bluuebunny/crossref_metadata_2025 huggingface dataset:
Hindlimb casting decreases muscle mass in part by proteasome-dependent proteolysis but independent of protein synthesis
Authors: Krawiec Brian J. , Frost Robert A. , Vary Thomas C. , Jefferson Leonard S. , Lang Charles H.
Published: July 2005

The hypothesis of the present study was that rats subjected to short-term unilateral hindlimb immobilization would incur skeletal muscle wasting and concomitant alterations in protein synthesis, controllers of translation, and indexes of protein degradation. Rats were unilaterally casted for 1, 3, or 5 days to avoid complications associated with other disuse models. In the casted limb, gastrocnemius wet weight decreased 12% after 3 days and thereafter remained constant. In contrast, the contralateral control leg displayed a steady growth rate over time. The rate of protein synthesis and translational efficiency were unchanged in the immobilized muscle at day 5. The total amount and phosphorylation state of regulators of translational initiation and elongation were unaltered. The mRNA contents of polyubiquitin and the ubiquitin ligases muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle RING finger 1 (MuRF1) were elevated in immobilized muscle at all time points, with peak expression occurring at day 3. Daily injection of the type II glucocorticoid receptor antagonist RU-486 did not prevent decreases in gastrocnemius wet weight nor increases in mRNA for MAFbx/Atrogin-1 and MuRF1. However, in vivo administration of the proteasome inhibitor Velcade prevented 53% of wet weight loss associated with 3 days of immobilization. These data suggest that the loss of skeletal muscle mass in this model of disuse appears to be glucocorticoid independent, can be partially rescued with a potent proteasome inhibitor, and is associated with enhanced mRNA expression of multiple factors that contribute to ubiquitin- proteasome-dependent degradation and are likely to control the remodeling of immobilized skeletal muscle during atrophy.
In vitro model of acute esophagitis in the cat
Authors: Cheng Ling , Cao Weibiao , Fiocchi Claudio , Behar Jose , Biancani Piero , Harnett Karen M.
Published: July 2005

We have shown that IL-1β and IL-6, possibly originating from the mucosa in response to injury, inhibit neurally mediated contraction of esophageal circular muscle but do not affect ACh-induced contraction, reproducing the effect of experimental esophagitis on esophageal contraction. To examine the interaction of mucosa and circular muscle in inflammation, we examined the effect of HCl on in vitro esophageal mucosa and circular muscle. Circular muscle strips, when directly exposed to HCl, contracted normally. However, when circular muscle strips were exposed to supernatants of mucosa incubated in HCl (2–3 h, pH 5.8), contraction decreased, and the inhibition was partially reversed by an IL-6 antibody. Supernatants from the mucosa of animals with in vivo-induced acute esophagitis (AE) similarly reduced contraction. IL-6 levels were higher in mucosal tissue from AE animals than in control mucosa and in AE mucosa supernatants than in normal mucosa supernatants. IL-6 levels increased significantly in normal mucosa and supernatants in response to HCl, suggesting increased production and release of IL-6 by the mucosa. IL-6 increased H2O2 levels in the circular muscle layer but not in mucosa. Exposure of the mucosa to HCl caused IL-1β to increase only in the mucosa and not in the supernatant. These data suggest that HCl-induced damage occurs first in the mucosa, leading to the production of IL-1β and IL-6 but not H2O2. IL-1β appears to remain in the mucosa. In contrast, IL-6 is produced and released by the mucosa, eventually resulting in the production of H2O2 by the circular muscle, with this affecting circular muscle contraction.
Cardiovascular responses to water drinking: does osmolality play a role?
Authors: Brown Clive M. , Barberini Luc , Dulloo Abdul G. , Montani Jean-Pierre
Published: July 2005

Water drinking activates the autonomic nervous system and induces acute hemodynamic changes. The actual stimulus for these effects is undetermined but might be related to either gastric distension or to osmotic factors. In the present study, we tested whether the cardiovascular responses to water drinking are related to water's relative hypoosmolality. Therefore, we compared the cardiovascular effects of a water drink (7.5 ml/kg body wt) with an identical volume of a physiological (0.9%) saline solution in nine healthy subjects (6 male, 3 female, aged 26 ± 2 years), while continuously monitoring beat-to-beat blood pressure (finger plethysmography), cardiac intervals (electrocardiography), and cardiac output (thoracic impedance). Total peripheral resistance was calculated as mean blood pressure/cardiac output. Cardiac interval variability (high-frequency power) was assessed by spectral analysis as an index of cardiac vagal tone. Baroreceptor sensitivity was evaluated using the sequence technique. Drinking water, but not saline, decreased heart rate ( P = 0.01) and increased total peripheral resistance ( P < 0.01), high-frequency cardiac interval variability ( P = 0.03), and baroreceptor sensitivity ( P = 0.01). Neither water nor saline substantially increased blood pressure. These responses suggest that water drinking simultaneously increases sympathetic vasoconstrictor activity and cardiac vagal tone. That these effects were absent after drinking physiological saline indicate that the cardiovascular responses to water drinking are influenced by its hypoosmotic properties.
NO-independent mechanism mediates tempol-induced renal vasodilation in SHR
Authors: de Richelieu Louise Tilma , Sorensen Charlotte Mehlin , Holstein-Rathlou Niels-Henrik , Salomonsson Max
Published: July 2005

