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Mobile elements inserted in the distant past have taken on important functions
Abstract
Current evidence on the long-term evolutionary effect of insertion of sequence elements is reviewed. There are three criteria for inclusion of an example: (i) the element was inserted far in the past and thus the event is not a transient mutation; (ii) the element is a member of a large group of similar sequences; (iii) the element now serves a useful function. There are 21 examples from Drosophila, sea urchin, human and mouse genomes that meet these criteria. Taken together, these examples show that the insertion of sequence elements in the genome has been a significant source of regulatory variation in evolution.
... The results of our genomic positioning of Cer elements indicates that a number of these elements lie within or proximal to genes. Previous studies of LTR retrotransposons in a variety of plant and animal species have revealed that these elements may be coopted for a variety of host gene functions, including promoter, splicing, and terminator activities (e.g., Britten 1997; Medstrand et al. 2001). In an initial effort to determine whether Cer elements contribute to gene function, we screened C. elegans EST databases (dbEST-C. ...
... There is a growing body of evidence that transposable elements play an important role in genome evolution by contributing to the structure and/or function of genes (e.g., McDonald 1995a,b; Britten 1997; Medstrand et al. 2001). For example, there are >100 reported examples of essential gene structures and functions in mammals that are attributable to retrotransposons or retrotransposonderived sequences (Brosius 1999; see also http://www.ncbi.nlm.nih. ...
... gov/Makalowski/ScrapYard/). LTRs are known to possess promoter, polyadenylation, and enhancer functions (e.g., Medstrand et al. 2001; Britten 1997). For this reason, LTR retrotransposon insertions in or near genes have been postulated to be a significant factor in regulatory evolution in both plants and animals (e.g., McDonald 1993 McDonald , 1995a ). ...
We report the results of sequence analysis and chromosomal distribution of all distinguishable long terminal repeat (LTR) retrotransposons (Cer elements) in the Caenorhabditis elegans genome. Included in this analysis are all readily recognizable full-length and fragmented elements, as well as solo LTRs. Our results indicate that there are 19 families of Cer elements, some of which display significant subfamily structure. Cer elements can be clustered based on their tRNA primer binding sites (PBSs). These clusters are in concordance with our reverse transcriptase- and LTR-based phylogenies. Although we find that most Cer elements are located in the gene depauperate chromosome ends, some elements are located in or near putative genes and may contribute to gene structure and function. The results of RT-PCR analyses are consistent with this prediction.
... The mechanisms underlying these rearrangements are just the kind of processes needed to explain the patterns of genome conservation and scrambling found by comparing whole genome sequences. There is abundant documentation that these mechanisms have been used in evolution (Britten, 1997; Brosius, 1999; Nekrutenko and Li, 2001; Bailey et al., 2003; Jordan et al., 2003), they occur in nature (Bregliano and Kidwell, 1983; Engels, 1989; Prescott, 2000; Lerman et al., 2003), and they can execute key evolutionary processes in the laboratory, like exon shuffling (Moran et al., 1999). An especially illuminating example of natural genetic engineering is the mammalian immune system. ...
... Errede et al., 1981). The evidence is quite solid that this process has taken place during evolution (Britten, 1997; Brosius, 1999; Jordan et al., 2003 ), and transcript profiling during mouse oocyte development indicates that retroviral promoters regulate expression of many embryonic functions (Peaston et al., 2004). Similarly, insertion of a DNA segment encoding a functional domain is more likely to add new capabilities to a protein than are random changes in sequence or addition of random polypeptide components. ...
Physicists question whether there are 'universals' in biology. One reason is that the prevailing theory of biological evolution postulates a random walk to each new adaptation. In the last 50 years, molecular genetics has revealed features of DNA sequence organization, protein structure and cellular processes of genetic change that suggest evolution by Natural Genetic Engineering. Genomes are hierarchically organized as systems assembled from DNA modules. Each genome is formatted and integrated by repetitive DNA sequence elements that do not code for proteins, much as a computer drive is formatted. These formatting elements constitute codons in multiple genetic codes for distinct functions such as transcription, replication, DNA compaction and genome distribution to daughter cells. Consequently, there is a computation-ready Genome System Architecture for each species. Whole-genome sequencing indicates that rearrangement of genetic modules plus duplication and reuse of existing genomic systems are fundamental events in evolution. Studies of genetic change show that cells possess mobile genetic elements and other natural genetic engineering activities to carry out the necessary DNA reorganizations. Natural genetic engineering functions are sensitive to biological inputs and their non-random operations help explain how novel genome system architectures can arise in evolution.
... The primate-specific Alu family of mobile, middle repetitive short-interspersed elements (SINEs) constitutes about 10% of the human genome [6,7]. They have an increased concentration of transcription factor binding sites and examples of their potential to control gene transcription both positively and negatively have been described891011. We recently identified the insertion of an AluSx SINE in the promoter of the human cathelicidin antimicrobial peptide (CAMP) gene that provides an essential cis-element that may be crucial for an effective innate immune response in humans [12]. ...
... Early in primate evolution (about 60 million years ago), the major groups of Hominidae (humans and other apes), OWMs, NWMs and prosimians (lemurs and lorises) evolved independently and the origin and amplification of Alu elements was concomitant with this primate radia- tion [7] . Examples of Alu elements implicated in gene regulation have been identified9101121,22,26,33343536. Identification of convincing examples of evolutionarilyfixed , novel regulatory patterns requires evidence of: 1) a ...
About 45% of the human genome is comprised of mobile transposable elements or "junk DNA". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection.
PCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone.
We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55-60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D.
... For example, Siepel et al. have estimated that about 3.7% of all elements with high phastCons scores are ancestral repeats [40]. Some of these functions may be cis-regulatory [28] or the result of regaining of transposon activity, known as domestication [24,[41][42][43][44][45][46]. It has been estimated that about 0.05 of human transposons are currently active [47]. ...
... For example, Siepel et al. have estimated that about 3.7% of all elements with high phastCons scores are ancestral repeats [40]. Some of these functions may be cis-regulatory [28] or the result of regaining of transposon activity, known as domestication [24,414243444546. It has been estimated that about 0.05 of human transposons are currently active [47]. ...
Abstract Background The rate at which neutral (non-functional) bases undergo substitution is highly dependent on their location within a genome. However, it is not clear how fast these location-dependent rates change, or to what extent the substitution rate patterns are conserved between lineages. To address this question, which is critical not only for understanding the substitution process but also for evaluating phylogenetic footprinting algorithms, we examine ancestral repeats: a predominantly neutral dataset with a significantly higher genomic density than other datasets commonly used to study substitution rate variation. Using this repeat data, we measure the extent to which orthologous ancestral repeat sequences exhibit similar substitution patterns in separate mammalian lineages, allowing us to ascertain how well local substitution rates have been preserved across species. Results We calculated substitution rates for each ancestral repeat in each of three independent mammalian lineages (primate – from human/macaque alignments, rodent – from mouse/rat alignments, and laurasiatheria – from dog/cow alignments). We then measured the correlation of local substitution rates among these lineages. Overall we found the correlations between lineages to be statistically significant, but too weak to have much predictive power (r2
... The biased decay to conserve a local sequence is also reported for other ancient retrotransposons. For example, MIR families contain more conserved core regions than other regions (Smit and Riggs, 1995; Britten, 1997). In these cases, the 3Vtails as well as promoter regions, both of which are required for completion of LINE retrotransposition in the genome, are missing, indicating that these SINEs have not propagated since their early expansion but exist as ancient SINEs. ...
... Transposable elements have the potential to evolve into functional elements due to their repetitive properties. Repetitive elements could contain DNA-binding sites in common, which might function as coregulatory elements for a new developmental network leading to innovate new traits of mammals (Britten and Davidson, 1969; Britten, 1997). Both of two examples of exapted AmnSINE1 maintained evolutionary conservation whereas they showed different evolutionary rates and selective constraints (Fig. 7). ...
Discovery of a large number of conserved non-coding elements (CNEs) in vertebrate genomes provides a cornerstone to elucidate molecular mechanisms of macroevolution. Extensive comparative genomics has proven that transposons such as short interspersed elements (SINEs) were an important source of CNEs. We recently characterized AmnSINE1, a SINE family in Amniota genomes, some of which are present in CNEs, and demonstrated that two AmnSINE1 loci play an important role in mammalian-specific brain development by functioning as an enhancer (Sasaki et al. Proc. Natl. Acad. Sci. USA 2008). To get more information about AmnSINE1s, we here performed a multi-species search for AmnSINE1, and revealed the distribution and evolutionary history of these SINEs in amniote genomes. The number of AmnSINE1 regions in amniotes ranged from 160 to 1200; the number in the eutherians were under 500 and the largest was that in chicken. Phylogenetic analysis established that each AmnSINE1 locus has evolved uniquely, primarily since the divergence of mammals from reptiles. These results support the notion that AmnSINE1s were amplified as an ancient retroposon in a common ancestor of Amniota and subsequently have survived for 300 Myr because of functions acquired by mutation-coupled exaptation prior mammalian radiation. On the basis of sequence homology and conserved synteny, we detected the orthologs of AmnSINE1 for candidates of further enhancer analysis, which are more conserved than two loci that were shown to have been involved in mammalian brain development. The present work provides a comprehensive data set to test the role of AmnSINE1s, many of which were exapted and contributed to mammalian macroevolution.
