Antisense transcription is a widespread phenomenon in mammalian genomes, leading to production of RNAs molecules referred to as natural antisense transcripts (NATs). NATs apply diverse transcriptional and post‐transcriptional regulatory mechanisms to carry out a wide variety of biological roles that are important for the normal functioning of living cells, but their dysfunctions can be associated with human diseases. In this review, we attempt to provide a molecular basis for the involvement of NATs in the etiology of human disorders such as cancers and neurodegenerative and cardiovascular diseases. We also discuss the pros and cons of oligonucleotide‐based therapies targeted against NATs, and we comment on state‐of‐the‐art progress in this promising area of clinical research. WIREs RNA 2018, 9:e1461. doi: 10.1002/wrna.1461This article is categorized under: RNA in Disease and Development > RNA in DiseaseRegulatory RNAs/RNAi/Riboswitches > Regulatory RNAsRNA Interactions with Proteins and Other Molecules > Small Molecule–RNA Interactions
For a long time, retrocopies were considered ‘junk DNA’, but numerous studies have shown that retrocopies may gain functionality and become so-called retrogenes. Retrogenes may code fully functional proteins that coexist with parental gene products or may even replace them. Retrocopies may also function as regulatory RNAs and, for example, become a source of small interfering RNAs, act as trans natural antisense transcripts or as alternative targets for miRNAs. Numerous researchers have emphasized that retrogenes play a crucial role in various organisms’ developmental stages and diseases. Despite the ever-growing evidence of the importance of retrocopies, resources dedicated to retroposition are very limited. Here, we report an update of the RetrogeneDB, which, to the best of our knowledge, is the largest database dedicated to retrocopies. It provides annotations of 86 458 retrocopies in 62 animal and 37 plant species. The database contains information about the retrocopies’ localization, open reading frame conservation, expression, RNA Polymerase II activity and the alternative transcription start site studies. Orthologous relationships between retrogenes were also determined, which made retrocopy conservation studies much more valuable. Additionally, based on the RNA-Seq data from the Geuvadis project, the expression levels of retrocopies were estimated in a total of 50 individuals from 5 human populations. The information is now presented in a new, more user-friendly web interface, with easy access to the source data, which may be used for the downstream analysis. RetrogeneDB is freely available at http://yeti.amu.edu.pl/retrogenedb. Database URL: http://yeti.amu.edu.pl/retrogenedb Secondary database URL: http://rhesus.amu.edu.pl/retrogenedb
Transposable elements, often considered to be not important for survival, significantly contribute to the evolution of transcriptomes, promoters, and proteomes. Reverse transcriptase, encoded by some transposable elements, can be used in trans to produce a DNA copy of any RNA molecule in the cell. The retrotransposition of protein-coding genes requires the presence of reverse transcriptase, which could be delivered by either non-long terminal repeat (non-LTR) or LTR transposons. The majority of these copies are in a state of “relaxed” selection and remain “dormant” because they are lacking regulatory regions; however, many become functional. In the course of evolution, they may undergo subfunctionalization, neofunctionalization, or replace their progenitors. Functional retrocopies (retrogenes) can encode proteins, novel or similar to those encoded by their progenitors, can be used as alternative exons or create chimeric transcripts, and can also be involved in transcriptional interference and participate in the epigenetic regulation of parental gene expression. They can also act in trans as natural antisense transcripts, microRNA (miRNA) sponges, or a source of various small RNAs. Moreover, many retrocopies of protein-coding genes are linked to human diseases, especially various types of cancer.
Gene duplication is a major driver of organismal evolution. One of the main mechanisms of gene duplications is retroposition, a process in which mRNA is first transcribed into DNA and then reintegrated into the genome. Most gene retrocopies are depleted of the regulatory regions. Nevertheless, examples of functional retrogenes are rapidly increasing. These functions come from the gain of new spatio-temporal expression patterns, imposed by the content of the genomic sequence surrounding inserted cDNA and/or by selectively advantageous mutations, which may lead to the switch from protein coding to regulatory RNA. As recent studies have shown, these genes may lead to new protein domain formation through fusion with other genes, new regulatory RNAs or other regulatory elements. We utilized existing data from high-throughput technologies to create a complex description of retrogenes functionality. Our analysis led to the identification of human retroposed genes that substantially contributed to transcriptome and proteome. These retrocopies demonstrated the potential to encode proteins or short peptides, act as cis- and trans- Natural Antisense Transcripts (NATs), regulate their progenitors’ expression by competing for the same microRNAs, and provide a sequence to lncRNA and novel exons to existing protein-coding genes. Our study also revealed that retrocopies, similarly to retrotransposons, may act as recombination hot spots. To our best knowledge this is the first complex analysis of these functions of retrocopies.
Gene retroposition leads to considerable genetic variation between individuals. Recent studies revealed the presence of at least 208 retroduplication variations (RDVs), a class of polymorphisms, in which a retrocopy is present or absent from individual genomes. Most of these RDVs resulted from recent retroduplications. In this study, we used the results of Phase 1 from the 1000 Genomes Project to investigate the variation in loss of ancestral (i.e. shared with other primates) retrocopies among different human populations. In addition, we examined retrocopy expression levels using RNA-Seq data derived from the Ilumina BodyMap project, as well as data from lymphoblastoid cell lines provided by the Geuvadis Consortium. We also developed a new approach to detect novel retrocopies absent from the reference human genome. We experimentally confirmed the existence of the detected retrocopies and determined their presence or absence in the human genomes of 17 different populations. Altogether, we were able to detect 193 RDVs; the majority resulted from retrocopy deletion. Most of these RDVs had not been previously reported. We experimentally confirmed the expression of 11 ancestral retrogenes that underwent deletion in certain individuals. The frequency of their deletion, with the exception of one retrogene, is very low. The expression, conservation and low rate of deletion of the remaining 10 retrocopies may suggest some functionality. Aside from the presence or absence of expressed retrocopies, we also searched for differences in retrocopy expression levels between populations, finding 9 retrogenes that undergo statistically significant differential expression.
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