We investigated whether tempol, a superoxide dismutase mimetic, affected renal hemodynamics and arterial pressure in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. We also examined whether tempol affected exaggerated renal vasoconstrictor responses to ANG II in SHR. To test whether the effects of tempol were due to a restored NO system, we used the NOS inhibitor Nw-nitro-l-arginine methyl ester (l-NAME). Renal blood flow (RBF) and mean arterial pressure (MAP) were measured in vivo by electromagnetic flowmetry and arterial catheterization in 10- to 12-wk-old anesthetized SHR and SD rats. Systolic arterial pressure (SAP) was measured in conscious rats using the tail cuff method. Tempol (1 mM) was given in the drinking water to SD (SD-T) and SHR (SHR-T) for 5–7 days for RBF measurements and for 15 days for SAP measurements. Age-matched SD (SD-C) and SHR (SHR-C) were used as controls. ANG II (1–4 ng) was administered as a bolus via a renal artery catheter. l-NAME was administered intravenously for 15–20 min. Renal vascular resistance (RVR) was elevated in SHR-C compared with SD-C. In SHR-T, baseline RVR was not different from SD-C and SD-T rats. Tempol had no effect on RVR in SD. l-NAME elevated RVR to the same extent in all four groups. Arterial pressure was not affected by tempol. The RVR responses to ANG II were higher in SHR-C than in the SD-C group. ANG II responses were not different between SHR-T and SD-T. Overall, tempol reduced the renovascular responses to ANG II in SHR. l-NAME elevated the effects of ANG II in SD-C rats but had no effect on the ANG II responses in the other groups. Thus l-NAME treatment did not influence tempol’s effects on baseline RVR or ANG II responses. We conclude that in SHR, tempol has a significant renal vasodilator effect and that it normalizes the increased renovascular ANG II sensitivity. As the effects of l-NAME are not greater in SHR-T rats, it is not likely that the elevated renal resistance and ANG II sensitivity in SHR are due to reactive oxygen species-induced quenching of nitric oxide.
Enhanced tubuloglomerular feedback in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension
Authors: Mitchell Kenneth D. , Mullins John J.
Published: July 2005

The present study was performed to evaluate tubuloglomerular feedback responses in transgenic rats [TGR(Cypa1a1Ren2)] with inducible malignant hypertension and to determine the degree to which feedback responsiveness is modulated by ANG II in these rats. Male Cyp1a1-Ren2 rats were fed a normal diet containing the aryl hydrocarbon indole-3-carbinol (I3C; 0.3%), for 5–6 days to stimulate expression of the Cyp1a1-Ren2 transgene and, thereby, to induce malignant hypertension. Stop-flow pressure (SFP) feedback responses to a late proximal perfusion rate of 40 nl/min were assessed in pentobarbital sodium-anesthetized rats during control conditions and after administration of the AT1 receptor antagonist candesartan (0.1 mg/kg iv). Rats induced with I3C ( n = 6) exhibited elevated mean arterial pressure and increased maximal SFP feedback responses compared with noninduced rats ( n = 4; 163 ± 4 vs. 130 ± 2 mmHg, P < 0.01 and 16.3 ± 1.4 vs. 11.7 ± 0.5 mmHg, P < 0.05, respectively). Systemic candesartan decreased arterial pressure (to 98 ± 7 and to 101 ± 5 mmHg, respectively, P < 0.001) and attenuated SFP feedback responses (to 2.0 ± 0.4 and to 3.3 ± 0.9 mmHg, respectively, P < 0.01) in both hypertensive and normotensive rats. In additional experiments, peritubular capillary infusion of 10−3 M candesartan did not alter arterial pressure but attenuated feedback responses in both hypertensive (19.3 ± 1.4 to 8.8 ± 0.9 mmHg, P < 0.01, n = 9) and normotensive Cyp1a1-Ren2 rats (9.0 ± 0.8 to 4.7 ± 0.6 mmHg, P < 0.01, n = 7). The present findings indicate that Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension exhibit augmented tubuloglomerular feedback responses. The data also show that AT1 receptor activation by ANG II contributes to the enhanced feedback responsiveness in Cyp1a1-Ren2 rats with malignant hypertension.
Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis
Authors: Schrage William G. , Wilkins Brad W. , Dean Vicki L. , Scott John P. , Henry Nancy K. , Wylam Mark E. , Joyner Michael J.
Published: July 2005

