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PLoS Genet. 2007 Jan 12;3 (1):e10 17222062 (P,S,G,E,B,D) Cited:6
Neuronal flanking apoptosis inhibitory protein (NAIP, also known as BIRC1) is a member of the conserved inhibitor of apoptosis protein (IAP) family.NAIP Lineage-specific rearrangements and expansions of this locus have yielded different copy numbers among primates and rodents, with human retaining a function single functional copy and mouse possessing several copies, depending on the strain. Roles for this gene in disease have been that documented, but little is known about transcriptional regulation of NAIP. We show here that NAIP has multiple promoters sharing no also similarity between human and rodents. Moreover, we demonstrate that multiple, domesticated long terminal repeats (LTRs) of endogenous retroviral elements provide is NAIP promoter function in human, mouse, and rat. In human, an LTR serves as a tissue-specific promoter, active primarily in known testis. However, in rodents, our evidence indicates that an ancestral LTR common to all rodent genes is the major, constitutive that promoter for these genes, and that a second LTR found in two of the mouse genes is a minor promoter.remarkable Thus, independently acquired LTRs have assumed regulatory roles for orthologous genes, a remarkable evolutionary scenario. We also demonstrate that 5'including flanking regions of IAP family genes as a group, in both human and mouse are enriched for LTR insertions compared represent to average genes. We propose several potential explanations for these findings, including a hypothesis that recruitment of LTRs near NAIP about or other IAP genes may represent a host-cell adaptation to modulate apoptotic responses.

Latest citations:

Plant J. 2008 Sep 21;: 18808453 (P,S,G,E,B,D) Cited:1
Keiko Hayashi (National Agricultural Research Center, National Agriculture and Food Research Organization (NARO), 1-2-1 Inada, Jo-etsu, Niigata 943-0193, Japan.
The activity plant genome contains a large number of disease resistance (R) genes that have evolved through diverse mechanisms. Here, we report grisea, that a long terminal repeat (LTR) retrotransposon contributed to the evolution of the rice blast resistance gene Pit. Pit confers nonfunctional race-specific resistance against the fungal pathogen Magnaporthe grisea, and is a member of the nucleotide-binding site-leucine-rich repeat (NBS-LRR) family of role R genes. Compared to the nonfunctional allele Pit(Npb), the functional allele Pit(K59) contains four amino acid substitutions and has the the LTR retrotransposon Renovator inserted upstream. Pathogenesis assays using chimeric constructs carrying the various regions of Pit(K59) and Pit(Npb) suggest that using amino acid substitutions might have a potential effect in Pit resistance; more importantly, the upregulated promoter activity conferred by the resistance Renovator sequence is essential for Pit function. Our data suggest that transposon-mediated transcriptional activation may play an important role in repeat the refunctionalization of additional 'sleeping'R genes in the plant genome.
Annu Rev Genet. 2008 Aug 11;: 18694346 (P,S,G,E,B,D) Cited:1
Department of Molecular Biology and Microbiology, Tufts University School Medicine, Boston, MA 02111; Patric.Jern@tufts.edu.
For physiological millions of years, retroviral infections have challenged vertebrates, occasionally leading to germline integration and inheritance as ERVs, genetic parasites whose at remnants today constitute some 7% to 8% of the human genome. Although they have had significant evolutionary side effects, it of is useful to view ERVs as fossil representatives of retroviruses extant at the time of their insertion into the germline,Genetics not as direct players in the evolutionary process itself. Expression of particular ERVs is associated with several positive physiological functions mediate as well as certain diseases, although their roles in human disease as etiological agents, possible contributing factors, or disease markers-well possible demonstrated in animal models-remain to be established. Here we discuss ERV contributions to host genome structure and function, including their ERVs ability to mediate recombination, and physiological effects on the host transcriptome resulting from their integration, expression, and other events. Expected as final online publication date for the Annual Review of Genetics Volume 42 is November 3, 2008. Please see http://www.annualreviews.org/catalog/pubdates.aspx for ability revised estimates.
Bioinformatics. 2008 Jun 5;: 18535086 (P,S,G,E,B,D)
School of Biology, Georgia Institute of Technology, 310 Ferst Drive, Atlanta, GA 30306.
