Research advance1. The first detailed analysis of exonization events of one particular class of TE, long terminal repeat (LTR) containing elements, in the human genome indicates that 5.8% of human genes are associated with LTR elements and 50 distinct protein coding exons were comprised exclusively of LTR retrotransposon sequences. A detailed scenario of the exonization process of an alternatively spliced exon of the alpha 2 gene of the Interleukin 22 receptor (IL22RA2) was supported by new experimental data generated in this research. As a result of a single mutation in the proto-splice site, recruitment of the part of MaLR LTR as a novel exon in great ape species occurred prior to the divergence of orangutans and humans from a common ancestor (&sim 14 MYA). The majority of human LTR exonization events involve non-coding exon sequences in the 5' and 3' untranslated regions.Research advance2. Differences in the extent of TEs found in experimentally characterized protein sequences (CDS) caused by the specific bias of each search method are emphasized by the comparison of the results from three sequence similarity search approaches: (1) a profile-based approach, (2) BLAST methods and (3) RepeatMasker. Profile based methods show a valuable combination of sensitivity, measured by their ability to detect well-characterized cases of TE-derived CDS, and selectivity compared to the other methods evaluated. The non-overlap of hits and difference in the ability of each approach to recover known cases of TE-derived CDS indicates the need to use these complementary methods together for more accurate detection of CDS that evolved from TEs. On average, TE-derived exon sequences have low protein coding potential. In particular, non-coding TEs, such as Alu elements, are frequently exonized but unlikely to encode protein sequences. I hypothesize that many of these non-coding exonized TEs are involved in gene regulation via the formation of double stranded RNA (dsRNA) complexes with complementary TE-derived exons.Research advance3. The investigation of the relationship between human miRNAs and TEs shows that 55 experimentally verified human miRNA genes (&sim12%) originated from TEs. Sequence comparisons among vertebrate genomes revealed that, on average, TE-derived human miRNAs are significantly less conserved than non TE-derived miRNAs. However, there are TE-derived miRNAs that are relatively conserved, and most are related to the ancient L2 and MIR families. In addition to the known human miRNAs that were shown to be derived from TE sequences, an additional 85 novel TE-derived miRNA genes were predicted in this study. The dispersed repetitive nature of TE sequences provides for the emergence of multiple novel miRNA genes as well as numerous homologous target sites throughout the genome. Thus, TEs may represent a mechanism for the rapid deployment of miRNA based regulatory networks in the human genome.Research advance4. A group of seven closely related miRNA genes (hsa-mir-548) was found to be derived from the Made1 family of MITEs. These Made1 elements are nearly perfect palindromes which are able to form highly stable hairpin-loops, resembling pre-miRNA structures. The analysis of their expression profiles and functional affinities suggests cancer-related regulatory roles for hsa-mir-548.Research advance5. An original model for a siRNA-to-miRNA evolutionary transition mediated by DNA-type TEs is proposed. This model is supported by the presence of evolutionary intermediate TE sequences that encode both siRNAs and miRNAs in the Arabidopsis and rice genomes. These dual coding TEs can be expressed as read-through transcripts from the intronic regions of spliced RNA messages. The results indicate that ancestral miRNAs could have evolved from TEs prior to the full elaboration of the miRNA biogenesis pathway. The siRNA-to-miRNA evolutionary transition is representative of a number of other regulatory mechanisms that evolved to silence TEs and were later co-opted to serve as regulators of host gene expression. (Abstract shortened by UMI.)
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