Tumor suppressor protein 53 (p53) plays a central role in the control of genome stability, acting primarily through the transcriptional activation of stress‐response genes. However, many p53 binding sites are located at genomic locations with no obvious regulatory‐link to known stress‐response genes. We recently discovered p53 binding sites within retrotransposon‐derived elements in human and mouse subtelomeres. These retrotransposon‐derived p53 binding sites protected chromosome ends through transcription activation of telomere repeat RNA, as well as through the direct modification of (...) local chromatin structure in response to DNA damage. Based on these findings, I hypothesize that a class of p53 binding sites, including the retrotransposon‐derived p53‐sites found in subtlomeres, provide a primary function in genome stability by mounting a direct and local protective chromatin‐response to DNA damage. I speculate that retrotransposon‐derived p53 binding sites share features with telomere‐repeats through an evolutionary drive to monitor and maintain genome integrity. (shrink)

Cellular differentiation and multicellular development require the programmed expression of coregulated suites of genetic loci dispersed throughout the genome. How do functionally diverse loci come to share common regulatory motifs? A new paper finds that retrotransposons (RTEs) may play a role in providing common regulation to a group of functions expressed during the development of oocytes and preimplantation embryos. Examining cDNA libraries, Peaston et al.1 find that 13% of all processed transcripts in full-grown mouse oocytes contain RTE sequences, mostly from (...) the MT family of retroviral-like elements. Smaller but still significant percentages of RTE sequences are found in cDNA libraries from 2-cell embryos and blastocysts. A quarter of these RTE sequences are at the 5′ ends of chimeric transcripts that also contain exons from endogenous mouse loci. These chimeric transcripts display restricted expression in oocytes and preimplantation embryos and presumably originate from developmentally regulated LTR promoters. Some, but not all, chimeric transcripts encode novel protein products. BioEssays 27:122–125, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Retrotransposon-derived elements (RDEs) can disrupt gene expression, but are nevertheless widespread in metazoan genomes. This review presents a hypothesis that repressive RNA-binding proteins (RBPs) facilitate the large-scale accumulation of RDEs. Many RBPs bind RDEs in pre-mRNAs to repress the effects of RDEs on RNA processing, or the formation of inverted repeat RNA structures. RDE-binding RBPs often assemble on extended, multivalent binding sites across the RDE, which ensures repression of cryptic splice or polyA sites. RBPs thereby minimize the effects of (...) RDEs on gene expression, which likely reduces the negative selection against RDEs. While mutations that change splice sites in RDEs act as an off-on switch in exon formation, mutations that decrease the multivalency of RBP binding sites resemble a rheostat that enables a more gradual evolution of new RDE-derived exons. RBPs might also repress aberrant processing of active retrotransposons, thus increasing the chance that full-length copies are made. Taken together, in this review, it is proposed that RBPs facilitate the widespread accumulation of intronic RDEs by repressing RNA processing while chaperoning their potential to gradually evolve into new exons. (shrink)

This article proposes that cancers can be initiated by retrotransposon (RTN) activation through changes in the transcriptional regulation of nearby genes. I first detail the hypothesis and then discuss the nature of physiological stress(es) in RTN activation; the role of DNA demethylation in the initiation and propagation of new RTN states; the connection between ageing and cancer incidence and the involvement of activated RTNs in the chromosomal aberrations that feature in cancer progression. The hypothesis neither replaces nor invalidates other (...) theories of cancer, in particular the somatic mutation theory, but helps clarify and unify much of the hitherto poorly integrated, complex phenomenology of cancer. (shrink)

Studies of transcriptional control sequences responsible for regulated and basal‐level RNA synthesis from promoters of Drosophila melanogaster retrotransposons reveal novel aspects of gene regulation and lead to identification of trans‐acting factors that can be involved in RNA polymerase II transcription not only of retrotransposons, but of many other cellular genes. Comparisons between promoters of retrotransposons and some other Drosophila genes demonstrate that there is a greater variety in basal promoter structure than previously thought and that many promoters may contain essential (...) sequences downstream from the RNA start site. (shrink)