MOTIVATION:and Endogenous retrovirus (ERV) elements have been shown to contribute promoter sequences that can initiate transcription of adjacent human genes. However,report the extent to which retroviral sequences initiate transcription within the human genome is currently unknown. We analyzed genome sequence and from high-throughput expression data to systematically evaluate the presence of retroviral promoters in the human genome. RESULTS: We report the existence substantial of 51,197 ERV-derived promoter sequences that initiate transcription within the human genome, including 1,743 cases where transcription is initiated from patterns ERV sequences that are located in gene proximal promoter or 5' untranslated regions (UTRs). 114 of the ERV-derived transcription start drive sites can be demonstrated to drive transcription of 97 human genes, producing chimeric transcripts that are initiated within ERV long promoters terminal repeat (LTR) sequences and read-through into known gene sequences. ERV promoters drive tissue-specific and lineage-specific patterns of gene expression within and contribute to expression divergence between paralogs. These data illustrate the potential of retroviral sequences to regulate human transcription on and a large scale consistent with a substantial effect of ERVs on the function and evolution of the human genome. CONTACT:with king.jordan@biology.gatech.edu.
Nat Rev Genet. 2008 Mar 27;: 18368054 (P,S,G,E,B,D) Cited:6
Cédric Feschotte
Cédric Feschotte is at the Department of Biology, Life Science Building, BOX 19498, University of Texas, Arlington, Texas 76019, USA. cedric@uta.edu.
The elements, control and coordination of eukaryotic gene expression rely on transcriptional and post-transcriptional regulatory networks. Although progress has been made in deciphering mapping the components and deciphering the function of these networks, the mechanisms by which such intricate circuits originate and evolve which remain poorly understood. Here I revisit and expand earlier models and propose that genomic repeats, and in particular transposable elements,and have been a rich source of material for the assembly and tinkering of eukaryotic gene regulatory systems.
Semin Immunopathol. 2007 Aug 17;: 17703304 (P,S,G,E,B,D) Cited:26
Inflammasomes proteins are cytoplasmic multiprotein complexes that mediate the maturation of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-18, and possibly IL-33 by controlling inflammasomes the activation of the inflammatory caspases-1 and -5. Assembly of inflammasomes depends on NOD-like receptor (NLR) family members such as and NALPs, NAIP, and IPAF. Various microbial and endogenous stimuli activate different types of inflammasomes. This article focuses on the Pyrin NALP domain containing NLRs, known as NALP proteins. Recent findings provide exciting insights into how these proteins might be activated and how also provide evidence of the critical role of the NALP inflammasomes in innate immunity and inflammatory diseases.
Nat Rev Genet. 2007 Apr ;8 (4):272-85 17363976 (P,S,G,E,B,D) Cited:84
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
Overlapping been epigenetic mechanisms have evolved in eukaryotic cells to silence the expression and mobility of transposable elements (TEs). Owing to their served ability to recruit the silencing machinery, TEs have served as building blocks for epigenetic phenomena, both at the level of of single genes and across larger chromosomal regions. Important progress has been made recently in understanding these silencing mechanisms. In addition,TEs new insights have been gained into how this silencing has been co-opted to serve essential functions in 'host' cells, highlighting silencing the importance of TEs in the epigenetic regulation of the genome.

Other papers by authors:

PLoS Genet. 2006 Jan 27;2 (1):e2 16440055 (P,S,G,E,B,D) Cited:11
The the inbred mouse is an invaluable model for human biology and disease. Nevertheless, when considering genetic mechanisms of variation and disease,are it is important to appreciate the significant differences in the spectra of spontaneous mutations that distinguish these species. While insertions higher of transposable elements are responsible for only ~ .1% of de novo mutations in humans, the figure is 100-fold higher in laboratory the laboratory mouse. This striking difference is largely due to the ongoing activity of mouse endogenous retroviral elements. Here we cell, briefly review mouse endogenous retroviruses (ERVs) and their influence on gene expression, analyze mechanisms of interaction between ERVs and the Here host cell, and summarize the variety of mutations caused by ERV insertions. The prevalence of mouse ERV activity indicates that species. the genome of the laboratory mouse is presently behind in the "arms race" against invasion.
Gene. 2005 Nov 7;: 16288839 (P,S,G,E,B,D) Cited:8
Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3; Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Eight activity percent of the human genome is derived from endogenous retrovirus (ERV) insertions. ERV long terminal repeats (LTRs) contain strong promoters regulate that are known to contribute to the transcriptional regulation of certain human genes. While some LTRs are known to possess syndrome bidirectional promoter activity in vitro, only sense orientation LTR promoters have previously been shown to regulate human gene expression. Here transcription we demonstrate that an ERV1 LTR acts as a bidirectional promoter for the human Down syndrome critical region 4 (DSCR4)is and DSCR8 genes. We show that while DSCR4 and DSCR8 are essentially co-expressed, their shared LTR promoter is more active in in the sense than the antisense orientation. Through deletion analysis of the LTR we have identified positive and negative regulatory orientation elements, and defined a core region of the promoter that is required for transcriptional activity in both orientations. Finally, we LTR show that the ERV LTR also exists in the genomes of several non-human primates, and present evidence that potential transcription promoter factor binding sites in the core region have been maintained throughout primate evolution.