ATP released from circulating erythrocytes is a potential signal regulating muscle blood flow during exercise (exercise hyperemia), and intravascular ATP appears to blunt sympathetic vasoconstriction during exercise. Erythrocytes from patients with cystic fibrosis (CF) do not release ATP. The goal of the present study was to determine whether increases in forearm blood flow during exercise are blunted in CF patients and whether CF patients exhibit greater vasoconstrictor responsiveness during exercise. Nine control subjects and 10 CF patients who were free of other disease complications (∼96% O2 saturation) performed incremental rhythmic forearm exercise at 5, 10, and 15% of maximum handgrip strength for 21 min (7 min at each workload). We used a cold pressor test to evoke sympathetic vasoconstriction under resting conditions and at each exercise workload. As a control, subjects performed a second exercise bout without the cold pressor test. Continuous brachial artery blood velocity was monitored beat-to-beat, and vessel diameter was assessed by Doppler ultrasound. Artery diameter, as well as blood pressure, heart rate, and O2 saturation, was measured at steady-state exercise and at 1 min into the cold pressor stimulus. Blood pressure and heart rate responses to the forearm exercise and each cold pressor test were similar in both groups ( P > 0.05). Contrary to our hypothesis, forearm blood flow ( P = 0.91) and forearm vascular conductance ( P = 0.82) were similar at rest and at each level of exercise between CF patients and controls. Additionally, there was no difference in the degree of sympathetic vasoconstriction between groups at rest and at each level of exercise ( P = 0.22). Our results suggest that ATP released from the deformation of erythrocytes is not an obligatory signal for exercise hyperemia in human skeletal muscle.
Motor But Not Sensory Representation in Motor Cortex Depends on Postsynaptic Activity During Development and in Maturity
Authors: Chakrabarty Samit , Martin John H.
Published: July 2005

The movement representation in the primary motor cortex (M1) of the cat develops between postnatal weeks 7–12. The somatosensory representation in motor cortex is present by the age that the motor map begins to develop. In this study we examined the role of neural activity in development and maintenance of the M1 movement and somatosensory representations. We blocked activity of M1 neurons unilaterally for one month by intracortical infusion of the GABA agonist muscimol during the motor map development period in kittens and in mature cats. After the drug effects were no longer present, we used microstimulation and multiunit recording in the forelimb areas of M1 to determine the motor and somatosensory representations in the infused and noninfused sides. In both kittens and adults, there was a severe reduction or elimination of sites where microstimulation evoked a motor response in the inactivated compared with the control side. In contrast, there was no difference in the percentage, topography or receptive field modality of sites receiving somatosensory inputs on the inactivated and control sides. Moreover, the pattern of somatosensory input to M1 was similar before and after inactivation. This suggests that somatosensory input to M1 is stable after the connections initially develop. Since activity blockade had the same effects on the motor representation of kittens and adult cats, M1 neuronal activity, while possibly important in map development, is equally necessary for map maintenance.
GABAergic Signaling to Newborn Neurons in Dentate Gyrus
Authors: Wadiche Linda Overstreet , Bromberg Daniel A. , Bensen AeSoon L. , Westbrook Gary L.
Published: July 2005

Neurogenesis in the dentate gyrus begins before birth but then continues into adulthood. Consequently, many newborn granule cells must integrate into a preexisting hippocampal network. Little is known about the timing of this process or the characteristics of the first established synapses. We used mice that transiently express enhanced green fluorescent protein in newborn granule cells to examine their synaptic input. Although newborn granule cells had functional glutamate receptors, evoked and spontaneous synaptic currents were exclusively GABAergic with immature characteristics including slow rise and decay phases and depolarized reversal potentials. Synaptic currents in newborn granule cells were relatively insensitive to the GABAA receptor modulator zolpidem compared with neighboring mature granule cells. Consistent with the kinetics and pharmacology, newborn granule cells isolated by fluorescent cell sorting lacked the α1 GABAA receptor subunit. Our results indicate that newborn granule cells initially receive only GABAergic synapses even in the adult.
Cortical Representation of Space Around the Blind Spot
Authors: Awater Holger , Kerlin Jess R. , Evans Karla K. , Tong Frank
Published: July 2005

The neural mechanism that mediates perceptual filling-in of the blind spot is still under discussion. One hypothesis proposes that the cortical representation of the blind spot is activated only under conditions that elicit perceptual filling-in and requires congruent stimulation on both sides of the blind spot. Alternatively, the passive remapping hypothesis proposes that inputs from regions surrounding the blind spot infiltrate the representation of the blind spot in cortex. This theory predicts that independent stimuli presented to the left and right of the blind spot should lead to neighboring/overlapping activations in visual cortex when the blind-spot eye is stimulated but separated activations when the fellow eye is stimulated. Using functional MRI, we directly tested the remapping hypothesis by presenting flickering checkerboard wedges to the left or right of the spatial location of the blind spot, either to the blind-spot eye or to the fellow eye. Irrespective of which eye was stimulated, we found separate activations corresponding to the left and right wedges. We identified the centroid of the activations on a cortical flat map and measured the distance between activations. Distance measures of the cortical gap across the blind spot were accurate and reliable (mean distance: 6–8 mm across subjects, SD ∼1 mm within subjects). Contrary to the predictions of the remapping hypothesis, cortical distances between activations to the two wedges were equally large for the blind-spot eye and fellow eye in areas V1 and V2/V3. Remapping therefore appears unlikely to account for perceptual filling-in at an early cortical level.
What transposable elements tell us about genome organization and evolution: the case of Drosophila
Authors: Biémont C. , Vieira C.
Published: July 2005