Mature spermatozoa are permeable to foreign DNA and RNA molecules. Here I propose a model, whereby extrachromosomal genetic information, mostly encoded in the form of RNA in somatic cells, can cross the Weismann barrier and reach epididymal spermatozoa. LINE‐1 retrotransposon‐derived reverse transcriptase (RT) can play key roles in the process by expanding the RNA‐encoded information. Retrotransposon‐encoded RT is stored in mature gametes, is highly expressed in early embryos and undifferentiated cells, and becomes downregulated in differentiated cells. In turn, (...) RT plays a role in developmental control, as its inhibition arrests developmental progression of early embryos with globally altered transcriptomic profiles. Thus, sperm cells act as recipients, and transgenerational vectors of somatically derived genetic information which they pass to the next generation with the potential to modify the fate of the developing embryos. (shrink)

Horizontal transfer (HT) is the transmission of genetic material between non‐mating species, a phenomenon thought to occur rarely in multicellular eukaryotes. However, many transposable elements (TEs) are not only capable of HT, but have frequently jumped between widely divergent species. Here we review and integrate reported cases of HT in retrotransposons of the BovB family, and DNA transposons, over a broad range of animals spanning all continents. Our conclusions challenge the paradigm that HT in vertebrates is restricted to infective long (...) terminal repeat (LTR) retrotransposons or retroviruses. This raises the possibility that other non‐LTR retrotransposons, such as L1 or CR1 elements, believed to be only vertically transmitted, can horizontally transfer between species. Growing evidence indicates that the process of HT is much more general across different TEs and species than previously believed, and that it likely shapes eukaryotic genomes and catalyses genome evolution. (shrink)

The placenta invades the adjacent uterus and controls the maternal immune system, like a cancer invades surrounding organs and suppresses the local immune response. Intriguingly, placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood – they fail to silence repetitive DNA sequences that are silenced in healthy somatic cells. In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function. In cancer, hypomethylation is thought to contribute (...) to activation of oncogenes, genomic instability, and retrotransposon unsilencing; the latter, we postulate, is possibly the most important consequence. Activation of placental retrotransposon-derived genes in cancer underpins our hypothesis that hypomethylation of these genes drives cancer cell invasion. This alludes to an interesting paradox, that while placental retrotransposon-derived genes are essential for promoting early hominid life, the same genes promote disease-susceptibility and death through cancer. Placental and cancer cells fail to silence retrotransposons that are normally silenced in healthy tissues. This has created new genes that are essential for placental function, yet they are also expressed in cancer. We hypothesize that active retrotransposons are a double-edged sword, contributing both adaptive and deleterious functions to biology. (shrink)

The retrotransposon Long Interspersed Element 1 (LINE‐1 or L1) has played a major role in shaping the sequence composition of the mammalian genome. In our recent publication, “Heritable L1 retrotransposition in the mouse primordial germline and early embryo,” we systematically assessed the rate and developmental timing of de novo, heritable endogenous L1 insertions in mice. Such heritable retrotransposition events allow L1 to exert an ongoing influence upon genome evolution. Here, we place our findings in the context of earlier studies, (...) and highlight how our results corroborate, and depart from, previous research based on human patient samples and transgenic mouse models harboring engineered L1 reporter genes. In parallel, we outline outstanding questions regarding the stage‐specificity, regulation, and functional impact of embryonic and germline L1 retrotransposition, and propose avenues for future research in this field. -/- . (shrink)

The science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, (...) and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology. (shrink)

Endogenous retrovirsuses (ERVs) have long been known to influence gene expression in plants in important ways, but what of their roles in mammals? Our relatively sparse knowledge in that area was recently increased with the finding that ERVs can influence the expression of mammalian resident genes by disrupting transcriptional termination. For many mammalian biologists, retrotransposition is considered unimportant except when it disrupts the reading frame of a gene, but this view continues to be challenged. It has been known for some (...) time that integration into an intron can create novel transcripts and integration upstream of a gene can alter the expression of the transcript, in many cases producing phenotypic consequences and disease. The new findings on transcriptional termination extend the opportunities for retrotransposons to play a role in human disease. (shrink)

