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Results for “variable gene flow”

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PubMed2005

Population differentiation within and among Asian elephant (Elephas maximus) populations in southern India.

Southern India, one of the last strongholds of the endangered Asian elephant (Elephas maximus), harbours about one-fifth of the global population. We present here the first population genetic study of free-ranging Asian elephants, examining within- and among-population differentiation by analysing mitochondrial DNA (mtDNA) and nuclear microsatellite DNA differentiation across the Nilgiris-Eastern Ghats, Anamalai, and Periyar elephant reserves of southern India. Low mtDNA diversity and 'normal' microsatellite diversity were observed. Surprisingly, the Nilgiri population, which is the world's single largest Asian elephant population, had only one mtDNA haplotype and lower microsatellite diversity than the two other smaller populations examined. There was almost no mtDNA or microsatellite differentiation among localities within the Nilgiris, an area of about 15,000 km2. This suggests extensive gene flow in the past, which is compatible with the home ranges of several hundred square kilometres of elephants in southern India. Conversely, the Nilgiri population is genetically distinct at both mitochondrial and microsatellite markers from the two more southerly populations, Anamalai and Periyar, which in turn are not genetically differentiated from each other. The more southerly populations are separated from the Nilgiris by only a 40-km-wide stretch across a gap in the Western Ghats mountain range. These results variably indicate the importance of population bottlenecks, social organization, and biogeographic barriers in shaping the distribution of genetic variation among Asian elephant populations in southern India.

Animals↗
PubMed1997

Bernard-Soulier syndrome Karlstad: Trp 498-->Stop mutation resulting in a truncated glycoprotein Ib alpha that contains part of the transmembranous domain.

In Bernard-Soulier syndrome, a hereditary bleeding disorder, the platelets are deficient in the glycoprotein (GP) Ib-IX-V complex, a major receptor for the von Willebrand factor. The components of the complex are encoded by separate genes. Patients with this syndrome have a variable expression level of the receptor protein on platelets depending on the specific genetic abnormality. We describe a patient with life-long bleeding symptoms, who is homozygous for a unique stop mutation. Trp 498-->Stop in the GPIb alpha gene, resulting in a truncated GPIb alpha polypeptide chain. In contrast to previously reported truncated forms of GPIb alpha, this form contains a portion of the transmembranous domain as well as the juxtamembranous cysteines engaged in a disulphide bond with GPIb beta. Flow cytometry with GPIb alpha antibodies demonstrated the presence of GPIb on the patient's platelets, although in reduced amounts compared to normal controls. GPIX was similarly detectable. Immunoblotting demonstrated that the patient synthesized a truncated GPIb alpha of the expected size of 130 K, which was, however, sensitive to proteolysis. These studies show that GPIb alpha lacking the intracytoplasmic tail can be expressed at the platelet surface provided elements of the transmembranous domain are present.

Aged↗
PubMed2026

Cryptic serpentine divergence and substrate adaptation of Cardamine glauca in the Balkan Peninsula.

BACKGROUND AND AIMS: Serpentine soils represent one of the most challenging substrates for plant life due to skewed ratios of essential nutrients and toxic concentrations of metals. Plant adaptation to such conditions may lead to locally adapted edaphic ecotypes or, when reproductive barriers evolve, to distinct serpentine endemics. However, a third scenario may occur: cryptic edaphic divergence, where phenotypically similar lineages adapted to contrasting substrates exhibit deep genetic divergence. Here, we tested whether substrate-associated divergence reflects repeated serpentine adaptation or cryptic edaphic lineage divergence in Cardamine glauca (Brassicaceae) in Balkan peninsula - a hotspot of serpentine endemism in Europe. METHODS: We sampled and sequenced genomes of 43 individuals of C. glauca together with four individuals representing closely related taxa, C. plumieri and C. pancicii, from variable substrates across the Balkans. We combined phylogenomics, population genomic analyses of selection and a reciprocal transplant experiment to infer the most likely evolutionary scenario. KEY RESULTS: Phylogenomic analysis of 941 loci confirmed monophyly of C. glauca, including the local endemic C. pancicii, but revealed deep splits (∼2.2-3.2 Mya) between co-occurring serpentine and non-serpentine lineages. Population genomic analyses of replicated geographically proximate serpentine-non-serpentine population pairs demonstrated strong genome-wide differentiation and limited gene flow between edaphic types. Window-based analyses of local genomic divergence and tests for positive selection revealed candidate genes involved in ion transport, membrane transporter activity and metal homeostasis, consistent with the hypothesis of substrate-driven ecological adaptation. This was further supported by a significant substrate-of-origin fitness advantage in a reciprocal transplant experiment. CONCLUSIONS: Altogether, our results demonstrate that edaphic preferences may correspond with deep genetic divergence between similar-looking yet differently adapted lineages. The presence of cryptic edaphic lineages suggests that plant diversity may still be underestimated in genomically underexplored but edaphically diverse hotspots such as the Balkans.

