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PubMed1989

Mutation rates differ among regions of the mammalian genome.

In the traditional view of molecular evolution, the rate of point mutation is uniform over the genome of an organism and variation in the rate of nucleotide substitution among DNA regions reflects differential selective constraints. Here we provide evidence for significant variation in mutation rate among regions in the mammalian genome. We show first that substitutions at silent (degenerate) sites in protein-coding genes in mammals seem to be effectively neutral (or nearly so) as they do not occur significantly less frequently than substitutions in pseudogenes. We then show that the rate of silent substitution varies among genes and is correlated with the base composition of genes and their flanking DNA. This implies that the variation in both silent substitution rate and base composition can be attributed to systematic differences in the rate and pattern of mutation over regions of the genome. We propose that the differences arise because mutation patterns vary with the timing of replication of different chromosomal regions in the germline. This hypothesis can account for both the origin of isochores in mammalian genomes and the observation that silent nucleotide substitutions in different mammalian genes do not have the same molecular clock.

Animals↗
PubMed1989

Inversion polymorphisms in Trimerotropis pallidipennis (Orthoptera): clinical variation along an altitudinal gradient.

Six populations of Trimerotropis pallidipennis located along an altitudinal gradient in the Antinaco-Los Colorados valley (La Rioja, Argentina), were cytologically analysed. The male karyotype consists of 23 chromosomes (22 + XO) with three long pairs submetacentric, the X-chromosome metacentric and the remaining ones basically acrocentric. Populations from La Rioja were polymorphic for seven pericentric inversions. Correlations between chromosome frequencies and altitude were statistically tested. In most cases, variables were either positively or negatively related in a significant fashion. As a consequence, mean populational heterozygosis (measured as the mean number of heteromorphic bivalents per individual per population) was also positively correlated with altitude. These results suggest that altitude (or other correlated environmental variable) may exert a differential selective pressure on coadapted gene blocks in the mutually inverted sequences. The possible relation of these results with the central-marginal model is discussed.

Altitude↗
PubMed1994

Heritabilities for antler characteristics and body weight in yearling white-tailed deer.

Heritabilities for two body weights and five antler characteristics were estimated for a captive white-tailed deer (Odocoileus virginianus) herd maintained by the Texas Parks and Wildlife Department. Single male breeding pens with 10-14 female deer were used for five consecutive generations. To minimize selection and maintain a broad genetic base, different sets of sires and as many different dams as possible were randomly assigned as breeders each generation. All deer were accurately predigreed by sire and dam and, except for birth weight, traits were measured at 1.5 years of age. Heritabilities were estimated utilizing (1) sire and within-sire components of variance, and (2) regression of male progeny performance on sire performance. Theoretically, these procedures estimate the amount of additive genetic variance present in a population without indication of non-additive genetic (dominance and epistasis) and maternal effects. Heritabilities ranged from 0.00-0.17 (birth weight), 0.58-0.64 (body weight), 0.22-0.56 (antler points), 0.47-0.70 (main beam length), 0.03-0.43 (antler spread), 0.80-0.89 (basal circumference) and 0.71-0.86 (antler weight). These heritabilities, except for birth weight, suggest that substantial genetic change could be expected from individual selection if realistic selection differentials were used.

Animals↗
PubMed1997

Recent advances in understanding of vanilloid receptors: a therapeutic target for treatment of pain and inflammation in skin.

C-fiber sensory afferent neurons, which contain neuropeptides such as calcitonin-gene related peptide and substance P, mediate a wide variety of physiologic responses, including chemogenic pain, thermoregulation, and neurogenic inflammation. Capsaicin, the pungent constituent in red pepper, functions to activate and then, at higher doses and longer times, desensitize this class of neurons. This latter response provides the basis for the therapeutic application of capsaicin. A major advance in the field has been the identification of resiniferatoxin, a phorbol-related diterpene, as an analog of capsaicin that is ultrapotent but with differential selectivity. In particular, resiniferatoxin is only similar in potency for induction of pain but is much more effective for desensitization. Structure-activity analysis in whole animal experiments provides further evidence for dissociation of biologic endpoints, strongly arguing for the existence of vanilloid receptor subclasses. Using resiniferatoxin, we have been able to define specific, high-affinity receptors for capsaicin both in animal models such as rats and in man. Of great importance, the pharmacologic characterization in cultured dorsal root ganglion cells of the high-affinity resiniferatoxin-binding site and of the physiologic response believed to be directly coupled to the receptor, viz. calcium uptake, differed in structure-activity and in cooperativity. We conclude that multiple high-affinity vanilloid receptor subclasses mediate vanilloid response; moreover, the resiniferatoxin-selective subclass of vanilloid receptors is not the voltage-independent, cation-nonselective ion channel as previously believed. Optimization of ligands for the individual vanilloid receptor subclasses should revolutionize this therapeutic area.

Animals↗
PubMed2004

Signaling by the kinase MINK is essential in the negative selection of autoreactive thymocytes.

Signaling through the T cell antigen receptor leading to elimination (negative selection) or differentiation (positive selection) of developing thymocytes generates a self-tolerant T cell repertoire. Here we report that the serine-threonine kinase MINK selectively connects the T cell receptor to a signaling pathway that mediates negative but not positive selection. Analysis of this pathway suggested that the essential function of MINK in the elimination of self-reactive thymocytes may be associated with 'downstream' activation of Jun kinase and enhancement of expression of the proapoptotic molecule Bim.

Animals↗
PubMed2001

Contrasting evolution of the human leukocyte N-formylpeptide receptor subtypes FPR and FPRL1R.