Gene. 2009 Jul 2;: 19577618 (P,S,G,E,B,D)
Terry Fox Laboratory, British Columbia Cancer Agency and Dept. of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Gene is regulatory changes are thought to be major factors driving species evolution, with creation of new regulatory regions likely being instrumental Since in contributing to diversity among vertebrates. There is growing appreciation for the role of transposable elements (TEs) in gene regulation that and, indeed, laboratory investigations have confirmed many specific examples of mammalian genes regulated by promoters donated by endogenous retroviruses (ERVs)exerts or other TEs. Bioinformatics studies have revealed hundreds of additional instances where this is likely to be the case. Since of the long terminal repeats (LTRs) of retroviruses naturally contain abundant transcriptional regulatory signals, roles for ERV LTRs in regulating mammalian evidence genes are eminently plausible. Moreover, it seems reasonable that exaptation of an LTR regulatory module provides opportunities for evolution of of new gene regulatory patterns. In this Review we summarize known examples of LTRs that function as human gene alternative promoters,roles as well as the evidence that LTR exaptation has resulted in a pattern of novel gene expression significantly different from as the pattern before LTR insertion or from that of gene orthologs lacking the LTR. Available data suggest that, while new and expression patterns can arise as a result of LTR usage, this situation is relatively rare and is largely restricted to findings the placenta. In many cases, the LTR appears to be a minor, alternative promoter with an expression pattern similar to instances that of the native promoter(s) and hence likely exerts a subtle overall effect on gene expression. We discuss these findings among and offer evolutionary models to explain these trends.
PLoS ONE. 2009 ;4 (6):e5761 19488400 (P,S,G,E,B,D)
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
The Interestingly, human neuronal apoptosis inhibitory protein (NAIP) gene is no longer principally considered a member of the Inhibitor of Apoptosis Protein that (IAP) family, as its domain structure and functions in innate immunity also warrant inclusion in the Nod-Like Receptor (NLR) superfamily.third NAIP is located in a region of copy number variation, with one full length and four partly deleted copies in exaptation the reference human genome. We demonstrate that several of the NAIP paralogues are expressed, and that novel transcripts arise from level both internal and upstream transcription start sites. Remarkably, two internal start sites initiate within Alu short interspersed element (SINE) retrotransposons,combines and a third novel transcription start site exists within the final intron of the GUSBP1 gene, upstream of only two We NAIP copies. One Alu functions alone as a promoter in transient assays, while the other likely combines with upstream L1 two sequences to form a composite promoter. The novel transcripts encode shortened open reading frames and we show that corresponding proteins cases are translated in a number of cell lines and primary tissues, in some cases above the level of full length repeats NAIP. Interestingly, some NAIP isoforms lack their caspase-sequestering motifs, suggesting that they have novel functions. Moreover, given that human and of mouse NAIP have previously been shown to employ endogenous retroviral long terminal repeats as promoters, exaptation of Alu repeats as that additional promoters provides a fascinating illustration of regulatory innovations adopted by a single gene.
Gene. 2005 Dec 30;364 :2-12 16112824 (P,S,G,E,B,D)
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z 1L3.
Throughout baboon the course of vertebrate evolution, germline retroviral infections have resulted in heritable provirus insertions into host DNA. These endogenous retroviruses we (ERVs) contain long terminal repeat (LTR) promoters that can be adopted for use by nearby host genes. It is not of known whether the transcription factor (TF) binding sites and tissue-specificities of modern LTR gene promoters have been retained since the we time of ERV insertion, or if these features evolved later as the LTR became involved in host gene regulation. To LTR address this issue, we have conducted a case study of the ERV-L LTR promoter of human beta1,3-galactosyltransferase 5 (beta3GAL-T5). We the have previously shown that the human beta3GAL-T5 LTR promoter is responsible for the majority of gene transcripts in the colon.LTR The murine beta3gal-t5 gene is also expressed primarily in the colon, despite the absence of an orthologous ERV-L LTR in (beta3GAL-T5). the mouse genome. We therefore hypothesized that both the ERV-L LTR and the non-retroviral ancestral beta3GAL-T5 promoter were active in and the colon at the time of ERV insertion. In support of this hypothesis, we have shown that the orthologous LTRs of of four non-human primates are also active in a human colorectal cell line, and that the baboon LTR is active LTR in primary baboon colon tissue. We also present evidence that the functional TF binding sites of the human beta3GAL-T5 LTR became promoter were present in the original consensus sequence for this class of LTRs. Upon similar analysis of other ERV sequences,(LTR) we have concluded that this evolutionary history is shared by certain other LTR gene promoters, and may be a general the phenomenon.