Transposable elements (TEs) have been identified in every organism in which they have been looked for. The sequencing of large genomes, such as the human genome and those of Drosophila, Arabidopsis, Caenorhabditis, has also shown that they are a major constituent of these genomes, accounting for 15% of the genome of Drosophila, 45% of the human genome, and more than 70% in some plants and amphibians. Compared with the 1% of genomic DNA dedicated to protein-coding sequences in the human genome, this has prompted various researchers to suggest that the TEs and the other repetitive sequences that constitute the so-called “noncoding DNA”, are where the most stimulating discoveries will be made in the future (Bromham, 2002). We are therefore getting further and further from the original idea that this DNA was simply “junk DNA”, that owed its presence in the genome entirely to its capacity for selfish transposition. Our understanding of the structures of TEs, their distribution along the genomes, their sequence and insertion polymorphisms within genomes, and within and between populations and species, their impact on genes and on the regulatory mechanisms of genetic expression, their effects on exon shuffling and other phenomena that reshape the genome, and their impact on genome size has increased dramatically in recent years. This leads to a more general picture of the impact of TEs on genomes, though many copies are still mainly selfish or junk DNA. In this review we focus mainly on discoveries made in Drosophila, but we also use information about other genomes when this helps to elucidate the general processes involved in the organization, plasticity, and evolution of genomes.
LINEs, SINEs and processed pseudogenes: parasitic strategies for genome modeling
Authors: Dewannieux M. , Heidmann T.
Published: July 2005

Two major classes of retrotransposons have invaded eukaryotic genomes: the LTR retrotransposons closely resembling the proviral integrated form of infectious retroviruses, and the non-LTR retrotransposons including the widespread, autonomous LINE elements. Here, we review the modeling effects of the latter class of elements, which are the most active in humans, and whose enzymatic machinery is subverted to generate a large series of “secondary” retroelements. These include the processed pseudogenes, naturally present in all eukaryotic genomes possessing non-LTR retroelements, and the very successful SINE elements such as the human Alu sequences which have evolved refined parasitic strategies to efficiently bypass the original “protectionist” cis-preference of LINEs for their own retrotransposition.
Hybrid genome evolution by transposition
Authors: Fontdevila A.
Published: July 2005

Species hybridization is reviewed focusing on its role as a source of evolutionary novelties. Contrary to the view that hybrids are lineages devoid of evolutionary value, a number of case studies are given that show how hybrids are responsible for reticulate evolution that may lead to the origin of new species. Hybrid evolution is mediated by extensive genome repatterning followed by rapid stabilization and fixation of highly adapted genotypes. Some well-documented cases demonstrate that bursts of transposition follow hybridization and may contribute to the genetic instability observed after hybridization. The mechanism that triggers transposition in hybrids is largely unknown, but coupling of hybrid transposition and demethylation has been observed in mammals and plants. A natural scenario is proposed in which marginal small hybrid populations undergo transposition mediated genome reorganizations accompanied by exogenous and endogenous selection that, in concert with drift, lead to rapid fixation of high fitness hybrid genotypes. These genotypes may represent parental introgressed species or be entirely new species.
Clustering, duplication and chromosomal distribution of mouse SINE retrotransposons
Authors: Jurka J. , Kohany O. , Pavlicek A. , Kapitonov V.V. , Jurka M.V.
Published: July 2005

We analyzed potential mechanisms determining chromosomal distributions of the mouse B1 and B2 non-LTR retrotransposons, also known as SINE elements. We report that young B1 and B2 SINEs are underrepresented on chromosome X relative to autosomes, which is consistent with their integration in male germ lines. As the age of the SINE elements progresses, their densities on chromosome X increase relative to autosomal densities, possibly due to differences in ectopic recombination rates between chromosome X and autosomes. Furthermore, unlike young human Alus that tend to be integrated outside Alu-dense regions, young B1 and B2 elements are found mostly in SINE-rich clusters. The B1- or B2-rich clusters are more likely to contain duplicated elements than B1- or B2-poor chromosomal regions. We also present evidence indicating potential association of B1 and B2 elements with intra-chromosomal segmental duplications. No such association was found with inter-chromosomal duplications. We propose that the accumulation of mouse SINE elements observed in GC-rich regions may be due to the excess of DNA duplications over deletions in gene-rich regions that tend to be GC rich.
Heterochromatic distribution of HeT-A- and TART-like sequences in several Drosophila species
Authors: Berloco M. , Fanti L. , Sheen F. , Levis R.W. , Pimpinelli S.
Published: July 2005

Drosophila melanogaster telomeres contain arrays of two non-LTR retrotransposons called HeT-A and TART. Previous studies have shown that HeT-A- and TART-like sequences are also located at non-telomeric sites in the Y chromosome heterochromatin. By in situ hybridization experiments, we mapped TART sequences in the h16 region of the long arm close to the centromere of the Y chromosome of D. melanogaster. HeT-A sequences were localized in two different regions on the Y chromosome, one very close to the centromere in the short arm (h18-h19) and the other in the long arm (h13-h14). To assess a possible heterochromatic location of TART and HeT-A elements in other Drosophila species, we performed in situ hybridization experiments, using both TART and HeT-A probes, on mitotic and polytene chromosomes of D. simulans, D. sechellia, D. mauritiana, D. yakuba and D. teissieri. We found that TART and HeT-A probes hybridize at specific heterochromatic regions of the Y chromosome in all Drosophila species that we analyzed.
Retroelements: tools for sex chromosome evolution
Authors: Steinemann S. , Steinemann M.
Published: July 2005