Cardamine glauca↗
PubMed2006

The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis.

Understanding the molecular mechanism by which pluripotency is maintained in human embryonic stem cells (hESC) is important for the development of improved methods to derive, culture and differentiate these into cells of potential therapeutic use. Large-scale transcriptional comparison of the hES-NCL1 line derived from a day 8 embryo with H1 line derived from a day 5 embryo (WiCell Inc.) showed that only 0.52% of the transcripts analysed varied significantly between the two cell lines. This is within the variability range that has been reported when hESC derived from days 5-6 embryos have been compared with each other. This implies that transcriptional differences between the cell lines are likely to reflect their genetic profile rather than the embryonic stage from which they were derived. Bioinformatic analysis of expression changes observed when these cells were induced to differentiate as embryoid bodies suggested that quite a few of the downregulated genes were components of signal transduction networks. Subsequent analysis using western blotting, flow cytometry and antibody arrays implicated components of the PI3K/AKT kinase, MAPK/ERK and NFkappabeta pathways and confirmed that these components are decreased upon differentiation. Disruption of these pathways in isolation using specific inhibitors resulted in loss of pluripotency and/or loss of viability suggesting the importance of such signalling pathways in embryonic stem cell maintenance.

Cell Survival↗
PubMed1997

Selection of T lymphocytes bearing limited TCR-Vbeta regions in the lung of hypersensitivity pneumonitis and sarcoidosis.

Hypersensitivity pneumonitis (HP) and sarcoidosis are interstitial lung disorders (ILD) characterized by a lymphocytic alveolitis that, in the active phase of the disease, is sustained by different T-cell subsets, i.e., CD8+ cells in HP and CD4+ lymphocytes in sarcoid patients. To address the question of whether a bias in T-cell selection occurs in the lung of patients with HP and sarcoidosis, we analyzed the T-cell receptor beta chain variable region (TCR-Vbeta) repertoire by flow cytometry and polymerase chain reaction (PCR) analyses in blood and lung lymphocytes of 14 HP and 25 sarcoid patients. To verify whether these cells can be activated in vitro through the TCR, blood and lung lymphocytes were also assessed for their responsiveness to different superantigenic stimuli represented by staphylococcal enterotoxins, including SEA, SEB, SEC1, SEC2, SED, and SEE. Flow cytometry and PCR analyses demonstrated an overexpression of cells bearing Vbeta2, Vbeta3, Vbeta5, Vbeta6, and Vbeta8 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments were overrepresented in the lung rather than in the blood. Both in HP and sarcoid patients almost all T cells bearing the dominant Vbeta segment belonged to the T-cell subset that sustains the alveolitis, i.e., CD8 in HP patients and CD4 in sarcoid subjects. Follow-up studies demonstrated that the recovery of the alveolitis was characterized by the disappearance of cells bearing a limited T-cell repertoire. Interestingly, T-lymphocyte response to different superantigens demonstrated that the proliferation elicited by different staphylococcal toxins was more pronounced in the lung than in the blood. Taken together, our findings indicate a compartmentalization of cells bearing discrete Vbeta gene products in the pulmonary microenvironment and suggest that the expansion of specific Vbeta region subsets occurring in the lung might result from triggering by a specific antigen. In fact, the removal from exposure in HP patients or specific treatment in sarcoidosis resulted in the decrease of the overrepresented cell population accounting for the lymphocytic alveolitis.