Drosophila telomeres comprise DNA sequences that differ dramatically from those of other eukaryotes. Telomere functions, however, are similar to those found in telomerase‐based telomeres, even though the underlying mechanisms may differ. Drosophila telomeres use arrays of retrotransposons to maintain chromosome length, while nearly all other eukaryotes rely on telomerase‐generated short repeats. Regardless of the DNA sequence, several end‐binding proteins are evolutionarily conserved. Away from the end, the Drosophila telomeric and subtelomeric DNA sequences are complexed with unique combinations of proteins that (...) also modulate chromatin structure elsewhere in the genome. Maintaining and regulating the transcriptional activity of the telomeric retrotransposons in Drosophila requires specific chromatin structures and, while telomeric silencing spreads from the terminal repeats in yeast, the source of telomeric silencing in Drosophila is the subterminal arrays. However, the subterminal arrays in both species may be involved in telomere–telomere associations and/or communication. BioEssays 30:25–37, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Many viruses evolved mechanisms for capping the 5′‐ends of their plus‐strand RNAs as a means of hijacking the eukaryotic messenger RNA (mRNA) splicing/translation machinery. Although capping is critical for replication, the RNAs of these viruses have other essential functions including their requirement to be packaged as either genomes or pre‐genomes into progeny viruses. Recent studies indicate that human immunodeficiency virus type‐1 (HIV‐1) RNAs are segregated between splicing/translation and packaging functions by a mechanism that involves structural sequestration of the 5′‐cap. Here, (...) we examined studies reported for other viruses and retrotransposons that require both selective packaging of their RNAs and 5′‐RNA capping for host‐mediated translation. Our findings suggest that viruses and retrotransposons have evolved multiple mechanisms to control 5′‐cap accessibility, consistent with the hypothesis that removal or sequestration of the 5′ cap enables packageable RNAs to avoid capture by the cellular RNA processing and translation machinery. (shrink)

A combination of cytogenetic and molecular analyses has shown that several different transposable elements are involved in the restructuring of Drosophila chromosomes. Two kinds of elements, P and hobo, are especially prone to induce chromosome rearrangements. The mechanistic details of this process are unclear, but, at least some of the time, it seems to involve ectopic recombination between elements inserted at different chromosomal sites; the available data suggest that these ectopic recombination events are much more likely to occure between elements (...) in the same chromosome than between elements in different chromosomes. Other Drosophila transposons also appear to mediate chromosome restructuring by ectopic recombination; these include the retrotransposons BEL, roo, Docand I and the foldback element FB. In addition, two retrotransposons, HeT‐A and TART, have been found to be associated specifically with the ends of Drosophila chromosomes. Very limited data indicate that transposon‐mediated chromosome restructuring is occurring in natural populations of Drosophila. This suggests that transposable elements may help to shape the structure of the Drosophila genome and implies that they may have a similar role in other organisms. (shrink)

Genomes of higher eukaryotes contain abundant non‐coding repeated sequences whose overall biological impact is unclear. They comprise two categories. The first consists of retrotransposon‐derived elements. These are three major families of retroelements (LINEs, SINEs and LTRs). SINEs are clustered in gene‐rich regions and are found in promoters of genes while LINEs are concentrated in gene‐poor regions and are depleted from promoters. The second class consists of non‐coding tandem repeats (satellite DNAs and TTAGGG arrays), which are associated with mammalian centromeres, (...) heterochromatin and telomeres. Terminal TTAGGG arrays are involved in telomere capping and satellite DNAs are located in heterochromatin, which is implicated in transcription silencing by gene repositioning (relocalization). It is unknown whether interstitial TTAGGG sequences, which are present in many vertebrates, have a function. Here, evidence will be presented that retroelements and TTAGGG arrays are involved in regulation of gene expression. Retroelements can provide binding sites for transcription factors and protect promoter CpG islands from repressive chromatin modifications, and may be also involved in nuclear compartmentalization of transcriptionally active and inactive domains. Interstitial telomere‐like sequences can form dynamically maintained three‐dimensional nuclear networks of transcriptionally inactive domains, which may be involved in transcription silencing like classic heterochromatin. BioEssays 30:338–348, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Processed pseudogenes may serve as a genetic reservoir for evolutionary innovation. Here, we argue that through the activity of long interspersed element‐1 retrotransposons, processed pseudogenes disperse coding and noncoding sequences rich with regulatory potential throughout the human genome. While these sequences may appear to be non‐functional, a lack of contemporary function does not prohibit future development of biological activity. Here, we discuss the dynamic evolution of certain processed pseudogenes into coding and noncoding genes and regulatory elements, and their implication in (...) wide‐ranging biological and pathological processes. Also see the video abstract here: https://youtu.be/iUY_mteVoPI. (shrink)