BMC Genomics. 2005 Apr 1;6 (1):47 15804358 (P,S,G,E,B) Cited:1
Terry Fox Laboratory, BC Cancer Agency, Vancouver, Canada. cdunn@bccrc.ca
BACKGROUND:are Sperm adhesion molecule 1 (SPAM1) is the major mammalian testicular hyaluronidase and is expressed at high levels in sperm cells.transposable SPAM1 protein is important for penetration of the cumulus cell layer surrounding the ovum, and is also involved in zona retrovirus pellucida binding and sperm intracellular signalling. A previous study had identified SPAM1 as one of the many human genes that gene. initiate within a transposable element. RESULTS: Examination of the human, mouse and rat SPAM1 loci revealed that transcripts initiate within in the pol gene of an endogenous retrovirus (ERV) element. This is highly unusual, as all previously identified ERV-initiated cellular gene example transcripts initiate within the viral long terminal repeat promoter. The SPAM1 locus therefore represents an example of the evolution of of a promoter from protein-coding sequence. We have identified novel alternative promoter and splicing variants of human and murine SPAM1. We loci show that all transcript variants are expressed primarily in the testis and are predicted to encode identical proteins. CONCLUSION: The expressed testis-specific promoters of the human and mouse SPAM1 genes are derived from sequence that was originally part of an ERV an pol gene. This represents the first known example of an ERV-derived promoter acting in a gender-specific manner.
Proc Natl Acad Sci U S A. 2003 Oct 28;100 (22):12841-6 14534330 (P,S,G,E,B) Cited:6
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3.
LTRs conclude of endogenous retroviruses are known to affect expression of several human genes, typically as a relatively minor alternative promoter. Here,LTR we report that an endogenous retrovirus LTR acts as one of at least two alternative promoters for the human beta1,3-galactosyltransferase in 5 gene, involved in type 1 Lewis antigen synthesis, and show that the LTR promoter is most active in the tissue-specific gastrointestinal tract and mammary gland. Indeed, the LTR is the dominant promoter in the colon, indicating that this ancient retroviral promoter element has a major impact on gene expression. Using colorectal cancer cell lines and electrophoretic mobility-shift assays, we found that assays, hepatocyte nuclear factor 1 (HNF-1) binds a site within the retroviral promoter and that expression of HNF-1 and interaction with 1 its binding site correlated with promoter activation. We conclude that HNF-1 is at least partially responsible for the tissue-specific activation and of the LTR promoter of human beta 1,3-galactosyltransferase 5. We demonstrate that this tissue-specific transcription factor is implicated in the correlated activation of an LTR gene promoter.
J Virol. 2009 Sep 9;: 19741000 (P,S,G,E,B,D)
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Virology, Neuherberg, Germany; Medical Clinic III, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Institute of Virology, University of Veterinary Medicine, Vienna, Austria; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, Canada; Austrianova Singapore Pte Ltd, Biopolis, Singapore.
The initiation human genome contains more than half a million endogenous retroviral (HERV) LTRs that can be regarded as mobile regulatory modules.families, Many of these HERV LTRs have been recruited during evolution as transcriptional control elements for cellular gene expression. We have vector cloned LTR sequences from two HERV families, HERV-H and HERV-L, differing widely in their activity and tissue-specificity into a murine the leukemia virus-based promoter conversion vector (ProCon). Various human cell lines were infected with the HERV-MLV hybrid vectors and cell type-specific the expression of the reporter gene compared with the promoter specificity of the corresponding HERV LTRs in transient transfection assays. Transcription compared start site analysis of HERV-MLV hybrid vectors revealed preferential use of the HERV promoter initiation site. Our data show that cloned HERV LTRs function in the context of retroviral vectors in certain cell types and have the potential to be useful and as cell type-specific promoters in vector construction.