Adult↗
PubMed2006

Intra-arterial adenoviral mediated tumor transfection in a novel model of cancer gene therapy.

BACKGROUND: The aim of the present study was to develop and characterize a novel in vivo cancer gene therapy model in which intra-arterial adenoviral gene delivery can be characterized. In this model, the rat cremaster muscle serves as the site for tumor growth and provides convenient and isolated access to the tumor parenchyma with discrete control of arterial and venous access for delivery of agents. RESULTS: Utilizing adenovirus encoding the green fluorescent protein we demonstrated broad tumor transfection. We also observed a dose dependent increment in luciferase activity at the tumor site using an adenovirus encoding the luciferase reporter gene. Finally, we tested the intra-arterial adenovirus dwelling time required to achieve optimal tumor transfection and observed a minimum time of 30 minutes. CONCLUSION: We conclude that adenovirus mediated tumor transfection grown in the cremaster muscle of athymic nude rats via an intra-arterial route could be achieved. This model allows definition of the variables that affect intra-arterial tumor transfection. This particular study suggests that allowing a defined intra-tumor dwelling time by controlling the blood flow of the affected organ during vector infusion can optimize intra-arterial adenoviral delivery.

Adenoviridae↗
PubMed2005

Flight behavior of methyl-parathion-resistant and -susceptible western corn rootworm (Coleoptera: Chrysomelidae) populations from Nebraska.

Relative flight behavior of methyl-parathion-resistant and -susceptible western corn rootworm, Diabrotica virgifera virgifera LeConte populations, was studied as part of a larger effort to characterize the potential impact of insecticide resistance on adult life history traits and to understand the evolution and spread of resistance. A computer interfaced actograph was used to compare flight of resistant and susceptible individuals, and flight of resistant individuals with and without prior exposure to methyl-parathion. In each case, mean trivial and sustained flight durations were compared among treatments. In general, there were few differences in trivial or sustained flight characteristics as affected by beetle population, insecticide exposure, sex, or age and there were few significant interactions among variables. Tethered flight activity was highly variable and distributions of flight duration were skewed toward flights of short duration. Tethered flight activity was similar among resistant and susceptible beetles with the exception that susceptible beetles initiated more flights per beetle than resistant beetles. After sublethal exposure to methyl-parathion, total flight time, total trivial flight time, and mean number of flights per resistant beetle declined significantly. Because long-range flight was uncommon, short- to medium-duration flights may play an important role in determining gene flow and population spread of resistant D. v. virgifera. These results suggest that organophosphate-resistant beetles can readily move and colonize new areas, but localized selection pressure (e.g., management practices) and exposure to methyl-parathion may contribute to the small-scale differences in resistance intensity often seen in the field.

Animals↗
PubMed1998

Microgeographic genetic differentiation of Anopheles gambiae mosquitoes from Asembo Bay, western Kenya: a comparison with Kilifi in coastal Kenya.

Microgeographic differentiation in Anopheles gambiae from seven villages less than 10 km apart in Asembo Bay, western Kenya was estimated by analysis of variability in seven microsatellite loci. Results from the Asembo Bay villages were compared with specimens collected in Kilifi, coastal Kenya, 700 km to the east. Allele frequency distribution was very similar in all villages in Asembo Bay, but differed for the Kilifi population. Genetic differentiation among villages was low with loci-specific Fst falling within the range of 0.0000-0.0085. These low estimates of differentiation correspond to among-village migration indices greater than 5.66, suggesting a high level of gene flow within the Asembo population. The Nm value between Kilifi and Asembo Bay was 1.54, indicating much lower levels of gene flow. Average observed heterozygosity among the seven villages was in all but one case less than the expected heterozygosity, most likely indicating the presence of null alleles, but possibly the presence of randomly mating units (demes) smaller than the village. We conclude that there is likely no genetic structure at the level of the village in Asembo Bay but that gene flow is restricted between western and coastal Kenya, probably by the high elevation rift.

Alleles↗
PubMed1997

Relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma.