... But then the transposon activity apparently ceased, although some of the elements (mainly Alu and L1) are still being transposed from time to time disclosing themselves through deleterious mutations that cause hereditary diseases (reviewed in Smit, 1999; Kazazian, 2000). Being a large portion of the genome, the transposons should unavoidably have played an important role in the evolution, in particular providing new genes as well as new regulatory elements for multitudes of functional genes (reviewed in Britten, 1997; Smit, 1999; Kazazian, 2000; Brosius, 1999). However, despite a good number of examples of the involvement of former transposons in the particular gene functions (reviewed in Britten, 1997; Smit, 1999; for recent results see Hamdi et al., 2000 ), clear understanding of the evolutionary impact(s) of a given transposition in a given genomic site is very far from being reached. ...
... Being a large portion of the genome, the transposons should unavoidably have played an important role in the evolution, in particular providing new genes as well as new regulatory elements for multitudes of functional genes (reviewed in Britten, 1997; Smit, 1999; Kazazian, 2000; Brosius, 1999). However, despite a good number of examples of the involvement of former transposons in the particular gene functions (reviewed in Britten, 1997; Smit, 1999; for recent results see Hamdi et al., 2000 ), clear understanding of the evolutionary impact(s) of a given transposition in a given genomic site is very far from being reached. In particular, there are no examples unambiguously demonstrating the role of transposon insertions in speciation, although there were many speculations on this point (see, for example, Hamdi et al., 2000). ...
One of the evolutionary mechanisms for acquisition of novel functional sequences can be domestication of exogenous retroviruses that have been integrated into the germ line. The whole genome mapping of such elements in various species could reveal differences in positions of the retroviral integration and suggest possible roles of these differences in speciation. Here, we describe the number, locations and sequence features of the human endogenous retrovirus HERV-K (HML-2) long terminal repeat (LTR) sequences on human chromosome 21. We show that their distribution along the chromosome is not only non-random but also roughly correlated with the gene density. Amplification of orthologous LTR sites from a number of primate genomes produced patterns of presence and absence for each LTR sequence and allowed determination of the phylogenetic ages and evolutionary order of appearance of individual LTRs. The identity level and phylogenetic age of the LTRs did not correlate with their map locations. Thus, despite the non-random distribution of LTRs, they have apparently been inserted randomly into the chromosome relative to each other. As evidenced in previous studies of chromosomes 19 and 22, this is a characteristic of HERV-K integration.
... For example one family of RSR elements that function as transcriptional enhancers in the strongylocentrotid family of sea urchins evolved from repetitive sequence at the base of that family; RSR elements are absent from other sea urchins such as Heliocidaris and Lytechinus (Dayal et al. 2004). The co-option of transposable elements for regulatory elements has been well-documented (Britten 1997). An example of how transposable elements may become candidates for new regulatory elements is shown by the amphioxus FoxD gene (Yu et al. 2004). ...
Cephalochordates, the sister group of vertebrates + tunicates, are evolving particularly slowly. Therefore, genome comparisons between two congeners of Branchiostoma revealed so many conserved non-coding elements (CNEs), that it was not clear how many are functional regulatory elements. To more effectively identify CNEs with potential regulatory functions, we compared non-coding sequences of genomes of the most phylogenetically distant cephalochordate genera, Asymmetron and Branchiostoma, which diverged approximately 120 to160 mya. We found 113,070 non-coding elements conserved between the two species, amounting to 3.3% of the genome. The genomic distribution, target gene ontology, and enriched motifs of these CNEs all suggest that many of them are probably cis-regulatory elements. More than 90% of previously verified amphioxus regulatory elements were re-captured in this study. A search of the cephalochordate CNEs around 50 developmental genes in several vertebrate genomes revealed eight CNEs conserved between cephalochordates and vertebrates, indicating sequence conservation over >500 million years of divergence. The function of five CNEs was tested in reporter assays in zebrafish, and one was also tested in amphioxus. All five CNEs proved to be tissue-specific enhancers. Taken together, these findings indicate that even though Branchiostoma and Asymmetron are very distantly related, as they are evolving quite slowly, comparisons between them are likely optimal for identifying most of their tissue-specific cis-regulatory elements laying the foundation for functional characterizations and a better understanding of the evolution of developmental regulation in cephalochordates.
... A large part of the mammalian genome consists of interspersed repeats and transposable elements, whose role and effect on gene activity and function in genome evolution has been long debated (Britten 1997; Brosius 2003; van de Lagemaat et al. 2003; Kazazian 2004). Transcripts representing various classes of retrotransposons and repetitive sequences are abundantly represented (Fig. 5 ) in libraries of early mouse embryos (Evsikov et al. 2004; Peaston et al. 2004). ...
In one sense, development of multicellular organisms begins well before fertilization because the molecules and controlling mechanisms that direct early develop- ment are put in place during oogenesis. The informational content of a mammalian egg at fertilization is not only re- stricted to its DNA sequence, but also to various DNA and chromatin modifications, specific macromolecules (RNAs and proteins), and possibly the characteristic ar- chitecture of the cytoplasm and plasma membrane. These sources of stored, necessary information can be viewed as epigenetic controlling mechanisms (Fig. 1). In the ensu- ing text we will briefly touch on these subjects, delineat- ing what is presently known about them and, more im- portant, what still remains to be elucidated. The literature on these subjects is vast and space restrictions prevent us from citing each relevant paper, for which we apologize.
... Transposable elements (TEs) are known to exert a broad evolutionary impact, promoting genomic plasticity and eventually biological diversity [19, 20]. Exonized TEs have the potential to induce significant changes in functional noncoding regions of genes while, in extraordinary cases, some could even acquire a novel role as protein-coding modules21222324, in a biological process called " exaptation " [25]. Interestingly, it was relatively recently documented that TEs could preciously contribute in de novo gene-origination26272829. ...
The incidence of cancer in human is high as compared to chimpanzee. However previous analysis has documented that numerous human cancer-related genes are highly conserved in chimpanzee. Till date whether human genome includes species-specific cancer-related genes that could potentially contribute to a higher cancer susceptibility remains obscure. This study focuses on MYEOV, an oncogene encoding for two protein isoforms, reported as causally involved in promoting cancer cell proliferation and metastasis in both haematological malignancies and solid tumours. First we document, via stringent in silico analysis, that MYEOV arose de novo in Catarrhini. We show that MYEOV short-isoform start codon was evolutionarily acquired after Catarrhini/Platyrrhini divergence. Throughout the course of Catarrhini evolution MYEOV acquired a gradually elongated translatable open reading frame (ORF), a gradually shortened translation-regulatory upstream ORF, and alternatively spliced mRNA variants. A point mutation introduced in human allowed for the acquisition of MYEOV long-isoform start codon. Second, we demonstrate the precious impact of exonized transposable elements on the creation of MYEOV gene structure. Third, we highlight that the initial part of MYEOV long-isoform coding DNA sequence was under positive selection pressure during Catarrhini evolution. MYEOV represents a Primate Orphan Gene that acquired, via ORF expansion, a human-protein-specific coding potential.
... Recent evidence suggests that RAG1 and RAG2 were once components of a transposable element, and that the split nature of antigen receptor genes derives from germline insertion of this element into an ancestral receptor gene soon after the evolutionary divergence of jawed and jawless vertebrates. In addition to coding information, important gene regulatory functions are currently hypothesized to have originated from TEs that have, long ago, managed to insert themselves into the germ-line of eukaryotes (Britten, 1997; Kidwell and Lisch, 2000). Phylogenetic analysis has indicated that one major subclass of TEs, the LTR retrotransposons, is closely related to retroviruses. ...
