase III dependant mobile Alu elements - PubMed (original) (raw)

Evolution and distribution of RNA polymerase II regulatory sites from RNA polymerase III dependant mobile Alu elements

Ravi Shankar et al. BMC Evol Biol. 2004.

Abstract

Background: The primate-specific Alu elements, which originated 65 million years ago, exist in over a million copies in the human genome. These elements have been involved in genome shuffling and various diseases not only through retrotransposition but also through large scale Alu-Alu mediated recombination. Only a few subfamilies of Alus are currently retropositionally active and show insertion/deletion polymorphisms with associated phenotypes. Retroposition occurs by means of RNA intermediates synthesised by a RNA polymerase III promoter residing in the A-Box and B-Box in these elements. Alus have also been shown to harbour a number of transcription factor binding sites, as well as hormone responsive elements. The distribution of Alus has been shown to be non-random in the human genome and these elements are increasingly being implicated in diverse functions such as transcription, translation, response to stress, nucleosome positioning and imprinting.

Results: We conducted a retrospective analysis of putative functional sites, such as the RNA pol III promoter elements, pol II regulatory elements like hormone responsive elements and ligand-activated receptor binding sites, in Alus of various evolutionary ages. We observe a progressive loss of the RNA pol III transcriptional potential with concomitant accumulation of RNA pol II regulatory sites. We also observe a significant over-representation of Alus harboring these sites in promoter regions of signaling and metabolism genes of chromosome 22, when compared to genes of information pathway components, structural and transport proteins. This difference is not so significant between functional categories in the intronic regions of the same genes.

Conclusions: Our study clearly suggests that Alu elements, through retrotransposition, could distribute functional and regulatable promoter elements, which in the course of subsequent selection might be stabilized in the genome. Exaptation of regulatory elements in the preexisting genes through Alus could thus have contributed to evolution of novel regulatory networks in the primate genomes. With such a wide spectrum of regulatory sites present in Alus, it also becomes imperative to screen for variations in these sites in candidate genes, which are otherwise repeat-masked in studies pertaining to identification of predisposition markers.

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Figures

Figure 1

Representation of regulatory sites on Alu elements. 500 representative Alu sequences each of distinct evolutionary ages were selected for identification of most probable regulatory sites. 126 polymorphic Alus (POLY) from younger subfamilies which show insertion – deletion polymorphisms were also analysed. Sites were identified using local alignment based program as well as by probabilistic modelling approach. These sites are positionally conserved in all subfamilies.

Figure 2

Distribution of regulatory sites in various Alu subfamilies as well as polymorphic Alus. On the X-axis Alus of different evolutionary ages as well as polymorphic Alus (POLY) are represented. On the Y-axis the percentage of elements carrying these sites in various subfamilies is indicated.

Figure 3

Alu expansion and evolution of regulatory sites. With the help of LINEs, Alu may keep on retro-transposing or may get inactive/negatively selected. Alternatively, it may integrate upstream of a gene, accumulate mutations, evolve RNA pol II regulatory sites, get stabilized and control gene expression. This is supported by the presence of sparse regulatory sites, unhindered A box, recombinogenic sites initially in the younger and active Alus and its accumulation in older Alu subfamilies as well as significant presence of Alus harbouring regulatory sites in the promoter encompassing regions of the genes of signaling and metabolic pathways.

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Evolution and distribution of RNA polymerase II regulatory sites from RNA polymerase III dependant mobile Alu elements - PubMed (original) (raw)