Atopic asthma is characterized by chronic inflammation of the bronchial mucosa in which eosinophil- and immunoglobulin E (IgE)-dependent mechanisms are believed to be prominent. Therefore, specific proeosinophilic mediators such as interleukin (IL)-5 and essential cofactors for IgE switching in B-lymphocytes such as IL-4 could play a pivotal role in asthma. However, the exact role that individual inflammatory mediators play in the development of the disease in humans is still unknown. Using semiquantitative reverse transcriptase-polymerase chain reaction amplification in bronchial biopsies from 10 atopic asthmatics, we have tested the hypothesis that IL-4 and IL-5 mRNA expression relative to beta-actin mRNA correlates with validated indicators of disease severity. IL-4 and IL-5 mRNA copies relative to beta-actin mRNA were detected in bronchial biopsies from atopic asthmatics. The numbers of IL-5 mRNA copies relative to beta-actin mRNA correlated with disease severity assessed by the Aas asthma score (r = 0.70, p = 0.01), baseline FEV1 (r = -0.94, p = 0.001), baseline peak expiratory flow rate (r = -0.77, p = 0.01), peak expiratory flow rate variability over 2 wk (r = 0.69, p = 0.028), and the histamine PC20 (r = -0.72, p = 0.018). Conversely, the numbers of IL-4 mRNA copies relative to beta-actin mRNA did not correlate with asthma severity, but they positively correlated with total serum IgE concentrations (r = -0.90, p = 0.001). Our present results support the concept that IL-5 may determine asthma clinical expression and severity, and by inference they support the development of IL-5 targeted therapies.

Asthma↗
PubMed1989

Identification of T-cell receptor V beta deletion mutant mouse strain AU/ssJ (H-2q) which is resistant to collagen-induced arthritis.

Our laboratory is involved in investigating the role of T-cell receptor (Tcr) in collagen-induced arthritis (CIA). During these studies we found AU/ssJ (H-2q) mice to be resistant to CIA like SWR (H-2q), as compared with other H-2q strains with wild-type Tcr like DBA/1 and B10.Q. Upon screening with monoclonal antibodies F23.1 and KJ23a, AU/ssJ was found to be F23.1 negative (V beta 8 Tcr negative) and KJ23a positive (V beta 17a Tcr positive). Southern blot analysis on liver DNA using specific Tcr-V beta probes confirmed the deletion of V beta 8 gene family and also showed that AU/ssJ mice have deletions of V beta 9, V beta 13, V beta 12, and V beta 11 genes of Tcr. Further, these mice show a restriction fragment length polymorphism pattern with V beta 10, V beta 6, and V beta 17 probes similar to SWR mice as compared with B10 mice. Since SWR and AU/ssJ are from different backgrounds, these studies indicate that specific variable region beta chain genes of Tcr are crucial for susceptibility to CIA in mice. Furthermore, these studies identify an additional inbred strain which has also deleted 50% of its Tcr-V beta genes.

Animals↗
PubMed2004

Control of stochasticity in eukaryotic gene expression.

Noise, or random fluctuations, in gene expression may produce variability in cellular behavior. To measure the noise intrinsic to eukaryotic gene expression, we quantified the differences in expression of two alleles in a diploid cell. We found that such noise is gene-specific and not dependent on the regulatory pathway or absolute rate of expression. We propose a model in which the balance between promoter activation and transcription influences the variability in messenger RNA levels. To confirm the predictions of our model, we identified both cis- and trans-acting mutations that alter the noise of gene expression. These mutations suggest that noise is an evolvable trait that can be optimized to balance fidelity and diversity in eukaryotic gene expression.

Acid Phosphatase↗
PubMed2004

Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat.