... Previously, it had been reported that P movement in somatic cells also causes genetic damage and reduces the lifespans of D. melanogaster and D. simulans males (Woodruff, 1992;). When one adds to these results the reports that P-element transpositions in germ cells of D. melanogaster also reduce the fitness of offspring and can cause sterility due to excessive chromosome breakage (Henderson, Woodruff & Thompson, 1978; Fitzpatrick & Sved, 1986; Eanes et al., 1988; Ajioka & Hartl, 1989; Mackay, 1989), that TE insertions into coding regions of Drosophila genes are usually selected against in natural populations (Charlesworth & Langley, 1989; Eanes, Labate & Ajioka, 1989, and references therein; Charlesworth, Sniegowski & Stephan, 1994; Nitasaka, Yamazaki & Green, 1995; ten Have, Green & Howells, 1995), that Ty insertions in yeast are, on average, deleterious (Boeke, Eichinger & Natsoulis, 1991; Wilke & Adams, 1992; Wilke, Maimer & Adams, 1993), that TE events in germ cells cause human diseases (Sassaman et al., 1997; Kazazian, 1998; Levran, Doggett & Auerbach, 1998; Miki, 1998; Huie et al., 1999), and that TE mediated insertions and rearrangements can cause cancer (Miki et al., 1992; Petrij-Bosch et al., 1997; Swensen et al., 1997; Morse et al., 1988; Montagna et al., 1999), these results taken together highlight the negative impact of active transposableAgrawal, Eastman & Schatz, 1998; Hiom, Melek & Gellert, 1998), as modifiers of gene regulation (see references in McDonald, 1990), in formation of new introns (Nouaud et al., 1999 ), in repair of chromosome breaks (Moore & Haber, 1996; Teng et al., 1996), and in telomere formation (Mason & Biessmann, 1995; Pardue et al., 1997) (for reviews of this topic see Britten, 1997; Fedoroff, 1999). In addition, TE induce genomic changes that could be beneficial to their hosts, including exon shuffling (Moran, DeBerardinis & Kazazian, 1999), formation of novel splice junctions (Nurminsky et al., 1998), induction of inversions by ectopic recombination between TE (Montgomery et al., 1991; Lyttle & Haymer, 1992; Mathiopoulos et al., 1998; Andolfatto, Wall & Kreitman, 1999; Caceres et al., 1999), and induction of quantitative trait mutations (Mackay, Lyman & Jackson, 1992). ...
... In turn, combinations of genes encoding transcription factors are expressed in a spatial-and temporal-specific manner, forming the regulatory network upon which all living organisms are based (Cowden and Levine 2002; Dover 2000; Tautz 2000). Rearrangements of regulatory sequences are among the multiple differences that two species may exhibit (Britten 1997). A concern is how to discriminate between cause and effect for any difference between species or cell types. ...
The molecular foundations of evolution are difficult to trace because most protein sequences are virtually identical in closely related species. The largest fraction of sequence within the genome, however, is composed of noncoding sequences where regulatory elements locate to various sites. It has been suggested that changes in the activity of these elements may trigger evolutionary change. In Drosophila, the enhancer trap procedure identifies regulatory sequences in the genome after the insertion of a P-element-based construct. We generated new insertions and characterized their expression domains in the adult eye and larval imaginal disks using the white and LacZ reporter genes. Lines with robust expression patterns in D. melanogaster were analyzed in hybrids to test the conservation of regulatory mechanisms between species. Most of the enhancers used in this study modified their expression in hybrids with the mating species D. mauritiana and D. simulans. Expression changes resulted either in gain or loss of expression and were cell-type or hybrid-genome specific. Further characterization of a limited number of enhancers in D. melanogaster showed that expression domains could adapt to changes in cell number during development but not after the completion of cell proliferation. Also, expression of some enhancers appeared to be sensitive to heterochromatin from the Y but not the X chromosome. Taken together, these results demonstrate the high sensitivity of regulatory mechanisms of gene expression as a prime source of evolutionary change and suggest quantitative changes in available transcription factors as one of the mechanisms involved.
... Under this view, these elements are conceived as genomic parasites. Today, the view of TEs within genomes has changed considerably, and these elements have been shown to be major contributors to both genome evolution and function2345. The relationships between TEs and host genomes where they reside are now considered a continuum from parasitic to beneficial to genomes [6] . ...
Transposable elements (TEs), both DNA transposons and retrotransposons, are genetic elements with the main characteristic of being able to mobilize and amplify their own representation within genomes, utilizing different mechanisms of transposition. An almost universal feature of TEs in eukaryotic genomes is their inability to transpose by themselves, mainly as the result of sequence degeneration (by either mutations or deletions). Most of the elements are thus either inactive or non-autonomous. Considering that the bulk of some eukaryotic genomes derive from TEs, they have been conceived as "TE graveyards." It has been shown that once an element has been inactivated, it progressively accumulates mutations and deletions at neutral rates until completely losing its identity or being lost from the host genome; however, it has also been shown that these "neutral sequences" might serve as raw material for domestication by host genomes.
We have analyzed the sequence structural variations, nucleotide divergence, and pattern of insertions and deletions of several superfamilies of TEs belonging to both class I (long terminal repeats [LTRs] and non-LTRs [NLTRs]) and II in the genome of Anopheles gambiae, aiming at describing the landscape of deterioration of these elements in this particular genome. Our results describe a great diversity in patterns of deterioration, indicating lineage-specific differences including the presence of Solo-LTRs in the LTR lineage, 5'-deleted NLTRs, and several non-autonomous and MITEs in the class II families. Interestingly, we found fragments of NLTRs corresponding to the RT domain, which preserves high identity among them, suggesting a possible remaining genomic role for these domains.
We show here that the TEs in the An. gambiae genome deteriorate in different ways according to the class to which they belong. This diversity certainly has implications not only at the host genomic level but also at the amplification dynamic and evolution of the TE families themselves.
... FUNCTIONS OF Alu ELEMENTS Alu repeats affect the composition, organization, and expression of the genome. Owing to their own promoter or enhancer activity, Alu repeats may enhance transcription of the adjacent locus [25, 26]. Transcriptional suppression is also possible, as Alu elements may expedite nucleosome assembly on the adjacent region [27, 28] . ...
Highly repetitive DNA sequences account for more than 50% of the human genome. The L1 and Alu families harbor the most common mammalian long and short interspersed elements. An Alu element is a dimer of similar, but not identical, fragments of total size about 300 bp, and originates from the 7SL RNA gene. Each element contains a bipartite promoter for RNA polymerase III, a poly(A) tract located between the monomers, a 3"-terminal poly(A) tract, and numerous CpG islands, and is flanked by short direct repeats. Alu repeats constitute more than 10% of the human genome and are capable of retroposition. Possibly, these elements played an important part in genome evolution. Insertion of an Alu element into a functionally important genome region or other Alu-dependent alterations of gene functions cause various hereditary disorders and are probably associated with carcinogenesis. In total, 14 Alu families differing in diagnostic mutations are known. Some of these, which are present in the human genome, are polymorphic and relatively recently have been inserted into new loci. Alu copies transposed during ethnic divergence of the human population are useful markers for evolutionary genetic studies.
... Previously, it had been reported that P movement in somatic cells also causes genetic damage and reduces the lifespans of D. melanogaster and D. simulans males (Woodruff, 1992;). When one adds to these results the reports that P-element transpositions in germ cells of D. melanogaster also reduce the fitness of offspring and can cause sterility due to excessive chromosome breakage (Henderson, Woodruff & Thompson, 1978; Fitzpatrick & Sved, 1986; Eanes et al., 1988; Ajioka & Hartl, 1989; Mackay, 1989), that TE insertions into coding regions of Drosophila genes are usually selected against in natural populations (Charlesworth & Langley, 1989; Eanes, Labate & Ajioka, 1989, and references therein; Charlesworth, Sniegowski & Stephan, 1994; Nitasaka, Yamazaki & Green, 1995; ten Have, Green & Howells, 1995), that Ty insertions in yeast are, on average, deleterious (Boeke, Eichinger & Natsoulis, 1991; Wilke & Adams, 1992; Wilke, Maimer & Adams, 1993), that TE events in germ cells cause human diseases (Sassaman et al., 1997; Kazazian, 1998; Levran, Doggett & Auerbach, 1998; Miki, 1998; Huie et al., 1999), and that TE mediated insertions and rearrangements can cause cancer (Miki et al., 1992; Petrij-Bosch et al., 1997; Swensen et al., 1997; Morse et al., 1988; Montagna et al., 1999), these results taken together highlight the negative impact of active transposableAgrawal, Eastman & Schatz, 1998; Hiom, Melek & Gellert, 1998), as modifiers of gene regulation (see references in McDonald, 1990), in formation of new introns (Nouaud et al., 1999 ), in repair of chromosome breaks (Moore & Haber, 1996; Teng et al., 1996), and in telomere formation (Mason & Biessmann, 1995; Pardue et al., 1997) (for reviews of this topic see Britten, 1997; Fedoroff, 1999). In addition, TE induce genomic changes that could be beneficial to their hosts, including exon shuffling (Moran, DeBerardinis & Kazazian, 1999), formation of novel splice junctions (Nurminsky et al., 1998), induction of inversions by ectopic recombination between TE (Montgomery et al., 1991; Lyttle & Haymer, 1992; Mathiopoulos et al., 1998; Andolfatto, Wall & Kreitman, 1999; Caceres et al., 1999), and induction of quantitative trait mutations (Mackay, Lyman & Jackson, 1992). ...
Some transposable DNA elements in higher organisms are active in somatic cells, as well as in germinal cells. What effect
does the movement of DNA elements in somatic cells have on life history traits? It has previously been reported that somatically
active P and mariner elements in Drosophila induce genetic damage and significantly reduce lifespan. In this study, we report that the movement of P elements in somatic
cells also significantly reduces fitness, mating activity, and locomotion of Drosophila melanogaster. If other elements cause similar changes in life history traits, it is doubtful if transposable DNA elements remain active
for long in somatic cells in natural populations.