Many eukaryotic taxa inherit a heteromorphic sex chromosome pair. It is a generally accepted hypothesis that the sex chromosome pair is derived from a pair of homologous autosomes that has developed after the occurrence of a sex differentiator in an evolutionary process into two structurally and functionally different partners. In most of the analyzed systems the occurrence of the dominant sex differentiator is paralleled by the suppression of recombination within and close by that region. The recombinational isolation can spread in an evolutionary selection process from neighboring regions finally over the whole chromosome. Suppression of recombination strongly biases the distribution of retrotransposons in the genome. Our results and that from others indicate that the major force driving the evolution of Y chromosomes are retrotransposons, remodeling euchromatic chromosome structures into heterochromatic ones. In our model, intact or already eroded retrotransposons become trapped due to their inherent transposition mechanisms in non-recombining regions. The massive accumulation of retrotransposons interferes strongly with the activity of genes. We hypothesize that Y chromosome degeneration is a stepwise evolutionary process: (1) Massive accumulation of retrotransposons occurs in the non-recombining regions. (2) Heterochromatic nucleation centers are formed as a consequence of genomic defense against invasive parasitic elements; the established nucleation centers become epigenetically inherited. (3) Spreading of heterochromatin from the nucleation centers into flanking regions induces in an adaptive process gene silencing of neighbored genes that could either be still intact or in an already eroded condition, e.g., showing point mutations, deletions, insertions; the retroelements should be subjects to the same forces of deterioration as the genes themselves. (4) Constitutive silenced genes are not committed to the same genetic selection pressure as active genes and therefore more exposed to the decay process. (5) Gene dosage balance is reestablished by the parallel evolution of dosage compensation mechanisms. The evolving secondary sex chromosomes, neo-X and neo-Y, of Drosophila miranda are revealed to be a unique and potent model system to catch the evolutionary Y deterioration process in progress.
I element distribution in mitotic heterochromatin of Drosophila melanogaster reactive strains: identification of a specific site which is correlated with the reactivity levels
Authors: Dimitri P. , Bucheton A.
Published: July 2005

The I factor is a Drosophila melanogaster LINE-like element that efficiently transposes in the genetic system of I-R hybrid dysgenesis. It has been suggested that some of the I-related sequences located in the heterochromatin of D. melanogaster are involved in the regulation of I factor activity. In this work we have performed fluorescent in situ hybridization (FISH) mapping of I element sequences in mitotic heterochromatin of nine differentially reactive D. melanogaster strains. The results of our analysis showed that a single hybridization site mapping to region h28 of the distal heterochromatin of the X chromosome is present in three strains with low or intermediate levels of reactivity, while it is undetectable in six highly reactive strains. Together, these observations suggest a negative correlation between I sequences located at h28 and the level of reactivity. To this regard, it is intriguing that flamenco and COM, two loci that regulate the activity of D. melanogaster endogenous retroviruses also map to the distal heterochromatin of the X chromosome. Our data represent the first experimental evidence in favour of a silencing effect exerted by naturally occurring I element sequences located in pericentromeric heterochromatin.
Transposable elements as artisans of the heterochromatic genome in Drosophila melanogaster
Authors: Dimitri P. , Corradini N. , Rossi F. , Mei E. , Zhimulev I.F. , Vernì F.
Published: July 2005

Over 50 years ago Barbara McClintock discovered that maize contains mobile genetic elements, but her findings were at first considered nothing more than anomalies. Today it is widely recognized that transposable elements have colonized all eukaryotic genomes and represent a major force driving evolution of organisms. Our contribution to this special issue deals with the theme of transposable element-host genome interactions. We bring together published and unpublished work to provide a picture of the contribution of transposable elements to the evolution of the heterochromatic genome in Drosophila melanogaster. In particular, we discuss data on 1) colonization of constitutive heterochromatin by transposable elements, 2) instability of constitutive heterochromatin induced by the I factor, and 3) evolution of constitutive heterochromatin and heterochromatic genes driven by transposable elements. Drawing attention to these topics may have direct implications on important aspects of genome organization and gene expression.
ERVK9, transposons and the evolution of MHC class I duplicons within the alpha-block of the human and chimpanzee
Authors: Kulski J.K. , Anzai T. , Inoko H.
Published: July 2005

The genomic sequences within the alpha-block (∼288–310 kb) of the human and chimpanzee MHC class I region contains ten MHC class I genes and three MIC gene fragments grouped together within alternating duplicated genomic segments or duplicons. In this study, the chimpanzee and human genomic sequences were analyzed in order to determine whether the remnants of the ERVK9 and other retrotransposon sequences are useful genomic markers for reconstructing the evolutionary history of the duplicated MHC gene families within the alpha-block. A variety of genes, pseudogenes, autologous DNA transposons and retrotransposons such as Alu and ERVK9 were used to categorize the ten duplicons into four distinct structural groups. The phylogenetic relationship of the ten duplicons was examined by using the neighbour joining method to analyze transposon sequence topologies of selected Alu members, LTR16B and Charlie9. On the basis of these structural groups and the phylogeny of the duplicated transposon sequences, a duplication model was reconstructed involving four multipartite tandem duplication steps to explain the organization and evolution of the ten duplicons within the alpha-block of the chimpanzee and human. The phylogenetic analysis and inferred duplication history suggests that the Patr/HLA-F was the first MHC class I gene to have been fixed and not required as a precursor for further duplication within the alpha-block of the ancestral species.
A comparative study of retrotransposons in the centromeric regions of A and B chromosomes of maize
Authors: Theuri J. , Phelps-Durr T. , Mathews S. , Birchler J.
Published: July 2005

