RNA-based gene duplication: mechanistic and evolutionary insights

Abstract

The enzymatic machinery encoded by certain retrotransposons enables genes to duplicate via an RNA intermediate, a mechanism termed retroposition or retroduplication. In mammals, retroposition has produced thousands of gene copies, termed retrocopies. Retrocopies are expected to lack promoter sequences and were long regarded as pseudogenes with no functional relevance. However, cases of functional retrocopies, termed retrogenes, have accumulated in the literature, implying that retrocopies can be transcribed. Recent large-scale studies indicate that transcribed retrocopies are widespread. Retrocopies can become transcribed in various ways. For example, they can use promoters of other genes or retrotransposable elements in their vicinity, but they can (unexpectedly) also inherit promoters from their parental source genes. Retrocopies and retrogenes are frequently functionally transcribed in the testis, which is probably due to the permissive transcriptional state of chromatin during and after meiosis. Several 'out-of-the-X' autosomal retrogenes have been shown to functionally substitute their X-linked parental genes during and after meiotic sex-chromosome inactivation. Phylogenetic dating of out-of-the-X retrogenes in mammals has led to the reassessment of the age of our sex chromosomes. Detailed functional studies of young retrogenes have provided novel insights pertaining to the origin of new genes. For example, analyses of recent primate genes revealed that new gene functions can arise through changes in the localization of encoded proteins in the cell during evolution, whereas studies in Drosophila melanogaster uncovered the first example of a new gene with a behavioral phenotype. Studies of the process of retroposition have not only shed light on the origin of new genes, but have also provided other general insights pertaining to the evolution of mammalian genomes. For example, retrocopies have served as unique 'genomic archives' of mammalian transcriptomes, revealing extinct transcripts and gene expression activity during evolution. Gene copies originating from segmental duplication and retroposition have distinct features (such as the presence or absence of inherited regulatory sequences and introns) that profoundly influence their evolutionary fate. Studying RNA-based gene duplication is therefore a useful alternative to further enhance our understanding of the emergence of new genes and their functions.