Calcitonin gene-related peptide (CGRP) is believed to play a pivotal role in the pathogenesis of migraine via activation of CGRP receptors in the trigeminovascular system. The CGRP receptor antagonist, BIBN4096BS, has proven efficacy in the acute treatment of migraine attacks and represents a new therapeutic principle. We used an improved closed cranial window model to measure changes of the middle meningeal artery (MMA) and cortical pial artery/arteriole diameter (PA) and changes in local cortical cerebral blood flow (LCBF(Flux)) in anaesthetised artificially ventilated rats. The ability of BIBN4096BS (i.v.) to prevent the vasodilatatory actions of rat-alphaCGRP, betaCGRP and endogenously released CGRP following transcranial electrical stimulation (TES) was investigated. BIBN4096BS was per se without vasoactive effect on any of the measured variables and significantly inhibited the hypotension induced by both types of CGRP (P < 0.001). The alphaCGRP induced MMA dilatation was reduced from 97.4 +/- 14 to 2.1 +/- 1.3% (P < 0.001) and the betaCGRP induced dilatation was fully blocked by BIBN4096BS. ID(50) was 5.4 +/- 1.6 microg kg(-1) for alphaCGRP and 16.3 +/- 1.6 microg kg(-1) for betaCGRP. Transcranial electrical stimulation induced a 119.1 +/- 6.9% increase in MMA diameter. BIBN4096BS (333 microg kg(-1)) attenuated this increase (19.8 +/- 2.1%) (P < 0.001). Systemic CGRP and TES induced an increase in PA diameter that was not significantly inhibited by BIBN4096BS. The CGRP induced increase in LCBF(Flux) was similar not prevented by the antagonist. We suggest that systemic BIBN4096BS exerts its inhibitory action mainly on large dural blood vessels (MMA).

Animals↗
PubMed1999

Hypermutation targets a green fluorescent protein-encoding transgene in the presence of immunoglobulin enhancers.

Hypermutation introduces point mutations into the gene segments encoding immunoglobulin variable regions at a rate that is a million-fold higher than the spontaneous mutation rate in most of the genome. Because Ig enhancers are required to target hypermutation, transcription appears to play a critical role for the hypermutation mechanism. We have developed a novel system for detecting mutations that enables us to determine the influence of expression levels on the mutability of a transgene. This system utilizes a green fluorescent protein receptor gene and the powerful enumeration and quantification properties of flow cytometry. We have tested this system with several constructs bearing Ig enhancers in cell lines with active and inactive hypermutation systems.

Cell Line↗
PubMed1986

Genetic variability and differentiation of natural populations in three Japanese lung flukes, Paragonimus ohirai, Paragonimus iloktsuenensis and Paragonimus sadoensis (Digenea: Troglotrematidae).

The genetic differences among 3 closely related species, Paragonimus ohirai, Paragonimus iloktsuenensis and Paragonimus sadoensis, were assessed by electrophoretic analysis of allozymes. Fifteen enzymes were analyzed using starch gel electrophoresis. Seven of 18 loci were polymorphic. The most variable population (POs) was polymorphic at 6 of the loci (P = 0.333) with a heterozygosity H of 0.054. Genetic distances between P. ohirai and P. iloktsuenensis, between P. ohirai and P. sadoensis, and between P. iloktsuenensis and P. sadoensis were, on the average, 0.0375, 0.0809 and 0.0567, respectively; values which are well within the usual range for conspecific populations. An especially low estimate of genetic distance was obtained between sympatric populations of P. ohirai and P. iloktsuenensis (0.00059) in Sendai, indicating that gene flow occurred between the 2 species.

Animals↗
PubMed2000

Gene delivery to hypoxic cells in vitro.

Hypoxia in solid tumours has been correlated with poor prognosis and resistance to radiation and chemotherapy. Hypoxia is also a strong stimulus for gene expression. We previously proposed a gene therapy approach which exploits the presence of severe hypoxia in tumours for the induction of therapeutic genes. Hypoxic cells are known to have a reduced metabolic rate, transcription and translation. These facts may prevent gene transfer and therefore warranted further investigation. In this paper the feasibility of gene delivery in vitro under tumour conditions was demonstrated. DNA was delivered in vitro using a peptide-mediated non-viral system. Across a range of oxygen tensions and mammalian cell lines (including human tumour and endothelial cells) it was shown that hypoxic cells could be transfected. Transfection efficiencies varied depending on the level of hypoxia, cell characteristics and gene promoters used. An in vitro model of hypoxia/reoxygenation, designed to mimic the variable nature of tumour hypoxia, showed that hypoxic preconditioning and reoxygenation alone did not reduce transfection efficiency significantly; only chronic anoxia reduced transfection. The fact that neither intermediate hypoxia nor intermittent anoxia significantly reduced transfection is promising for future hypoxia-targeted gene therapy strategies.