... As such, they have the potential to " rewire " regulatory networks and to modulate host gene expression. Britten (Britten, 1997) has described a number of examples of the long-term evolutionary effects of insertion sequence elements from a wide variety of organisms. Using stringent criteria, he concluded that TEs provide a significant source of regulatory variation in evolution. ...
Several recent reports have challenged the idea that transposable elements (TEs) are mainly ‘selfish’ or ‘junk’ DNA with little importance for host evolution. It has been proposed that TEs have the potential to provide host genomes with the ability to enhance their own evolution. They might also be a major source of genetic diversity, allowing response to environmental changes. Because the relationships between TEs and host genomes are highly variable, and because the selfish, junk and beneficial DNA hypotheses are by no means mutually exclusive, a single label for these relationships appears to be inappropriate and potentially misleading.
... We have shown previously that interspersed repeats, particularly retrotransposons (RTs), have contributed significantly to the INDEL variation between humans and chimpanzees [7]. Because RT sequences located in or near genes have the capacity to significantly alter patterns of gene expression, it has long been recognized that these elements may be important factors in regulatory evolution8910111213141516 . Other sources of INDEL variation between chimpanzees and humans are simple tandem repeats (TRs) and other noninterspersed sequences (NISs) [17]. ...
ABSTRACT:
Although humans and chimpanzees have accumulated significant differences in a number of phenotypic traits since diverging from a common ancestor about six million years ago, their genomes are more than 98.5% identical at protein-coding loci. This modest degree of nucleotide divergence is not sufficient to explain the extensive phenotypic differences between the two species. It has been hypothesized that the genetic basis of the phenotypic differences lies at the level of gene regulation and is associated with the extensive insertion and deletion (INDEL) variation between the two species. To test the hypothesis that large INDELs (80 to 12,000 bp) may have contributed significantly to differences in gene regulation between the two species, we categorized human-chimpanzee INDEL variation mapping in or around genes and determined whether this variation is significantly correlated with previously determined differences in gene expression.
Extensive, large INDEL variation exists between the human and chimpanzee genomes. This variation is primarily attributable to retrotransposon insertions within the human lineage. There is a significant correlation between differences in gene expression and large human-chimpanzee INDEL variation mapping in genes or in proximity to them.
The results presented herein are consistent with the hypothesis that large INDELs, particularly those associated with retrotransposons, have played a significant role in human-chimpanzee regulatory evolution.
... The copy number assessment of these repeats in different known and nondescript breeds of buffalo may enable to establish a correlation , if any, towards the delineation of different breeds. Retrotransposons copies are reportedly involved in the regulation of transcription33343536. Presence of RsaI repeats in exonic database of various transcribing genes suggests that these sequences function as parts of mRNA. ...
Repetitive sequences are the major components of the eukaryotic genomes. Association of these repeats with transcribing sequences and their regulation in buffalo Bubalus bubalis has remained largely unresolved.
We cloned and sequenced RsaI repeat fragments pDp1, pDp2, pDp3, pDp4 of 1331, 651, 603 and 339 base pairs, respectively from the buffalo, Bubalus bubalis. Upon characterization, these fragments were found to represent retrotransposons and part of some functional genes. The resultant clones showed cross hybridization only with buffalo, cattle, goat and sheep genomic DNA. Real Time PCR, detected ~2 × 10(4) copies of pDp1, ~ 3000 copies of pDp2 and pDp3 and ~ 1000 of pDp4 in buffalo, cattle, goat and sheep genomes, respectively. RsaI repeats are transcriptionally active in somatic tissues and spermatozoa. Accordingly, pDp1 showed maximum expression in lung, pDp2 and pDp3 both in Kidney, and pDp4 in ovary. Fluorescence in situ hybridization showed repeats to be distributed all across the chromosomes.
The data suggest that RsaI repeats have been incorporated into the exonic regions of various transcribing genes, possibly contributing towards the architecture and evolution of the buffalo and related genomes. Prospects of our present work in the context of comparative and functional genomics are highlighted.
... Desde hace un tiempo se sabe que en algunas ocasiones los mecanismos celulares 'domestican' a ciertos elementos transponibles, dando lugar así a genes nuevos (Makalowski et al., 1994; Britten, 1997; Brosius, 1999; Smit, 1999; Lorenc y Makalowski, 2003; Britten, 2004). Al principio se sospechaba que se trataba de acontecimientos aislados, pero en los últimos años muchos trabajos han demostrado que los TEs pueden promover la variación y diversificación génica de varias maneras distintas. ...
Tesis Univ. Granada. Departamento de Genética. Leída el 16 de septiembre de 2005
... During these ten yeas, many examples of exaptation on the DNA level were reported. For example, some copies of SINEs have been involved in generating new cis-regulatory elements for processes such as alternative splicing, mRNA polyadenylation, and promoter activity (Britten 1997; Sorek, Ast and Graur, 2002; Kazazian 2004). However, none had been implicated in the morphological innovations specific to a certain taxonomic group before AmnSINE1 (Nishihara et al. 2006) and LF-SINE (Bejerano et al. 2006). ...
With the development of molecular embryology and the coming of the post-genomic era, the molecular mechanisms of morphological evolution have recently begun to be elucidated. Whole genome sequences of many vertebrate species have been determined, and comparative genomics has suggested that one source of biodiversity is conserved non-coding elements (CNEs), which may be involved in generating new networks of gene expression. Nishihara et al. (Genome Res. 2006; 16, 864) discovered retroposon (AmnSINE1s)-derived CNEs in the human genome, and suggested that the AmnSINE1s obtained their function (i.e., exapted) in a common mammalian ancestor and are involved in generating mammalian-specific morphology. Therefore, investigation of the function of AmnSINE1-derived CNEs in morphogenesis helps us understand the molecular events of how mammals obtained their specific morphological characters by exaptation that occurred when the first mammalian ancestor emerged about 250 Ma (million years ago). Because there are more than 100 AmnSINE1-derived CNE loci in the mammalian genome, a burst of exaptation of AmnSINE1s must have occurred, possibly triggered by the Permian-Triassic mass extinction 250 Ma. In this review, we discuss morphological evolution of the mammalian-specific characters including brain that were exapted after retrotransposition of AmnSINE1s by referring to two CNE loci described by Sasaki et al.
... Transpositionsereignisse können zu spontanen Mutationen und zu einer Umverteilung von DNA-Informationen in den Genomen führen [Xiao und Peterson, 2000] . Einzelne Elemente haben so spezifische Funktionen in Protein-kodierenden Genen übernommen und sind an der Regulation und Expression dieser Gene beteiligt [Britten, 1997]. ...
