Functional persistence of exonized mammalian-wide interspersed repeat elements (MIRs)

Abstract

Exonization of retroposed mobile elements, a process whereby new exons are generated following changes in non-protein-coding regions of a gene, is thought to have great potential for generating proteins with novel domains. Our previous analysis of primate-specific Alu-short interspersed elements (SINEs) showed, however, that during their 60 million years of evolution, SINE exonizations occurred in some primates, only to be lost again in some of the descendent lineages. This dynamic gain and loss makes it difficult to ascertain the contribution of exonization to genomic novelty. It was speculated that Alu-SINEs are too young to reveal persistent protein exaptation. In the present study we examined older mobile elements, mammalian-wide interspersed repeats (MIRs) that underwent active retroposition prior to the placental mammalian radiation ∼130 million years ago, to determine their contribution to protein-coding sequences. Of 107 potential cases of MIR exonizations in human, an analysis of splice sites substantiates a mechanism that benefits from 3Ј splice site selection in MIR sequences. We retraced in detail the evolution of five MIR elements that exonized at different times during mammalian evolution. Four of these are expressed as alternatively spliced transcripts; three in species throughout the mammalian phylogenetic tree and one solely in primates. The fifth is the first experimentally verified, constitutively expressed retroposed SINE element in mammals. This pattern of highly conserved, alternatively and constitutively spliced MIR sequences evinces the potential of exonized transposed elements to evolve beyond the transient state found in Alu-SINEs and persist as important parts of functional proteins.

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

“…The study also shows, in the case of a relatively recent exonization of an ancient MIR element, that exaptation can occur at any stage of TE decay (Fig. 3), and consequently also with any nondescript randomized DNA (Krull et al 2007). Recently, a mechanism was described by which a snoRNA (small nucleolar RNA) extended its RNA-coding region by alternative processing of its 3 0 end by introducing a single-point mutation near the site important for processing, generating both the canonical snoRNA and an extended variant (Mo et al 2013).…”

Characterization of the intronic portion of cadherin superfamily members, common cancer orchestrators

“…We analysed the presence of (1) DNAse1 hypersensitive sites, which mark for accessible chromatin; 36 (2) several histone methylation and acetylation marks, which commonly underlie promoter elements; 37 (3) ESTs, which mark for transcription; 38 and (4) DNA repetitive sequences, which have been shown to impact gene regulation. 39,40 We observed that, for all above-mentioned regulatory features, human cadherin introns displayed similar frequencies in comparison to all non-cadherin introns and to the random data set (P40.05, data not shown), with the exception of DNA repetitive sequences. Human cadherin and non-cadherin introns revealed significant differences in terms of frequency of two specific families of repeats: short interspersed nuclear elements (SINE) and long terminal repeats (LTRs).…”

“…All these repetitive elements are known to be involved in novel regulatory mechanisms and in exonization. 39,40 Given that the occurrence of exonization leads to the creation of new transcriptionally active regions, we analysed cadherin introns in terms of intron position and observed introns in positions 2 and 3 were not only longer but harboured a concomitant increased frequency of MIR, MaLR and CAGE tags in comparison with the rest of the human genome. This clearly suggests that the long cadherin introns at these two positions may in fact encode novel transcribed regulatory elements associated with MIR and MaLR repetitive elements.…”

“…[39][40][41] Therefore, we next analysed whether the unusual frequency of Alu, MIR and MaLR elements within cadherin introns was correlated with differential intronic transcription arising from cadherin introns.…”

Transposable elements as drivers of genomic and biological diversity in vertebrates

“…Another mammalian exon, derived from a MIR (mammalianwide interspersed repeat), is present in the gene for the zinc finger protein 639 (ZNF639), a putative transcriptional repressor. This exon is constitutively expressed in all tested mammals, and no transcript without MIR cassette has been detected (Krull et al 2007). Exon conservation was observed in placental mammals, marsupials and monotremes but not in non-mammalian vertebrates.…”