Evolutionary Origin and Functions of Retrogene Introns

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Molecular Biology and Evolution (Impact Factor: 9.11). 07/2009; 26(9):2147-56. DOI: 10.1093/molbev/msp125
Source: PubMed


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 although a few retrogenes evolved introns in their coding or 3' untranslated regions (untranslated region, UTR), most introns originated together with untranslated 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 downregulation 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.

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    • "This line of data is consistent with the prevalence of chimerism in retrogene evolution, which not only corroborates the feasibility of de novo emergence of introns, but also demonstrates the significant role that new genes play as a target in intron evolution. Although models like chimerism or intronization are well formulated in the context of intron evolution in retrogenes (Fablet et al., 2009; Zhu et al., 2009), the evolutionary cause and the functional necessity of intron gain is poorly characterised except a couple of cases documented in (Fablet et al., 2009). This survey supports that intron gain in UTRs does have functional consequence, but whether the fixation of these introns is selectively favored in the beginning is still unknown. "
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    ABSTRACT: Retrogenes are duplicated genes generated via retro-position, which were conventionally believed to contain no introns. However, emerging data showed that a significant number of retrogenes do have introns. Thus, these genes represent an attractive system to study how new genes evolve exon–intron structure. Comparison between par-ental genes and retrogenes revealed that retrogenes mainly evolve chimeric structures by fusing with local host genes or recruiting pre-existing intergenic sequences. Additionally, retrogenes could gain introns by inheriting introns of parental genes or by transforming parental exonic sequences. The functional necessity on intron gain in retrogenes remains largely elusive although limited data suggest that newborn introns play regulatory roles, enable exon shuffling and alternative splicing. Accumulation of population genomic data may help to understand which evolutionary force shapes the fixation of introns in both retrogenes and de novo originated genes given the same intron birth process acts on both type of new genes.
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    • "Because the CTAGE family is originally duplicated via retroposition , it is also interesting to understand how these human-specific copies acquired regulatory elements and get transcribed. There are several ways for new copies to acquire promoters, such as recruiting the promoter of a neighboring gene or utilizing promoter from LTR element (Romanish et al. 2007; Fablet et al. 2009). To study this, we first analyzed CTAGE15P, the ancestral copy that leads to the humanspecific expansion. "
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    • "The possible explanation can be given for this phenomenon. Due to the reverse transcription of mature mRNAs from parental source genes, these genes are therefore devoid of introns, which is the main reason for the performance of retrogenes [31]. Gene duplication via retrotransposition has been shown to be an important mechanism in evolution , affecting gene dosage and allowing for the acquisition of new gene functions [32]. "
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