Bacterial Artificial Chromosomes (BACs) derived from the B chromosome, based on homology with the B specific sequence, were subcloned and sequenced. Analysis of DNA sequence data indicated the presence of 23 common retroelements, as well as novel sequences of B chromosome origin. Generally, where the same retrotransposon type was observed in both A and B chromosomes, there were more copies per unit of sequence in the B centromeric region (the major site of B repeat) than in the A centromere, except for Huck-1. Based on previous estimates of the age of the major burst of transposition into the maize genome, the oldest retrotransposons (Ji-6 and Tekay, ∼5.0 and 5.2 million years ago, respectively) were found in the B centromere region only, while the next two oldest (Huck-1 and Opie-1) were found in both the A and B sequences. Phylogenetic analysis of Opie retroelements from both A and B centromeres indicated that some of the B Opie centromeric sequences share a more recent common ancestor with A Opie retroelements than they do with other B Opie centromeric sequences. These results imply that the supernumerary maize B chromosome has coexisted with the A chromosomes during that period of transposition. They also support the hypothesis that the B chromosome had its origins from A chromosome elements, or that alternative origins, such as being donated to the maize genome in a wide species cross, preceded six million years ago, because the spectrum of retrotransposons in the two chromosomes is quite similar.
Transcriptional interference mediated by retrotransposons within the genome of their host: lessons from alleles of the white gene from Drosophila melanogaster
Authors: Desset S. , Vaury C.
Published: July 2005

Systematic sequencing of model genomes has accelerated our knowledge on genome structure and shown that a large proportion of intergenic regions are made up of mobile element families. Among them, retrotransposons that are mobilized via an RNA intermediate and thus do not excise during their replication cycle are certainly essential factors able to imprint novel and heritable transcriptional regulation within the genome of their host. Today, a crucial complement to the systematic sequencing data is thus to elucidate the potential role of these elements in the regulation of nearby genes, and ultimately in the evolution of eukaryotic genomes.
Host defenses to transposable elements and the evolution of genomic imprinting
Authors: McDonald J.F. , Matzke M.A. , Matzke A.J.
Published: July 2005

Genomic imprinting is the differential expression of maternally and paternally inherited alleles of specific genes. Several organismic level hypotheses have been offered to explain the evolution of genomic imprinting. We argue that evolutionary explanations of the origin of imprinting that focus exclusively on the organismic level are incomplete. We propose that the complex molecular mechanisms that underlie genomic imprinting originally evolved as an adaptive response to the mutagenic potential of transposable elements (TEs). We also present a model of how these mechanisms may have been co-opted by natural selection to evolve molecular features characteristic of genomic imprinting.
APE-type non-LTR retrotransposons: determinants involved in target site recognition
Authors: Zingler N. , Weichenrieder O. , Schumann G.G.
Published: July 2005

Non-long terminal repeat (Non-LTR) retrotransposons represent a diverse and widely distributed group of transposable elements and an almost ubiquitous component of eukaryotic genomes that has a major impact on evolution. Their copy number can range from a few to several million and they often make up a significant fraction of the genomes. The members of the dominating subtype of non-LTR retrotransposons code for an endonuclease with homology to apurinic/apyrimidinic endonucleases (APE), and are thus termed APE-type non-LTR retrotransposons. In the last decade both the number of identified non-LTR retrotransposons and our knowledge of biology and evolution of APE-type non-LTR retrotransposons has increased tremendously.
Human endogenous retroviruses: from infectious elements to human genes
Authors: de Parseval N. , Heidmann T.
Published: July 2005

Mammalian genomes contain a heavy load (42% in humans) of retroelements, which are mobile sequences requiring reverse transcription for their replicative transposition. A significant proportion of these elements is of retroviral origin, with thousands of sequences resembling the integrated form of infectious retroviruses, with two LTRs bordering internal regions homologous to the gag, prt, pol, and env genes. These elements, named endogenous retroviruses (ERVs), are most probably the proviral remnants of ancestral germ-line infections by active retroviruses, which have thereafter been transmitted in a Mendelian manner. The complete sequencing of the human genome now allows a comprehensive survey of human ERVs (HERVs), which can be grouped according to sequence homologies into approximately 80 distinct families, each containing a few to several hundred elements. As reviewed here, strong similarities between HERVs and present-day retroviruses can be inferred from phylogenetic analyses on the reverse transcriptase (RT) domain of the pol gene or the transmembrane subunit (TM) of the env gene, which disclose interspersion of both classes of elements and suggest a common history and shared ancestors. Similarities are also observed at the functional levels, since despite the fact that most HERVs have accumulated mutations, deletions, and/or truncations, several elements still possess some of the functions of retroviruses, with evidence for viral-like particle formation, and occurrence of envelope proteins allowing cell-cell fusion and even conferring infectivity to pseudotypes. Along this line, a genomewide screening for human retroviral genes with coding capacity has revealed 16 fully coding envelope genes. These genes are transcribed in several healthy tissues including the placenta, three of them at a very high level. Besides their impact in modelling the genome, HERVs thus appear to contain still active genes, which most probably have been subverted by the host for its benefit and should be considered as bona fide human genes. Some of their characteristic features and possible physiological roles, as well as potential pathological effects inherited from their retroviral ancestors are also reviewed.
Impact of transposable elements on the evolution of mammalian gene regulation
Authors: Medstrand P. , van de Lagemaat L.N. , Dunn C.A. , Landry J.-R. , Svenback D. , Mager D.L.
Published: July 2005