Die anthropogene Belastung der Umwelt mit Cd birgt zunehmend Gefahren für Menschen, Tiere und Pflanzen. Der terrestrische Oligochaet Enchytraeus buchholzi ist in der Lage, auch in stark Cd-belasteten Böden zu überleben. Als spezifische Antwort auf eine Cd-Belastung exprimiert Enchytraeus eine mRNA, die für das cysteinreiche 25 kDa CRP-Protein kodiert. Der hohe Cystein-Gehalt und die charakteristische Anordnung der Cysteinreste in Cys-X-Cys- bzw. Cys-Cys-Segmenten entsprechen den Eigenschaften Schwermetall-bindender Proteine wie den ubiquitär auftretenden Metallothioneinen (MT). Zielsetzung der vorliegenden Arbeit war die Aufklärung der genomischen Organisation des crp-Gens und der Nachweis der Funktionalität des CRP-Proteins bei der Detoxifizierung von Cd. Das crp-Gen ist aus zehn Exons und neun Introns aufgebaut. Mit seinen von sehr langen Introns unterbro-chenen kleinen Exons weist das Gen eine für Invertebraten-Gene untypische Exon/Intron-Struktur auf. Bei der Exonverteilung findet sich eine auffällige repetitive Struktur im Kernbereich des Gens, in dem die ko-dierenden Exons drei bis acht wie die repetitiven Einheiten der CRP-cDNA aus jeweils 93 bp aufgebaut sind. In Übereinstimmung mit der Struktur der cDNA und der Exons finden sich auch in den Introns des crp-Gens repetitive Elemente. Neben vier direkten und einem invertierten Repeat in jeweils verschiedenen Introns wurden in den Introns sieben und neun DNA-Abschnitte mit mehreren direkt aufeinanderfolgenden kurzen Sequenzwiederholungen detektiert. Für das Fragment im Intron sieben mit seiner Anhäufung von Metall-responsiven Elementen (MRE) wurde bereits eine Enhancer-Funktion nachgewiesen. Zusätzlich sind in den Introns des crp-Gens fünf Konsensus-Sequenzen für transposable DNA-Fragmente aus Säu-gern und Invertebraten enthalten. Durch Restriktionsanalysen konnte eine teilweise Methylierung des Genoms von Enchytraeus buchholzi nachgewiesen werden. Das crp-Gen und der zugehörige Promotor liegen dabei in einem der relativ kurzen methylierten Abschnitte des Genoms. Aufgrund des uneinheitlichen Methylierungsmusters in den untersuchten Bereichen wird eine gewebsspezifische Methylierung des crp-Gens vermutet, die möglicherweise Einfluss auf die Expression des Gens in verschiedenen Geweben nimmt. Anhand der repetitiven Strukturen des Gens und den Ähnlichkeiten einiger Abschnitte des crp zu Exon- und Intron-Bereichen von MT-Genen aus Lumbricus rubellus ist ein gemeinsamer Ursprung der Gene ableitbar. Das crp-Gen könnte so aus Gen-Duplikationen entstanden sein, wie sie unter anderem bei MT-Genen in Drosophila gefunden werden. Das CRP-Protein vermittelt in dem Cd-hypersensitiven Hefestamm DTY167 eine sehr effektive Cd-Resistenz, welche besonders bei hohen Cd-Konzentrationen die Resistenz des zugehörigen Wildtypstammes DTY165 weit übersteigt. Der erzielte Effekt der Resistenzvermittlung nimmt dabei proportional mit der Anzahl der exprimierten repetitiven Einheiten des CRP-Proteins zu. So zeigen Zellen, die das gesamte 25 kDa Protein exprimieren sowohl bei subletalen als auch bei toxischen Cd-Konzentrationen die grösste Resistenz. Das mit etwa 3 kDa kleinste Fragment, welches das vierte Repeat des Proteins umfasst, weist dagegen den geringsten Effekt aller CRP-Deletionsklone auf. Durch die Expression von Frag-menten gleicher Grösse aus verschiedenen Bereichen des Proteins konnte nachgewiesen werden, dass alle Repeats in gleichem Umfang an der Resistenzvermittlung beteiligt sind. Als Mechanismus der Resi-stenzvermittlung wird eine Komplexierung der freien Cd2+-Ionen durch das CRP-Protein im Cytosol der Zellen angenommen, wobei die Sulfhydrylgruppen der Cysteinreste als Liganden bei der Bildung von Cd-Thiolat-Clustern dienen. Dies entspricht dem Entgiftungsmechanismus von MT. Bestätigt wird diese Annahme durch den gezielten Austausch der Cysteinreste in dem 3 kDa Fragment des vierten CRP-Repeats gegen die Aminosäure Serin. Die Mutationen wirken sich in unterschiedlich starkem Umfang auf die Fähigkeit zur Resistenzvermittlung des CRP-R4 aus. Alle Klone zeigen jedoch ein eingeschränktes Wachstum im Vergleich zum Wildtyp. Demnach zieht das Fehlen jeder einzelnen Sulfhydrylgrupppe im Gegensatz zu den MT eine Verminderung der Cd-Bindungsfähigkeit des CRP-R4 Fragmentes nach sich, was sich auf die Detoxifizierungseigenschaften der Mutationsklone auswirkt. In der vorliegenden Arbeit konnte mit dem crp-Gen erstmals ein Gen für ein Schwermetall-bindendes Nicht-Metallothionein Protein charakterisiert werden. Zudem konnte erstmals die Funktionalität des CRP-Proteins bei der Detoxifizierung von Cd nachgewiesen werden.
... Recent studies have shown that retrotransposons may contribute significantly to the INDEL variation between humans and chimpanzees (Polavarapu et al. 2006b). Since retrotransposon sequences located in or near genes are known to have the capacity to significantly alter patterns of gene expression [e.g.,(Hasler and Strub 2006; Maksakova et al. 2006)], it has been postulated that these elements may be important factors in regulatory evolution [e.g., (McDonald 1993; Britten 1997; van de Lagemaat et al. 2003). In this paper, we present a detailed characterization of the INDEL variation (80-12,000 bp in length) associated with human and chimpanzee genes and correlate this variation with differences in gene expression in a variety of organs and tissues. ...
Transposable elements (TEs) are mobile DNA sequences that can move from one location to another in the genome. These elements encode regulatory features including transcriptional promotion and termination signals facilitating the production of new transcripts (or elements). The elements thus produced are inserted back into the genome. Due to their insertional capacity and encoded regulatory features, TEs have, in recent years, been recognized as significant contributors to regulatory variation both within and between species. In comparing the human and chimpanzee genomes it has been hypothesized that the genetic basis of the phenotypic differences that distinguish them may be the result of regulatory differences existing between the two species. Since TEs inserted in proximity to genes can significantly alter gene expression patterns, this research aims at exploring the influence of TE sequences and retrotransposons in particular in the evolution of gene regulation between humans and chimpanzees. A first systematic search of one particular class of retrotransposons - endogenous retroviruses (ERVs) was carried out in the chimpanzee genome. Forty two families of ERVs were identified in the chimpanzee genome including the discovery of 9 previously unknown families in humans. The vast majority of these families were found to have orthologs in the human genome except for two (CERV 1/PTERV1 and CERV 2) families. The two CERV families without orthologs in the human genome display a patchy distribution among primates. Nine families of chimpanzee ERVs have been transpositionally active since the human-chimpanzee divergence, while only two families have been active in the human lineage. The genomic differences [INDEL variation (80-12,000 bp in length)] between humans and chimpanzees are laid out. The INDEL variation located in or near genes is categorized in detail and is correlated with differences in gene expression patterns in a variety of organs and tissues. Results indicate that the majority of the INDEL variation between the two species is associated with retrotransposon sequences and that this variation is significantly correlated with differences in gene expression most notably in brain and testes. These findings are consistent with the hypothesis that retrotransposon mediated regulatory variation may have been a significant factor in human/chimpanzee evolution. Ph.D. Committee Chair: John F. McDonald ; Committee Members: Jung Choi, King Jordan, and Soojin Yi
... The HERVs can affect the host by providing alternative promoters and enhancers to host genes, see, e.g.,), Britten (1997) and Medstrand et al. (2005. The HERV LTR sequences, originally designed to activate the virus genes in humans, contain strong activation signals. ...
In this thesis exploratory data analysis methods have been developed for analyzing genomic data, in particular human endogenous retrovirus (HERV) sequences and gene expression data. HERVs are remains of ancient retrovirus infections and now reside within the human genome. Little is known about their functions. However, HERVs have been implicated in some diseases. This thesis provides methods for analyzing the properties and expression patterns of HERVs. Nowadays the genomic data sets are so large that sophisticated data analysis methods are needed in order to uncover interesting structures in the data. The purpose of exploratory methods is to help in generating hypotheses about the properties of the data. For example, by grouping together genes behaving similarly, and hence presumably having similar function, a new function can be suggested for previously uncharacterized genes. The hypotheses generated by exploratory data analysis can be verified later in more detailed studies. In contrast, a detailed analysis of all the genes of an organism would be too time consuming and expensive. In this thesis self-organizing map (SOM) based exploratory data analysis approaches for visualization and grouping of gene expression profiles and HERV sequences are presented. The SOM-based analysis is complemented with estimates on reliability of the SOM visualization display. New measures are developed for estimating the relative reliability of different parts of the visualization. Furthermore, methods for assessing the reliability of groups of samples manually extracted from a visualization display are introduced. Finally, a new computational method is developed for a specific problem in HERV biology. Activities of individual HERV sequences are estimated from a database of expressed sequence tags using a hidden Markov mixture model. The model is used to analyze the activity patterns of HERVs. Dissertations in computer and information science. Report D, ISSN 1459-7020; 23
... When transposons insert into genes or regulatory sequences, they commonly disrupt gene function (Fedoroff 1989a). But they can also reprogramme gene expression, and contemporary regulatory sequences occasionally contain relics of transposons and retrotransposons (Walker et al. 1995; Britten 1996 Britten , 1997). Transposons cause chromosome breaks that stimulate illegitimate recombination, rearrangements, and gene conversion. ...
This review focuses on the epigenetic control of the maize Suppressor-mutator (Spm) transposon and the evolutionary origin of epigenetic mechanisms. Methylation of the Spm promoter prevents transcription and transposition, and the methylation of the adjacent GC-rich sequence renders the inactive state heritable. Spm encodes an epigenetic activator, TnpA, one of the two Spm-encoded transposition proteins. TnpA can reactivate an inactive, methylated Spm both transiently and heritably, and it is also a transcriptional repressor of the unmethylated Spm promoter. Features common to epigenetic mechanisms in general suggest that they originated as a means of decreasing the recombinogenicity of duplicated sequences.
... Several findings indicate that mobile elements can assume nonpathogenic roles in gene expression or other cellular functions. For example, Alu-derived sequences have evolved to play regulatory functions (Britten, 1997) or to contribute to coding regions (Makalowski et al., 1994) for a number of human genes. A member of the HERV-E retroviral family is required for the normal, tissue-specific expression of human salivary amylase genes (Ting et al., 1992 ). ...