Nucleic Acids Res. 2009 Jul 15;: 19605564 (P,S,G,E,B,D)
The Terry Fox laboratory, British Columbia Cancer Agency, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada, Howard Hughes Medical Institute, Rheumatology Division, Washington University School of Medicine, St Louis, MO 63110, USA and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Stochastic activating expression is a hallmark of the Ly49 family that encode the main MHC class-I-recognizing receptors of mouse natural killer (NK)promoter cells. This highly polygenic and polymorphic family includes both activating and inhibitory receptor genes and is one of genome's fastest study evolving loci. The inhibitory Ly49 genes are expressed in a stochastic mono-allelic manner, possibly under the control of an upstream complex bi-directional early promoter and show mono-allelic DNA methylation patterns. To date, no studies have directly addressed the transcriptional regulation of regulatory the activating Ly49 receptors. Our study shows differences in DNA methylation pattern between activating and inhibitory genes in C57BL/6 and the F1 hybrid mouse strains. We also show a bias towards bi-allelic expression of the activating receptors based on allele-specific single-cell possibly RT-PCR in F1 hybrid NK cells for Ly49d and Ly49H expression in Ly49h(+/-) mice. Furthermore, we have identified a region have of high sequence identity with possible transcriptional regulatory capacity for the activating Ly49 genes. Our results also point to a with likely difference between NK and T-cells in their ability to transcribe the activating Ly49 genes. These studies highlight the complex studies regulation of this rapidly evolving gene family of central importance in mouse NK cell function.
Nat Methods. 2009 May ;6 (5):370-6 19404254 (P,S,G,E,B,D)
Developmental and Stem Cell Biology Program, Toronto, Ontario, Canada.
Induced expression pluripotent stem (iPS) cells may be of use in regenerative medicine. However, the low efficiency of reprogramming is a major Transposon impediment to the generation of patient-specific iPS cell lines. Here we report the first selection system for the isolation of stem human iPS cells. We developed the EOS (Early Transposon promoter and Oct-4 (Pou5f1) and Sox2 enhancers) lentiviral vector to specifically syndrome-specific express in mouse and human embryonic stem cells but not in primary fibroblasts. The bicistronic EOS vector marked emerging mouse germ and human iPS cell colonies with EGFP, and we used puromycin selection to aid the isolation of iPS cell lines we that expressed endogenous pluripotency markers. These lines differentiated into cell types from all three germ layers. Reporter expression was extinguished iPS upon differentiation and therefore monitored the residual pluripotent cells that form teratomas. Finally, we used EOS selection to establish Rett vector syndrome-specific mouse and human iPS cell lines with known mutations in MECP2.

Latest similar papers:

PLoS ONE. 2009 ;4 (6):e5761 19488400 (P,S,G,E,B,D)
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
The Interestingly, human neuronal apoptosis inhibitory protein (NAIP) gene is no longer principally considered a member of the Inhibitor of Apoptosis Protein that (IAP) family, as its domain structure and functions in innate immunity also warrant inclusion in the Nod-Like Receptor (NLR) superfamily.third NAIP is located in a region of copy number variation, with one full length and four partly deleted copies in exaptation the reference human genome. We demonstrate that several of the NAIP paralogues are expressed, and that novel transcripts arise from level both internal and upstream transcription start sites. Remarkably, two internal start sites initiate within Alu short interspersed element (SINE) retrotransposons,combines and a third novel transcription start site exists within the final intron of the GUSBP1 gene, upstream of only two We NAIP copies. One Alu functions alone as a promoter in transient assays, while the other likely combines with upstream L1 two sequences to form a composite promoter. The novel transcripts encode shortened open reading frames and we show that corresponding proteins cases are translated in a number of cell lines and primary tissues, in some cases above the level of full length repeats NAIP. Interestingly, some NAIP isoforms lack their caspase-sequestering motifs, suggesting that they have novel functions. Moreover, given that human and of mouse NAIP have previously been shown to employ endogenous retroviral long terminal repeats as promoters, exaptation of Alu repeats as that additional promoters provides a fascinating illustration of regulatory innovations adopted by a single gene.