Recent developments in studies of sperm‐mediated gene transfer (SMGT) now provide solid ground for the notion that sperm cells can act as vectors for exogenous genetic sequences. A substantive body of evidence indicates that SMGT is potentially useable in animal transgenesis, but also suggests that the final fate of the exogenous sequences transferred by sperm is not always predictable. The analysis of SMGT‐derived offspring has shown the existence of integrated foreign sequences in some cases, while in others stable modifications of (...) the genome are difficult to detect. The appearance of SMGT‐derived modified offspring on the one hand and, on the other hand, the rarity of actual modification of the genome, suggest inheritance as extrachromosomal structures. Several specific factors have been identified that mediate distinct steps in SMGT. Among those, a prominent role is played by an endogenous reverse transcriptase of retrotransposon origin. Mature spermatozoa are naturally protected against the intrusion of foreign nucleic acid molecules; however, particular environmental conditions, such as those occurring during human assisted reproduction, can abolish this protection. The possibility that sperm cells under these conditions carry genetic sequences affecting the integrity or identity of the host genome should be critically considered. These considerations further suggest the possibility that SMGT events may occasionally take place in nature, with profound implications for evolutionary processes. BioEssays 27: 551–562, 2005. © 2005 Wiley periodicals, Inc. (shrink)

Roderic Page’s new book, Tangled Trees: Phylogeny, Cospeciation and Coevolution (2003), is a worthwhile read for anyone interested in either methodological issues in systematics, or how organisms shape one another’s selective environments. “Cospeciation,” for the uninitiated, is the concurrent speciation of two or more lineages that are ecologically associated (e.g. host-parasite associations, as well as mutualistic or symbiotic associations). “Coevolution,” in contrast, is the reciprocal adaptation of hosts and parasite taxa. The main focus of Page’s book is thus when, how (...) and why the branching process of host taxa mirrors that of parasite taxa. “Parasite” here is broadly conceived to be anything from a louse to a virus to a retrotransposon, and “host” may be anything from a genome to a whale. (shrink)

Whoever compares the genomes of distantly related species might find aberrantly high sequence similarity at certain loci. Such anomaly can only be explained by genetic material being transferred through other means than reproduction, that is, a horizontal transfer. Between multicellular organisms, the transferred material will likely turn out to be a transposable element. Because TEs can move between loci and invade chromosomes by replicating themselves, HT of TEs profoundly impacts genome evolution. Yet, very few studies have quantified HTT at large (...) taxonomic scales. Indeed, this task currently faces difficulties that range from the variable quality of available genome sequences to limitations of analytical procedures, some of which have been overlooked. Here we review the many challenges that an extensive analysis of HTT must overcome, we expose biases and limits of current methods, suggest solutions or workarounds, and reflect upon approaches that could be developed to better quantify this phenomenon. With the large amount of genomic resources now available, horizontal transfer of transposable elements can be studied as an evolutionary process, rather than as isolated cases. We discuss some of the difficulties encountered in detecting and counting such transfers and propose guidelines and directions for future research in this area. (shrink)

Throughout the animal kingdom, p53 genes function to restrain mobile elements and recent observations indicate that transposons become derepressed in human cancers. Together, these emerging lines of evidence suggest that cancers driven by p53 mutations could represent “transpospoathies,” i.e. disease states linked to eruptions of mobile elements. The transposopathy hypothesis predicts that p53 acts through conserved mechanisms to contain transposon movement, and in this way, prevents tumor formation. How transposon eruptions provoke neoplasias is not well understood but, from a broader (...) perspective, this hypothesis also provides an attractive framework to explore unrestrained mobile elements as inciters of late‐onset idiopathic disease.Also see the video abstract here. (shrink)