Animals↗
PubMed2006

Noise in protein expression scales with natural protein abundance.

Noise in gene expression is generated at multiple levels, such as transcription and translation, chromatin remodeling and pathway-specific regulation. Studies of individual promoters have suggested different dominating noise sources, raising the question of whether a general trend exists across a large number of genes and conditions. We examined the variation in the expression levels of 43 Saccharomyces cerevisiae proteins, in cells grown under 11 experimental conditions. For all classes of genes and under all conditions, the expression variance was approximately proportional to the mean; the same scaling was observed at steady state and during the transient responses to the perturbations. Theoretical analysis suggests that this scaling behavior reflects variability in mRNA copy number, resulting from random 'birth and death' of mRNA molecules or from promoter fluctuations. Deviation of coexpressed genes from this general trend, including high noise in stress-related genes and low noise in proteasomal genes, may indicate fluctuations in pathway-specific regulators or a differential activation pattern of the underlying gene promoters.

Flow Cytometry↗
PubMed2003

Habitat preference and the marine-speciation paradox.

Marine organisms challenge the classical theories of local adaptation and speciation because their planktonic larvae have the potential to maintain high gene flow. The marine-speciation paradox is illustrated by contact zones between incipient species that are so large that allopatric divergence seems unlikely. For this reason any mechanism preventing sympatric larvae of two incipient species from coexisting in the same habitats can be a powerful promoter of speciation. The contact zone between two hybridizing taxa of mussel, Mytilus edulis and M. galloprovincialis, in Europe provides an excellent example. Although the zone itself extends over thousands of kilometres, the opportunities for interbreeding are considerably reduced by the small-scale mosaic structure of the zone, where local patches of each taxon alternate at scales of kilometres or less, in response to locally variable ecological factors. Habitat choice by settling larvae would be a less costly mechanism than post-settlement selection to maintain such a mosaic structure. Unfortunately the role of selective settlement has remained hypothetical because larvae could not be scored by classical genetic markers. PCR markers allowed us to study larvae and settlement in ecologically contrasting sites within the zone. We show that only a subset of the genotypes present in the plankton settle in some sites, and that the adults on these sites show the same genetic bias. Genetically based variation in pre-settlement processes therefore accounts for the ecological segregation observed, though it is not the only factor involved in limiting successful interbreeding. The present dataset also supports previous reports of partial spawning asynchrony.

Animals↗
PubMed1987

Contrasting patterns of geographic variation in the cosmopolitan sibling species Drosophila melanogaster and Drosophila simulans.

An electrophoretic study was carried out to compare the geographic pattern of genetic variation in Drosophila simulans with that of its sibling species, Drosophila melanogaster. An identical set of 32 gene-protein loci was studied in four geographically distant populations of D. simulans and two populations of D. melanogaster, all originating from Europe and Africa. The comparison yielded the following results: tropical populations of D. simulans were, in terms of the number of unique alleles, average heterozygosity per locus, and percentage of loci polymorphic, more variable than conspecific-temperate populations; some loci in both species showed interpopulation differences in allele frequencies that suggest latitudinal clines; and temperate-tropical genetic differentiation between populations was much less in D. simulans than in D. melanogaster. Similar differences between these two species have previously been shown for chromosomal, quantitative, physiological, and middle-repetitive DNA variation. Estimates of Nm (number of migrants per generation) from the spatial distribution of rare alleles suggest that both species have similar levels of interpopulation gene flow. These observations lead us to propose two competing hypotheses: the low level of geographic differentiation in D. simulans is due to its evolutionarily recent worldwide colonization and, alternatively, D. simulans has a narrower niche than D. melanogaster. Geographic variation data on different genetic elements (e.g., mitochondrial DNA, two-dimensional proteins, etc.) are required before these hypotheses can be adequately tested.

Animals↗