BMC Genomics. 2009 Apr 24;10 (1):187 19393062 (P,S,G,E,B)
ABSTRACT:herbivore. BACKGROUND: The Type I interferons (IFN) have major roles in the innate immune response to viruses, a function that is Bos believed to have led to expansion in the number and complexity of their genes, although these genes have remained confined genes to single chromosomal region in all mammals so far examined. IFNB and IFNE define the limits of the locus, with have all other Type I IFN genes except IFNK distributed between these boundaries, strongly suggesting that the locus has broadened as exception IFN genes duplicated and then evolved into a series of distinct families. RESULTS: The Type I IFN locus in Bos and taurus has undergone significant rearrangement and expansion compared to mouse and human, however, with the constituent genes separated into two into sub-loci separated by >700 kb. The IFNW family is greatly expanded, comprising 24 potentially functional genes and at least 8 separated pseudogenes. The IFNB (n= 6), represented in human and mouse by one copy, are also present as multiple copies in genomes Bos taurus. The IFNT, which encode a non-virally inducible, ruminant-specific IFN secreted by the pre-implantation conceptus, are represented by three the genes and two pseudogenes. The latter have sequences intermediate between IFNT and IFNW. A new Type I IFN family (IFNX)to of four members, one of which is a pseudogene, appears to have diverged from the IFNA lineage at least 83 a million years ago, but is absent in all other sequenced genomes with the possible exception of the horse, a non-ruminant complexity herbivore. CONCLUSION: In summary, we have provided the first comprehensive annotation of the Type I IFN locus in Bos taurus,The thereby providing an insight into the functional evolution of the Type I IFN in ruminants. The diversity and global spread of of the ruminant species may have required an expansion of the Type I IFN locus and its constituent genes to of provide broad anti-viral protection required for foraging and foregut fermentation.
PLoS One. 2009 ;4 (4):e5179 19365549 (P,S,G,E,B,D)
Department of Medical Sciences, Section of Virology, Uppsala University, Uppsala, Sweden.
BACKGROUND:allowed Retroviral LTRs, paired or single, influence the transcription of both retroviral and non-retroviral genomic sequences. Vertebrate genomes contain many thousand and endogenous retroviruses (ERVs) and their LTRs. Single LTRs are difficult to detect from genomic sequences without recourse to repetitiveness or sensitive presence in a proviral structure. Understanding of LTR structure increases understanding of LTR function, and of functional genomics. Here we range, develop models of orthoretroviral LTRs useful for detection in genomes and for structural analysis. PRINCIPAL FINDINGS: Although mutated, ERV LTRs A are more numerous and diverse than exogenous retroviral (XRV) LTRs. Hidden Markov models (HMMs), and alignments based on them, were modular created for HML-(human MMTV-like), general-beta-, gamma- and lentiretroviruslike LTRs, plus a general-vertebrate LTR model. Training sets were XRV LTRs numerous and RepBase LTR consensuses. The HML HMM was most sensitive and detected 87% of the HML LTRs in human chromosome a 19 at 96% specificity. By combining all HMMs with a low cutoff, for screening, 71% of all LTRs found by inserted RepeatMasker in chromosome 19 were found. HMM consensus sequences had a conserved modular LTR structure. Target site duplications (TG-CA), TATA HMMs (occasionally absent), an AATAAA box and a T-rich region were prominent features. Most of the conservation was located in, or into adjacent to, R and U5, with evidence for stem loops. Several of the long HML LTRs contained long ORFs inserted and after the second A rich module. HMM consensus alignment allowed comparison of functional features like transcriptional start sites (sense and difficult antisense) between XRVs and ERVs. CONCLUSION: The modular conserved and redundant orthoretroviral LTR structure with three A-rich regions is reminiscent the of structurally relaxed Giardia promoters. The five HMMs provided a novel broad range, repeat-independent, ab initio LTR detection, with prospects three for greater generalisation, and insight into LTR structure, which may aid development of LTR-targeted pharmaceuticals.
J Virol. 2009 Jun ;83 (12):6098-105 19339349 (P,S,G,E,B,D)
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
Many complementary phenotypic differences exist between Homo sapiens and its closest relatives, chimpanzees, and these differences can arise as a result of presence variations in the regulation of certain genes common to these closely related species. Human-specific endogenous retroviruses (HERVs) and their solitary the long terminal repeats (LTRs) are probable candidates for such a role due to the presence of regulatory elements, such as genes. enhancers, promoters, splice sites, and polyadenylation signals. In this study we show for the first time that HERVs can participate promoters in the specific antisense regulation of human gene expression owing to their LTR promoter activity. We found that two HERV two LTRs situated in the introns of genes SLC4A8 (for sodium bicarbonate cotransporter) and IFT172 (for intraflagellar transport protein 172) in candidates the antisense orientation serve in vivo as promoters for generating RNAs complementary to the exons of enclosing genes. The antisense sites, transcripts formed from LTR promoter were shown to decrease the mRNA level of the corresponding genes. The human-specific regulation of vivo these genes suggests their involvement in the evolutionary process.
Mol Cell Biol. 2009 May ;29 (9):2456-68 19273603 (P,S,G,E,B,D)
Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, Canada.