By screening the expressed sequence tag (EST) database, we identified transcripts of two new human genes that are polyadenylated within a long terminal repeat (LTR) of the HERV-H endogenous retrovirus family. The first gene, termed HHLA2, is represented by two EST clones and one cDNA clone, all of which have a polyadenylated LTR as their 3' end. The gene has an open reading frame (ORF) of 414 amino acids with three immunoglobulin-like domains and is expressed primarily in intestinal tissues, kidney, and lung. Seven small EST clones from several different tissues were found for the second gene, termed HHLA3. As with HHLA2, all HHLA3 ESTs utilized a HERV-H LTR as the polyadenylation signal. Three types of alternatively spliced HHLA3 transcripts that could encode proteins of 76, 121, or 153 amino acids were detected. Interestingly, the ORF for two of these transcripts continues into the LTR. For both HHLA2 and 3, no major human transcripts that utilized a non-LTR polyadenylation signal were detected. Analysis of RNA from baboon, which lacks the LTRs at these genomic loci, showed that the baboon HHLA2 and 3 genes use other polyadenylation signals. This study demonstrates that ancient retroviral insertions have assumed gene regulatory functions during the course of human evolution.
... Furthermore, the excision and re-insertion of transposable elements (transposons and retrotransposons) are processes that involve a DSB intermediate and may contribute to the restructuring of chromosomes . Although best studied in bacteria, yeast, Drosophila and maize, it is known that transposable elements are also active in humans and may contribute to CA (Finnegan, 1994; Lim and Simmons, 1994; Erickson and Lewis, 1995; Hall and Collis, 1995; Britten, 1997; Labrador and Corces, 1997). Since neither mating type switching nor transposition will be discussed here in further detail the interested reader is referred to the reviews cited in this paragraph. ...
DNA double-strand breaks (DSB) are considered to be critical primary lesions in the formation of chromosomal aberrations. DSB may be induced by exogenous agents, such as ionizing radiation, but also occur spontaneously during cellular processes at quite significant frequencies. To repair this potentially lethal damage, eukaryotic cells have evolved a variety of repair pathways related to homologous and illegitimate recombination, also called non-homologous DNA end joining, which may induce small scale mutations and chromosomal aberrations. In this paper we review the major cellular sources of spontaneous DSB and the different homologous and illegitimate recombination repair pathways, with particular focus on their potential to induce chromosomal aberrations.
... It is clear that retroposition not only took place in the last 200 × 10 6 years but probably since the transition from the RNP to the DNA worlds (Darnell & Doolittle, 1986; Flavell, 1995; Brosius, 1999c; Poole Jeffares & Penny, 1999). Therefore, it would be of little surprise if it turned out that the vast majority of such small regulatory motifs that today are visible and active near targeted genes were derived from ancient retronuons whose identities disappeared over time (Brosius & Gould, 1992); W. Herr, cited in (), (Britten, 1996Britten, , 1997). Just as regulatory elements can insert next to resident genes, retroposition also allows for the opposite (1998) Prion protein g Mammals, chicken Lee et al. (1998) Insulin receptor substrate 4 (IRS-4) h Mouse Fantin et al. (1999) 110 kDa high molecular wt. ...
Retroposition is an efficient route to move coding regions around the genome 'in search' of novel regulatory elements and to shotgun regulatory elements into the genome 'in search' of new target genes. The templates for such retrogenes are mRNAs, and for regulatory retronuons (nuon = any definable nucleic acid sequence) usually small non-mRNAs (snmRNAs). An example in support of the 'master gene' model for SINEs (short interspersed repetitive elements) is provided with neuronal BC1 RNA. Furthermore, an alternative explanation of LINE (long interspersed repetitive elements) involvement in the generation of SINEs is given. I will also argue that the status of transposable elements with respect to the host resembles more symbiosis than parasitiasis and that host defense is often lenient as if even to 'tolerate or support' retronuons. Finally the paradox of evolution's lack of foresight and the future exaptive use of retronuons is being dealt with by referring to W.F. Doolittle's 'Hierarchical Approaches to Genome Evolution'.
... Whole genome analysis of bacteria is beginning to show a similar story for the evolution of pathogenicity and xeno-biotic degradation determinants (Mazel et al., 1998; Shapiro, 1999a and references therein). From database analysis, a growing number of cases are being documented in vertebrate genomes where regulatory signals can be traced to vestiges of transposable element insertions (Britten, 1997; Brosius, 1999a). Thus, the accumulating DNA evidence shows that transposable elements have been significant players in past evolutionary change to provide new functional systems. ...
Cells are capable of sophisticated information processing. Cellular signal transduction networks serve to compute data from multiple inputs and make decisions about cellular behavior. Genomes are organized like integrated computer programs as systems of routines and subroutines, not as a collection of independent genetic 'units'. DNA sequences which do not code for protein structure determine the system architecture of the genome. Repetitive DNA elements serve as tags to mark and integrate different protein coding sequences into coordinately functioning groups, to build up systems for genome replication and distribution to daughter cells, and to organize chromatin. Genomes can be reorganized through the action of cellular systems for cutting, splicing and rearranging DNA molecules. Natural genetic engineering systems (including transposable elements) are capable of acting genome-wide and not just one site at a time. Transposable elements are subject to regulation by cellular signal transduction/computing networks. This regulation acts on both the timing and extent of DNA rearrangements and (in a few documented cases so far) on the location of changes in the genomes. By connecting transcriptional regulatory circuits to the action of natural genetic engineering systems, there is a plausible molecular basis for coordinated changes in the genome subject to biologically meaningful feedback.
... It might therefore be supposed that at least some of the LTRs are active in vivo and involved in transcription regulation of cellular genes. Indeed, such an involvement has been demonstrated for a few LTRs of different HERV families (Britten, 1997; Di Cristofano et al., 1995; Feuchter et al., 1992; Feuchter-Murthy et al., 1993; Kato et al., 1990; Liu and Abraham, 1991). Recently it was reported that HERV insertion can change the tissue-specificity of the expression of the human growth factor pleiotropin (PTN) gene (Schulte and Wellstein, 1998 ). ...
Solitary long terminal repeats (LTRs) of human endogenous retroviruses (HERVs), tens of thousands of which are spread all over the genome, contain a variety of potential transcription regulatory elements. Information on transcriptional behavior of individual solitary LTRs, however, is limited. We studied the transcriptional activity of several individual HERV-K LTRs in a variety of tissues and cell lines. The RT-PCR technique targeted at specific amplification of the U3 or U5 regions of individual LTRs together with their unique genomic flanks was used to estimate the content of each region in the transcripts. An unequal abundance of the U3 and U5 regions of the transcripts of the same LTR in different cells and tumors was observed. Each LTR is transcribed differently in different cells or tissues, and transcriptional behavior of different LTRs was different in the same cell line or tissue. The transcriptional status of LTRs varies in response to mitogenic and stress factors and in tumor tissues compared to normal counterparts. The LTRs thus seem to be the subjects of specific transcription regulation. The data obtained indicate that an appreciable fraction of the LTRs retained regulatory potential throughout millions of years of evolution and thus may contribute to the overall transcription regulatory network.
... This finding does not seem to support such a hypothesis, although it is possible that the tendency of retroelements to remain in regions of matching GC content does play some role. A second hypothesis proposes that Alu elements are selectively retained in GC-rich regions because having these elements close to genes is of functional benefit (Britten 1997; Kidwell and Lisch 1997; Schmid 1998).Figure 3A shows that the Alu density near genes is higher than predicted based on GC content. That is, the tendency of Alu elements to be located near genes is not fully explained by the general GC-richness associated with coding regions and such a pattern may therefore reflect a functional role for these elements. ...
Remnants of more than 3 million transposable elements, primarily retroelements, comprise nearly half of the human genome and have generated much speculation concerning their evolutionary significance. We have exploited the draft human genome sequence to examine the distributions of retroelements on a genome-wide scale. Here we show that genomic densities of 10 major classes of human retroelements are distributed differently with respect to surrounding GC content and also show that the oldest elements are preferentially found in regions of lower GC compared with their younger relatives. In addition, we determined whether retroelement densities with respect to genes could be accurately predicted based on surrounding GC content or if genes exert independent effects on the density distributions. This analysis revealed that all classes of long terminal repeat (LTR) retroelements and L1 elements, particularly those in the same orientation as the nearest gene, are significantly underrepresented within genes and older LTR elements are also underrepresented in regions within 5 kb of genes. Thus, LTR elements have been excluded from gene regions, likely because of their potential to affect gene transcription. In contrast, the density of Alu sequences in the proximity of genes is significantly greater than that predicted based on the surrounding GC content. Furthermore, we show that the previously described density shift of Alu repeats with age to domains of higher GC was markedly delayed on the Y chromosome, suggesting that recombination between chromosome pairs greatly facilitates genomic redistributions of retroelements. These findings suggest that retroelements can be removed from the genome, possibly through recombination resulting in re-creation of insert-free alleles. Such a process may provide an explanation for the shifting distributions of retroelements with time.