Transposable elements (TEs) are present in all organisms and nearly half of the human and mouse genome is derived from ancient transpositions. This fact alone suggests that TEs have played a major role in genome organization and evolution. Studies undertaken over the last two decades or so clearly show that TEs of various kinds have played an important role in organism evolution. Here we review the impact TEs have on the evolution of gene regulation and gene function with an emphasis on humans. Understanding the mechanisms resulting in genomic change is central to our understanding of gene regulation, genetic disease and genome evolution. Full comprehension of these biological processes is not possible without an in depth knowledge of how TEs impact upon the genome.
Endogenous retroviruses and animal reproduction
Authors: Prudhomme S. , Bonnaud B. , Mallet F.
Published: July 2005

Endogenous retroviruses (ERV), as part of the host genetic heritage, are transmissible to the next generation in a Mendelian way. Their abundance in animal genomes and their expression primarily detected in germ cells, embryonic tissues and cancer cell lines, raised the question of their biological significance. This article reviews the possible role of ERVs in the physiology and diseases of animal reproduction, from Drosophila to human. In males, there is no trivial involvement of ERVs in a physiological process. Conversely, a spermatogenesis defect was associated in the human male with HERV-K expression and HERV15-induced chromosomal alteration, leading to cancer and infertility, respectively. In females, the study of insect ERVs (IERV) pointed out the overlap between genetics and virology with the genetic-dependent regulation of ZAM and the non-infectious and infectious life cycles of gypsy. The pattern of ERVs expression in rodent, ovine and human females suggest a hormone-dependent mechanism consistent with the mammalian oestrus cycle regulation. The differentiation of the mammary epithelium and breast tumorigenesis involving the mouse mammary tumour viruses (MMTV) illustrate the intimate connection between endogenous and exogenous retroviruses. Last, as a major site of ERVs transcription, placenta contributed to our understanding of ERVs modulation of neighbouring gene expression. As an interface, i.e. a site of conflicts and exchanges, placenta should resist infection and protect the foetus against the maternal immune system. Retroviral envelopes could theoretically provide such features due to receptor interference, immunosuppression and fusion properties, as shown by the HERV-W envelope involved in the syncytiotrophoblast formation. We conclude with an insight on the evolutionary and epigenetic consequences of the relationships of ERV guests with their animal hosts.
Evolutionary forces generating sequence homogeneity and heterogeneity within retrotransposon families
Authors: Brookfield J.F.Y.
Published: July 2005

Genome projects allow us to sample copies of a retrotransposon sequence family residing in a host genome. The variation in DNA sequence between these individual copies will reflect the evolutionary process that has spread the sequences through the genome. Here I review quantitatively the expected diversity of elements belonging to a transposable genetic element family. I use a simple neutral model for replicative mobile DNAs such as retrotransposons to predict the extent of sequence variability between members of a single family of transposable elements, both within and between species. The effects of horizontal transfer are also explored. I also consider the impact on these distributions of an increase in transposition rate arising from a mutational change in copy of the sequence. In addition, I consider the question of the interaction between retrotransposons and their hosts, and the causes of the abundance of transposable elements in the genomes that they occupy.
Ribonuclease H evolution in retrotransposable elements
Authors: Malik H.S.
Published: July 2005

Eukaryotic and prokaryotic genomes encode either Type I or Type II Ribonuclease H (RNH) which is important for processing RNA primers that prime DNA replication in almost all organisms. This review highlights the important role that Type I RNH plays in the life cycle of many retroelements, and its utility in tracing early events in retroelement evolution. Many retroelements utilize host genome-encoded RNH, but several lineages of retroelements, including some non-LTR retroposons and all LTR retrotransposons, encode their own RNH domains. Examination of these RNH domains suggests that all LTR retrotransposons acquired an enzymatically weak RNH domain that is missing an important catalytic residue found in all other RNH enzymes. We propose that this reduced activity is essential to ensure correct processing of the polypurine tract (PPT), which is an important step in the life cycle of these retrotransposons. Vertebrate retroviruses appear to have reacquired their RNH domains, which are catalytically more active, but their ancestral RNH domains (found in other LTR retrotransposons) have degenerated to give rise to the tether domains unique to vertebrate retroviruses. The tether domain may serve to control the more active RNH domain of vertebrate retroviruses. Phylogenetic analysis of the RNH domains is also useful to “date” the relative ages of LTR and non-LTR retroelements. It appears that all LTR retrotransposons are as old as, or younger than, the “youngest” lineages of non-LTR retroelements, suggesting that LTR retrotransposons arose late in eukaryotes.
The recent evolution of human L1 retrotransposons
Authors: Boissinot S. , Furano A.V.
Published: July 2005