Nonautonomous elements retrotransposon subfamilies are often amplified in preference to their coding-competent relatives. However, the mechanisms responsible for such replicative success are stem poorly understood. Here, we demonstrate that the autonomous MusD long terminal repeat (LTR) retrotransposons are subject to greater epigenetic silencing and than their nonautonomous cousins, the early transposons (ETns), which are expressed at a 170-fold-higher level than MusD in mouse embryonic coding-competent stem (ES) cells. We show that, in ES cells, 5' LTRs and the downstream region of MusD elements are more selection heavily methylated and are associated with less-activating and more-repressive histone modifications than the highly similar ETnII sequences. The internal region with of MusD likely contributes to their silencing, as transgenes with MusD, compared to those with ETnII sequences, show reduced reporter a gene expression and a higher level of repressive histone marks. Genomic distribution patterns of MusD and ETn elements are consistent LTRs with stronger selection against MusD elements within introns, suggesting that MusD-associated silencing marks can negatively impact genes. We propose a consistent model in which nonautonomous retrotransposons may gain transcriptional and retrotranspositional advantages over their coding-competent counterparts by elimination of the CpG-rich advantages retroviral sequence targeting the autonomous subfamilies for silencing.
Genetics. 2007 Dec ;177 (4):1975-85 18073417 (P,S,G,E,B,D) Cited:4
Transposable the elements (TEs) represent approximately 45% of the human genome and 50-90% of some grass genomes. While most elements contain inactivating technique mutations, others are reversibly inactivated (silenced) by epigenetic mechanisms, including cytosine methylation. Previous studies have shown that retrotransposons can influence called the expression of adjacent host genes. In this study, the methylation patterns of TEs and their flanking sequences in different methylation tissues were undertaken using a novel technique called transposon methylation display (TMD). TMD was successfully applied on a highly copied of ( approximately 1000 copies), newly amplified LTR retrotransposon family in rice called Dasheng. We determined that the methylation status of the a subset of LTRs varies in leaves vs. roots. In addition, we determined that tissue-specific LTR methylation correlated with tissue-specific sequences expression of the flanking rice gene. Genes showing tissue-specific expression were in opposite orientation relative to the LTR. Antisense transcripts highly were detected in the tissue where the sense transcripts from that gene were not detected. Comparative analysis of Dasheng LTR Comparative methylation in the two subspecies, japonica vs. indica revealed LTR-mediated differences in subspecies gene expression. Subspecies-specific expression was due either or to polymorphic Dasheng insertion sites between the two subspecies or to subspecies-specific methylation of LTRs at the same locus accounted differences for observed differences in the expression of adjacent genes.
Proc Natl Acad Sci U S A. 2007 Nov 5;: 17984064 (P,S,G,E,B,D) Cited:2
Dactylaplasia,of characterized by missing central digital rays, is an inherited mouse limb malformation that depends on two genetic loci. The first we locus, Dac, is an insertional mutation around the dactylin gene that is inherited as a semidominant trait. The second locus expresses is an unlinked modifier, mdac/Mdac, that is polymorphic among inbred strains. Mdac dominantly suppresses the dactylaplasia phenotype in mice carrying dactylaplasia Dac. However, little is known about either locus or the nature of their interaction. Here we show that Dac is not a LTR retrotransposon insertion caused by the type D mouse endogenous provirus element (MusD). This insertion exhibits different epigenetic states buds, and spatiotemporally expresses depending on the mdac/Mdac modifier background. In dactylaplasia mutants (Dac/+ mdac/mdac), the LTRs of the insertion contained about unmethylated CpGs and active chromatin. Furthermore, MusD elements expressed ectopically at the apical ectodermal ridge of limb buds, accompanying the D dactylaplasia phenotype. On the other hand, in Dac mutants carrying Mdac (Dac/+ Mdac/mdac), the 5' LTR of the insertion was Ectopic heavily methylated and enriched with inactive chromatin, correlating with inhibition of the dactylaplasia phenotype. Ectopic expression was not observed in correlates the presence of Mdac, which we refined to a 9.4-Mb region on mouse chromosome 13. We report a pathogenic mutation protect caused by MusD. Our findings indicate that ectopic expression from the MusD insertion correlates with the dactylaplasia phenotype and that either Mdac acts as a defensive factor to protect the host genome from pathogenic MusD insertions.