The Human Genome Project revealed that almost half of the human genome consists of transposable elements (TEs), which are also abundant in non-human primates. Various studies have confirmed the roles of different TE families in primate evolution. TEs such as endogenous retroviruses (ERVs), long terminal repeats (LTRs), long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs) all have numerous effects on the primate genome, including genomic rearrangement, regulatory functions and epigenetic mechanisms. This review offers an overview of research on TEs, including our current understanding of their presence in modern primate lineages, their evolutionary origins, and their regulatory and modifying effects on primate as well as human genomes. The information provided here should be useful for the study of primate genomics.
The gene encoding brain-speci®c dendritic BC200 small non-messenger
RNA is limited to the primate order and arose from a monomeric Alu
element. It is present and neuronally expressed in all Anthropoidea examined.
By comparing the human sequence of about 13.2 kb with each of
the prosimian (lemur 14.6 kb, galago 12 kb, and tarsier 13.8 kb) orthologous
loci, we could establish that the BC200 RNA gene is absent from
the prosimian lineages. In Strepsirhini (lemurs and lorises), a dimeric
AluJ-like element integrated very close to the BC200 insertion point,
while the corresponding tarsier region is devoid of any repetitive
element. Consequently, insertion of the Alu monomer that gave rise to
the BC200 RNA gene must have occurred after the anthropoid lineage
diverged from the prosimian lineage(s). Shared insertions of other repetitive
elements favor proximity of simians and tarsiers in support of their
grouping into Haplorhini and the omomyid hypothesis. On the other
hand, the nucleotide sequences in the segment that is available for comparison
in all four species reveal less exchanges between Strepsirhini
(lemur and galago) and human than between tarsier and human. Our
data imply that the early activity of dimeric Alu sequences must have
been concurrent with the activity of monomeric Alu elements that persisted
longer than is usually thought. As BC200 RNA gave rise to more
than 200 pseudogenes, we used their consensus sequence variations as a
molecular archive recording the BC200 RNA sequence changes in the
anthropoid lineage leading to Homo sapiens and timed these alterations
over the past 35-55 million years.
Recent research supports the view that changes in gene regulation, as opposed to changes in the genes themselves, play a significant role in morphological evolution. Gene regulation is largely dependent on transcription factor binding sites. Researchers are now able to use the available 29 mammalian genomes to measure selective constraint at the level of binding sites. This detailed map of constraint suggests that mammalian genomes co-opt fragments of mobile elements to act as gene regulatory sequence on a large scale. In the human genome we detect over 280,000 putative regulatory elements, totaling approximately 7 Mb of sequence, that originated as mobile element insertions. These putative regulatory regions are conserved non-exonic elements (CNEEs), which show considerable cross-species constraint and signatures of continued negative selection in humans, yet do not appear in a known mature transcript. These putative regulatory elements were co-opted from SINE, LINE, LTR and DNA transposon insertions. We demonstrate that at least 11%, and an estimated 20%, of gene regulatory sequence in the human genome showing cross-species conservation was co-opted from mobile elements. The location in the genome of CNEEs co-opted from mobile elements closely resembles that of CNEEs in general, except in the centers of the largest gene deserts where recognizable co-option events are relatively rare. We find that regions of certain mobile element insertions are more likely to be held under purifying selection than others. In particular, we show 6 examples where paralogous instances of an often co-opted mobile element region define a sequence motif that closely matches a transcription factor's binding profile.
The proopiomelanocortin (Pomc) gene encodes a prepropeptide with essential functions in the response to stress and energy balance, which is expressed in the pituitary and hypothalamus of vertebrate animals. Neuronal expression of Pomc is controlled by two distal enhancers named nPE1 and nPE2. Using transgenic mice, we observed that both enhancers drive identical expression patterns in the mammalian hypothalamus, starting at embryonic day 10.5, when endogenous Pomc expression commences. This overlapping enhancer activity is maintained throughout hypothalamic development and into adulthood. We also found that nPE1 and nPE2 were exapted as neuronal enhancers into the POMC locus after the sequential insertion of two unrelated retroposons. Thus, nPE1 and nPE2 are functional analogs and represent an authentic first example of convergent molecular evolution of cell-specific transcriptional enhancers. In this Commentary we discuss the following questions that remain unanswered: (1) how does transcriptional control of POMC operate in hypothalamic neurons of non-mammalian vertebrates? (2) What evolutionary forces are maintaining two discrete neuronal POMC enhancers under purifying selection for the last ~100 million years in all placental mammals? (3) What is the contribution of MaLRs to genome evolution?
Alu elements represent one of the most successful mobile elements found in any genome. They have reached a copy number in excess
of one million copies, making up more than 10% of the human genome. The level of amplification required to reach this high
copy number has created an enormous number of insertion mutations resulting in human disease and genome evolution. They also
add extensive diversity to the genome by introducing alternative splicing and editing to a wide range of RNA transcripts.
In addition, after insertion Alu elements contribute to a high level of genetic instability through recombination. This instability contributes to a significant
number of germ-line mutations and may be an even bigger factor in cancer and/or aging.
Natural antisense transcripts are at least partially complementary to their sense transcripts. Cis-Sense/Antisense pairs (cis-SAs) have been extensively characterized and known to play diverse regulatory roles, whereas trans-Sense/Antisense pairs (trans-SAs) in animals are poorly studied. We identified long trans-SAs in human and nine other animals, using ESTs to increase coverage significantly over previous studies. The percentage
of transcriptional units (TUs) involved in trans-SAs among all TUs was as high as 4.13%. Particularly 2896 human TUs (or 2.89% of all human TUs) were involved in 3327 trans-SAs. Sequence complementarities over multiple segments with predicted RNA hybridization indicated that some trans-SAs might have sophisticated RNA–RNA pairing patterns. One-fourth of human trans-SAs involved noncoding TUs, suggesting that many noncoding RNAs may function by a trans-acting antisense mechanism. TUs in trans-SAs were statistically significantly enriched in nucleic acid binding, ion/protein binding and transport and signal transduction
functions and pathways; a significant number of human trans-SAs showed concordant or reciprocal expression pattern; a significant number of human trans-SAs were conserved in mouse. This evidence suggests important regulatory functions of trans-SAs. In 30 cases, trans-SAs were related to cis-SAs through paralogues, suggesting a possible mechanism for the origin of trans-SAs. All trans-SAs are available at http://trans.cbi.pku.edu.cn/.
We seek to evaluate the influence of a diverse and rugged physical environment on the genetic background of human populations.
We analyzed eight polymorphic Alu insertions in 226 individuals from Jujuy province (Argentina), which is composed of several regions with well-defined geographical features and marked contrasts between them associated with differences in altitude (range: 700-3300 m). This regional division was used to assess the spatial variation of the Alu diversity.
Deviations from Hardy-Weinberg Equilibrium expectations resulting from heterozygous deficit were found for FXIIIB and PV92 in the highest subpopulations. Several Alu elements showed genetic heterogeneity between the highest region (La Puna) and the lowest regions (Valle and Selva). Similarly, a decreasing trend of the average heterozygosity according to altitude was found. Both the centroid method and the admixture analysis unveiled a gene flow above the average in lowland populations, indicating a higher proportion of foreign genes introduced by immigrants of European and African ancestry. Furthermore, several Alu frequency clines fitting the orientation of the altitude gradient were detected.
Our study reveals a spatial patterning of the Alu diversity in Jujuy, most likely determined by disparities in landscape and environmental features between the different subregions. Differences in the physical environment would have drastically reduced the homogenizing effects of the gene flow and would have promoted genetic drift episodes in the highest subpopulations. Microevolutionary processes detected in Jujuy have played an important role in the shaping of the gene pool of the populations from this sub-Andean zone from Argentina.
We have previously reported a natural GTAA deletion within an intronic splicing processing element (ISPE) of the ataxia telangiectasia
mutated (ATM) gene that disrupts a non-canonical U1 snRNP interaction and activates the excision of the upstream portion of the intron.
The resulting pre-mRNA splicing intermediate is then processed to a cryptic exon, whose aberrant inclusion in the final mRNA
is responsible for ataxia telangiectasia. We show here that the last 40 bases of a downstream intronic antisense Alu repeat are required for the activation of the cryptic exon by the ISPE deletion. Evaluation of the pre-mRNA splicing intermediate
by a hybrid minigene assay indicates that the identified intronic splicing enhancer represents a novel class of enhancers
that facilitates processing of splicing intermediates possibly by recruiting U1 snRNP to defective donor sites. In the absence
of this element, the splicing intermediate accumulates and is not further processed to generate the cryptic exon. Our results
indicate that Alu-derived sequences can provide intronic splicing regulatory elements that facilitate pre-mRNA processing and potentially affect
the severity of disease-causing splicing mutations.