L1 elements are the most successful retrotransposons in mammals and are responsible for at least 30% of human DNA. Far from being indolent genomic parasites, L1 elements have evolved and amplified rapidly during human evolution. Indeed during just the last 25 million years (MY) five distinct L1 families have emerged and generated tens of thousands of copies. The most recently evolved human specific L1 family is currently active and L1 copies have been accumulating in the human genome at about the same rate per generation as the currently active L1 families in Old World rats and mice. At times during the last 25 MY L1 activity constituted a significant enough genetic load to be subject to negative selection. During these same times, and in apparent response to the host, L1 underwent adaptive evolution. Understanding the molecular basis for these evolutionary changes should help illuminate one of the least understood but most important aspects of L1 biology, namely the extent and nature of the interaction between L1 and its host.
Extinction of LINE-1 activity coincident with a major mammalian radiation in rodents
Authors: Grahn R.A. , Rinehart T.A. , Cantrell M.A. , Wichman H.A.
Published: July 2005

LINE-1 transposable elements (L1s) are ubiquitous in mammals and are thought to have remained active since before the mammalian radiation. Only one L1 extinction event, in South American rodents in the genus Oryzomys, has been convincingly demonstrated. Here we examine the phylogenetic limits and evolutionary tempo of that extinction event by characterizing L1s in related rodents. Fourteen genera from five tribes within the Sigmodontinae subfamily were examined. Only the Sigmodontini, the most basal tribe in this group, demonstrate recent L1 activity. The Oryzomyini, Akodontini, Phyllotini, and Thomasomyini contain only L1s that appear to have inserted long ago; their L1s lack open reading frames, have mutations at conserved amino acid residues, and show numerous private mutations. They also lack restriction site-defined L1 subfamilies specific to any species, genus or tribe examined, and fail to form monophyletic species, genus or tribal L1 clusters. We determine here that this L1 extinction event occurred roughly 8.8 million years ago, near the divergence of Sigmodon from the remaining Sigmodontinae species. These species appear to be ideal model organisms for studying the impact of L1 inactivity on mammalian genomes.
Abundance, distribution and dynamics of retrotransposable elements and transposons: similarities and differences
Authors: Hua-Van A. , Le Rouzic A. , Maisonhaute C. , Capy P.
Published: July 2005

Retrotransposable elements and transposons are generally both found in most eukaryotes. These two classes of elements are usually distinguished on the basis of their differing mechanisms of transposition. However, their respective frequencies, their intragenomic dynamics and distributions, and the frequencies of their horizontal transfer from one species to another can also differ. The main objective of this review is to compare these two types of elements from a new perspective, using data provided by genome sequencing projects and relating this to the theoretical and observed dynamics. It is shown that the traditional division into two classes, based on the transposition mechanisms, becomes less obvious when other factors are taken into consideration. A great diversity in distribution and dynamics within each class is observed. In contrast, the impact on and the interactions with the genome can show striking similarities between families of the two classes.
Human endogenous retroviruses in the primate lineage and their influence on host genomes
Authors: Mayer J. , Meese E.
Published: July 2005

Primates emerged about 60 million years ago. Since that time various primate-targeting retroviruses have integrated in the germ line of primate species, and some drifted to fixation. After germ line fixation, continued activity of proviruses resulted in intragenomic spread of so-called endogenous retroviruses (ERVs). Variant ERVs emerged, amplified in the genome and profoundly altered genome structures and potentially functionality. Importantly, ERVs are genome modifiers of exogenous origin. The human genome contains about 8% of sequences of retroviral origin. The human ERVs (HERVs) comprise many distinct families that amplified to copy numbers of up to several thousand. We review here the evolution of several well-characterized HERV families in the human lineage since initial germ line fixation. It is apparent that endogenous retroviruses profoundly affected the genomes of species in the evolutionary lineage leading to Homo sapiens.
Transposable elements in mosquitoes
Authors: Boulesteix M. , Biémont C.
Published: July 2005

We describe the current state of knowledge about transposable elements (TEs) in different mosquito species. DNA-based elements (class II elements), non-LTR retrotransposons (class I elements), and MITEs (Miniature Inverted Repeat Transposable Elements) are found in the three genera, Anopheles, Aedes and Culex, whereas LTR retrotransposons (class I elements) are found only in Anopheles and Aedes. Mosquitoes were the first insects in which MITEs were reported; they have several LTR retrotransposons belonging to the Pao family, which is distinct from the Gypsy-Ty3 and Copia-Ty1 families. The number of TE copies shows huge variations between classes of TEs within a given species (from 1 to 1000), in sharp contrast to Drosophila, which shows only relatively minor differences in copy number between elements (from 1 to 100). The genomes of these insects therefore display major differences in the amount of TEs and therefore in their structure and global composition. We emphasize the need for more population genetic data about the activity of TEs, their distribution over chromosomes and their frequencies in natural populations of mosquitoes, to further the current attempts to develop a transgenic mosquito unable to transmit malaria that is intended to replace the natural populations.