MBE Advance Access published online on June 24, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp125
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Research Article |
Evolutionary origin and functions of retrogene introns
1 Center for Integrative Genomics, University of Lausanne, Genopode Building, CH–1015 Lausanne, Switzerland
Corresponding authors: Marie Fablet (fablet{at}biomserv.univ-lyon1.fr) and Henrik Kaessmann (Henrik.Kaessmann{at}unil.ch)
Received for publication March 9, 2009. Revision received June 10, 2009. Accepted for publication June 20, 2009.
Retroposed genes (retrogenes) originate via the reverse transcription of mature messenger RNAs from parental source genes and are therefore usually devoid of introns. Here we characterize a particular set of mammalian retrogenes that acquired introns upon their emergence and thus represent rare cases of intron gain in mammals. We find that while a few retrogenes evolved introns in their coding or 3’ untranslated regions, most introns originated together with untranslated (UTR) exons in the 5’ flanking regions of the retrogene insertion site. They emerged either de novo or through fusions with 5’ UTR exons of host genes into which the retrogenes inserted. Generally, retrogenes with introns display high transcription levels and show broader spatial expression patterns than other retrogenes. Our experimental expression analyses of individual intron–containing retrogenes show that 5’ UTR introns may indeed promote higher expression levels, at least in part through encoded regulatory elements. By contrast, 3’ UTR introns may lead to down–regulation of expression levels via nonsense–mediated decay mechanisms. Notably, the majority of retrogenes with introns in their 5’ flanks depend on distant, sometimes bidirectional CpG dinucleotide–enriched promoters for their expression that may be recruited from other genes in the genomic vicinity. We thus propose a scenario where the acquisition of new 5’ exon–intron structures was directly linked to the recruitment of distant promoters by these retrogenes, a process potentially facilitated by the presence of proto–splice sites in the genomic vicinity of retrogene insertion sites. Thus, the primary role and selective benefit of new 5’ introns (and UTR exons) was probably initially to span the often substantial distances to potent CpG promoters driving retrogene transcription. Later in evolution, these introns then obtained additional regulatory roles in fine–tuning retrogene expression levels. Our study provides novel insights regarding mechanisms underlying the origin of new introns, the evolutionary relevance of intron gain, and the origin of new gene promoters.
Key Words: Retrogenes • origin of new gene functions • intron evolution • promoter evolution • gene expression
2 Current address: Laboratoire de Biométrie et Biologie Evolutive, Université de Lyon, Université Lyon 1, CNRS, UMR 5558, Villeurbanne, France.
3 Current address: Ecole Polytechnique Fédéral de Lausanne (EPFL), Biomolecular Screening Facility, Building AAB, Station 15, CH–1015 Lausanne.