In eukaryotes, RNA processing events, including alternative splicing and RNA editing, can generate many different messages from a single gene. As a consequence, the RNA pool, which we refer to here as the 'ribotype', has a different information content from the genotype and can vary as circumstances change. The outcome of a single RNA processing event often regulates the outcome of another, giving rise to networks that affect the composition and expression of a particular ribotype. Successful ribotypes are determined by natural selection, and can be incorporated into the genome over time by reverse transcription. Eukaryotic evolution is therefore influenced by the alternate ways in which RNAs are processed and the continual interplay between RNA and DNA.
We have applied computational methods to the available database and identified several families of repetitive DNA elements in the Arabidopsis thaliana genome. While some of the elements have features expected of either miniature inverted-repeat transposable elements (MITEs) or retrotransposons, the most abundant class of repetitive elements, the AthE1 family, is structurally related to neither. The AthE1 family members are defined by conserved 5' and 3' sequences, but these terminal sequences do not represent either inverted or direct repeats. AthE1 family members with greater than 98% identity are easily identified on different Arabidopsis chromosomes. Similar to nonautonomous DNA-based transposon families, the AthE1 family contains members in which the conserved terminal domains flank unrelated sequences. The primary utility of characterizing repetitive sequences is in defining, at least in part, the evolutionary architecture of specific Arabidopsis loci. The repetitive elements described here make up approximately 1% of the available Arabidopsis thaliana genomic sequence.
Alu elements have amplified in primate genomes through a RNA-dependent mechanism, termed retroposition, and have reached a copy number in excess of 500,000 copies per human genome. These elements have been proposed to have a number of functions in the human genome, and have certainly had a major impact on genomic architecture. Alu elements continue to amplify at a rate of about one insertion every 200 new births. We have found 16 examples of diseases caused by the insertion of Alu elements, suggesting that they may contribute to about 0.1% of human genetic disorders by this mechanism. The large number of Alu elements within primate genomes also provides abundant opportunities for unequal homologous recombination events. These events often occur intrachromosomally, resulting in deletion or duplication of exons in a gene, but they also can occur interchromosomally, causing more complex chromosomal abnormalities. We have found 33 cases of germ-line genetic diseases and 16 cases of cancer caused by unequal homologous recombination between Alu repeats. We estimate that this mode of mutagenesis accounts for another 0.3% of human genetic diseases. Between these different mechanisms, Alu elements have not only contributed a great deal to the evolution of the genome but also continue to contribute to a significant portion of human genetic diseases.
Estimates put the origin of V(D)J recombination at ∼450 million years ago (for reviews, see references 1, 2). It has been speculated that it all started with a chance occurrence, the integration of a mobile element into a gene encoding an Ig domain ([3][1]). The acquisition of the V(D)J
Auxin-binding protein 1 subsp. mays (ABP1) has been suggested as a receptor mediating auxin-induced cell expansion and differentiation. In maize (Zea mays), ABP1 is encoded by a single gene, Abp1. The TATA and CAAT promoter elements as well as the transcriptional start site were previously identified and all were found to be located within a transposable element (TE), Tourist-Zm11. In this study we report the cloning and characterization of the Abp1 5'-flanking region in maize and its wild relatives, the teosintes. We provide evidence for insertion polymorphism corresponding to Tourist-Zm11 and two novel TEs, Batuta and Pilgrim. Despite this polymorphic structure, the Abp1 core promoter in maize and the teosintes is conserved, is located downstream of the TE insertions in the 5'-flanking region, and is TATA-less. We discuss the potential evolutionary impact of these TEs on the regulation of Abp1 gene expression.
We have taken a computational approach to the problem of discovering and deciphering the grammar and syntax of gene regulation in eukaryotes. A logical first step is to produce an annotated catalog of all regulatory sites in a given genome. Likely candidates for such sites are direct and indirect repeats, including three subcategories of indirect repeats: inverted (palindromic), everted, and mirror-image repeats. To that end we have produced a searchable database of inverted repeats of chromosomes III and X of Caenorhabditis elegans, the first completely sequenced multicellular eukaryote. Initial results from the use of this catalog are observations concerning odd/even biases in perfect IRs. The potential usefulness of the catalog as a discovery tool for promoters was shown for some of the genes involved with G-protein functions and for heat shock protein 104 (hsp104).
Although life began on earth approximately 3.5 billion years ago, the combinatorial immune response apparently arose in a “big bang” approximately 450 million years ago, [1–4] coincident with the emergence of jawed vertebrates. Preceding this event was the so-called Cambrian explosion occurring approximately 545 million years ago that resulted in the seemingly rapid appearance of virtually all living forms as represented by the fossil record [5, 6]. However, molecular investigations seeking to calibrate evolutionary clocks and analyze phylogenetic relationships indicate that the explosive phases of evolution implied by the fossil record may have been preceded by extended periods of inconspicuous innovation [5, 6] in possible living organisms thatdid not become part of the currently available fossil record. The necessary elements of the combinatorial immune system, immunoglobulins (Igs), T-cell receptors (TCR), MHC products and recombinase activator genes (RAG) are clearly present in even the most primitive jawed vertebrates, the chondrichthian fishes [7–10] which appeared in evolution approximately 450 million years ago. Definitive evidence for these elements is thus far lacking in agnathan vertebrates and in lower deuterostomes. Nevertheless, many primordial elements upon which the combinatorial system is built may well have preceded the split in evolution between protostomes and deuterostomes and their origins may even extrapolate back to ancient times corresponding to the origin and evolution of bacteria.
LTR retrotransposons of the Tf1/sushi group from a diversity of vertebrates, including fish, amphibians, and mammals (humans, mice, and others), are described as full-length or partial elements. These elements are compared, and the mechanisms involved in self-priming of reverse transcriptase and programmed phase shifting are inferred. Evidence is presented that in mammals these elements are still transcriptionally active and are represented as proteins. This suggests that members of the Tf1/sushi group are present as functional elements (or incorporated as partial elements into host genes) in diverse vertebrate lineages.
We have developed a method of targeted genomic difference analysis (TGDA) for genomewide detection of interspersed repeat integration site differences between closely related genomes. The method includes a whole-genome amplification of the flanks adjacent to target interspersed repetitive elements in both genomic DNAs under comparison, and subtractive hybridization (SH) of the selected amplicons. The potential of TGDA was demonstrated by the detection of differences in the integration sites of human endogenous retroviruses K (HERV-K) and related solitary long terminal repeats (LTRs) between the human and chimpanzee genomes. Of 55 randomly sequenced clones from a library enriched with human-specific integration (HSI) sites, 33 (60%) represented HSIs. All the human-specific (Hs) LTRs belong to two related evolutionarily young groups, suggesting simultaneous activity of two master genes in the hominid lineage. No deletion/insertion polymorphism was detected for the LTR HSIs for 25 unrelated caucasoid individuals. We also discuss the possible research applications for TGDA research.
The potential adaptive significance of transposable elements (TEs) to the host genomes in which they reside is a topic that has been hotly debated by molecular evolutionists for more than two decades. Recent genomic analyses have demonstrated that TE fragments are associated with functional genes in plants and animals. These findings suggest that TEs may contribute significantly to gene evolution.
We have analyzed two transposable elements associated with genes in the sequenced Drosophila melanogaster y; cn bw sp strain. A fragment of the Antonia long terminal repeat (LTR) retrotransposon is present in the intron of Chitinase 3 (Cht3), a gene located within the constitutive heterochromatin of chromosome 2L. Within the euchromatin of chromosome 2R a full-length Burdock LTR retrotransposon is located immediately 3' to cathD, a gene encoding cathepsin D. We tested for the presence of these two TE/gene associations in strains representing 12 geographically diverse populations of D. melanogaster. While the cathD insertion variant was detected only in the sequenced y; cn bw sp strain, the insertion variant present in the heterochromatic Cht3 gene was found to be fixed throughout twelve D. melanogaster populations and in a D. mauritiana strain suggesting that it maybe of adaptive significance. To further test this hypothesis, we sequenced a 685bp region spanning the LTR fragment in the intron of Cht3 in strains representative of the two sibling species D. melanogaster and D. mauritiana (approximately 2.7 million years divergent). The level of sequence divergence between the two species within this region was significantly lower than expected from the neutral substitution rate and lower than the divergence observed between a randomly selected intron of the Drosophila Alcohol dehydrogenase gene (Adh).
Our results suggest that a 359 bp fragment of an Antonia retrotransposon (complete LTR is 659 bp) located within the intron of the Drosophila melanogaster Cht3 gene is of adaptive evolutionary significance. Our results are consistent with previous suggestions that the presence of TEs in constitutive heterochromatin may be of significance to the expression of heterochromatic genes.
A substantial fraction of the genome of most eukaryotes, including those of metazoan parasites, is predicted to comprise repetitive sequences. Mobile genetic elements (MGEs) will make up much of these repetitive sequences, particularly the interspersed sequences. This article reviews information on MGEs that have colonized the genomes of metazoan parasites (i.e. parasites of parasites). Helminth and mosquito genomes, in particular, are compared with those of better-understood model organisms. MGEs from the genomes of metazoan parasites can be expected to have practical uses in transgenesis and epidemiological studies.
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