BMC Genomics. 2007 Aug 28;8 (1):291 17725822 (P,S,G,E,B)
ABSTRACT:role BACKGROUND: Retrotransposons have been shown to contribute to evolution of both structure and regulation of protein coding genes. It has evolutionary been postulated that the primary mechanism by which retrotransposons contribute to structural gene evolution is through insertion into an intron of or a gene flanking region, and subsequent incorporation into an exon. RESULTS: We found that Long Terminal Repeat (LTR) retrotransposons tracing are associated with 1,057 human genes (5.8%). In 256 cases LTR retrotransposons were observed in protein-coding regions, while 50 distinct the protein coding exons in 45 genes were comprised exclusively of LTR RetroTransposon Sequence (LRTS). We go on to reconstruct the a evolutionary history of an alternatively spliced exon of the Interleukin 22 receptor, alpha 2 gene (IL22RA2) derived from a sequence comprised of retrotransposon of the Mammalian apparent LTR retrotransposons (MaLR) family. Sequencing and analysis of the homologous regions of genomes of a several primates indicate that the LTR retrotransposon was inserted into the IL22RA2 gene at least prior to the divergence of in Apes and Old World monkeys from a common ancestor (roughly 25 MYA). We hypothesize that the recruitment of the part experimental of LTR as a novel exon in great ape species occurred prior to the divergence of orangutans and humans from strategy a common ancestor (roughly 14 MYA) as a result of a single mutation in the proto-splice site. CONCLUSIONS: Our analysis exclusively of LRTS exonization events has shown that the patterns of LRTS distribution in human exons support the hypothesis that LRTS to played a significant role in human gene evolution by providing cis-regulatory sequences. The important alternative way to contribute to the indicate evolution of gene structure and function, a direct incorporation of LTR sequences into protein coding regions was observed less frequently.LTR Combination of computational and experimental approaches used for tracing the history of the LTR exonization process of IL22RA2 gene presents ancestor a promising strategy that could facilitate further studies of transposon initiated gene evolution.
Nucleic Acids Res. 2007 Jul 7;: 17617638 (P,S,G,E,B,D) Cited:3
It in is generally assumed that transposable elements, including endogenous retroviruses (ERVs), are silenced by DNA methylation/chromatin structure in mammalian cells. However,HERV-E, there have been very few experimental studies to examine the methylation status of human ERVs. In this study, we determined unmethylated and compared the methylation status of the 5' long terminal repeats (LTRs) of different copies of the human endogenous retrovirus environment, (HERV) family HERV-E, which are inserted in various genomic contexts. We found that three HERV-E LTRs which function as alternative six gene promoters in placenta are unmethylated in that tissue but heavily methylated in blood cells, where these LTRs are not since active promoters. This difference is not solely due to global hypomethylation in placenta, since two general measures of methylation levels different of HERV-E and HERV-K LTRs suggest only 10-15% lower overall HERV methylation in placenta compared to blood. Comparisons between methylation three levels of the LTR-derived gene promoters and six random HERV-E LTRs in placenta showed that the former display significantly lower gene methylation levels than random LTRs. Moreover, the differences in methylation between LTRs cannot always be explained by their genomic environment,by since methylation of flanking sequences can be very different from methylation of the LTR itself.
Genetics. 2007 Apr 15;: 17435252 (P,S,G,E,B,D) Cited:7
Osaka University.
Massive of accumulation of retrotransposons, comprising more than 40% of human and mouse genomes, is one of the major events in the in evolution of the genome. However, most retrotransposons have lost retrotransposition-competency, which makes studying their role in genome evolution elusive. Intracisternal a A particle (IAP) elements are long terminal repeat (LTR)-type mouse retrotransposons consisting of full-length and internally-deleted types. Some are retrotransposition-competent Based and their upregulated activity has been reported in mutant mice deficient in genome defense systems, suggesting that IAP elements provide endogenous a unique platform for studying the interaction between retrotransposons and mammalian genomes. Using the IAP element as a model case,supplied here we show that mobilization of retrotransposons alters the mouse transcriptome. Retrotransposition assay in cultured cells demonstrated that a subset their of internally-deleted IAP elements, called IDelta1 type, retrotranspose efficiently when supplied with functional IAP proteins. Furthermore, the IDelta1 type IAP studying element exhibited substantial transcription inducing activity in the flanking region. Genome-wide transcript analysis of embryonic stem (ES) cells identified IAP-induced IAP transcripts, including fusion transcripts between IAP sequence and endogenous genes. Unexpectedly, nearly half of these IAP elements obtained from ES individual cells derived from 129 mouse strain were absent in the C57BL/6 genome, suggesting that IAP-driven transcription contributes to the unique of trait of individual mouse strain. Based on these data, we propose that retrotransposons are one of the drivers that shape upregulated the mammalian transcriptome.
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