N-formylpeptides are phagocyte chemoattractants that act by binding to two structurally related receptors, FPR (formylpeptide receptor) and FPRL1R (FPR-like-1 receptor), which are encoded by the human genes FPR1 and FPRL1. Single nucleotide polymorphisms (SNPs) in the FPR coding region have been reported and two have been associated with the disease juvenile periodontitis; however, their frequency and linkage relationships are unknown. Here we systematically analyzed polymorphism in the open reading frames of FPR1 and FPRL1 by direct sequencing of cloned alleles from random blood donors from North America. For FPR1 we detected five non-synonymous SNPs and two synonymous SNPs in a sample of 26 chromosomes one each from 17 Caucasian and nine black random blood donors. Although all five non-synonymous SNPs were common in Caucasians, Blacks, and Asians, notable differences in allele frequency were found for each SNP in the different racial groups, suggesting differential selective pressures. We found that the FPR1 polymorphisms are linked in 15 common haplotypes. No polymorphisms were detected in FPRL1 after sampling 44 chromosomes from 36 random blood donors from the same three racial groups. Thus FPR1 and FPRL1, though they originated from a common gene, appear to have undergone markedly different evolutionary events.

Amino Acid Sequence↗
PubMed2004

Landscape genetics of alpine-snowbed plants: comparisons along geographic and snowmelt gradients.

The genetic structure of three snowbed-herb species (Peucedanum multivittatum, Veronica stelleri, and Gentiana nipponica) was analyzed using allozymes across nine populations arranged as a matrix of three snowmelt gradients x three geographic locations within 3 km in the Taisetsu Mountains, northern Japan. Phenologically asynchronous populations are packed within a local area in alpine snowbeds, because flowering season of alpine plants depends strongly on the timing of snowmelt. Moderate genetic differentiation was detected among local populations in every species (FST=0.03-0.07). There was a significant correlation between the geographic distance and genetic distance in the P. multivittatum populations, but not in the V. stelleri and G. nipponica populations. On the other hand, a significant correlation between the phenological distance caused by snowmelt timing and genetic distance was detected in the V. stelleri and G. nipponica populations, but not in the P. multivittatum populations. The snowmelt gradient or geographic separation influenced hierarchical genetic structure of these species moderately (FRT <0.04). Restriction of gene flow due to phenological separation and possible differential selection along the snowmelt gradient may produce genetic clines at microgeographic scale in these species.

Enzymes↗
PubMed2005

Comparing Bayesian estimates of genetic differentiation of molecular markers and quantitative traits: an application to Pinus sylvestris.

Comparison of the level of differentiation at neutral molecular markers (estimated as F(ST) or G(ST)) with the level of differentiation at quantitative traits (estimated as Q(ST)) has become a standard tool for inferring that there is differential selection between populations. We estimated Q(ST) of timing of bud set from a latitudinal cline of Pinus sylvestris with a Bayesian hierarchical variance component method utilizing the information on the pre-estimated population structure from neutral molecular markers. Unfortunately, the between-family variances differed substantially between populations that resulted in a bimodal posterior of Q(ST) that could not be compared in any sensible way with the unimodal posterior of the microsatellite F(ST). In order to avoid publishing studies with flawed Q(ST) estimates, we recommend that future studies should present heritability estimates for each trait and population. Moreover, to detect variance heterogeneity in frequentist methods (ANOVA and REML), it is of essential importance to check also that the residuals are normally distributed and do not follow any systematically deviating trends.

Bayes Theorem↗
PubMed1996

The method of deriving human T-cell clones alters the proportion of IL-10-producing cells.

It is now well documented that the mode of primary stimulation in the mouse determines the ratio of Th1-, Th0- or Th2-type T cells obtained. In this paper we determine whether driving and cloning human peripheral blood mononuclear cells (PBMC) non-specifically with interleukin-2 (IL-2) and/or IL-4 and mitogen, will differentially select T cells for IL-10 production. The presence of IL-2 during culture (with or without IL-4) yielded predominantly Th1-type clones (81% of clones with IL-2 alone and 77% with IL-2 + IL-4) and a low frequency of Th0-type clones (19% of clones with IL-2 and 10% of clones with IL-2 + IL-4), whereas IL-4 alone increased the yield of the IL-4 producing Th0 (35%) clones. The proportions of IL-2-producing clones did not alter with treatment; however, the combination of IL-2 + IL-4 altered the proportions of IL-10-producing clones. 47% of IL-2-cultured cells and 51% of IL-4-cultured cells produced IL-10 respectively, whereas only 22% of clones driven with IL-2 + IL-4 produced detectable levels of IL-10. Thus in the preliminary experiments described here we have demonstrated that the cytokines used to initially drive out human T cells and maintain the T-cell growth can skew the Th1/Th2/Th0 cytokine profiles of the clones obtained from mitogen-stimulated cultures. Moreover and unexpectedly the proportion of IL-10-producing cells is altered. These results are important in interpreting analysis of the cytokine profiles of human T cells and raise questions concerning how we should derive T-cell clones for a cytokine analysis that truly reflects the in vivo situation.

Cell Division↗
PubMed1998

Population structure of Andean Triatoma infestans: allozyme frequencies and their epidemiological relevance.

Triatoma infestans (Hemiptera: Reduviidae) from 22 Andean localities in Bolivia (n = 968) and Peru (n = 37) were analysed by multi-locus enzyme electrophoresis. Among 12 gene-enzyme systems analysed, GPD, 6GPD and PGM were polymorphic, ACON, G6PD, GPI, 1DH, LAP, MDH, ME, PEP-A and PEP-B were monomorphic. Allozyme frequencies were analysed in relation to geographical and climatic factors, and the presence or absence of Trypanosoma cruzi infection. At one locality (Vallegrande, Bolivia), the frequency of 6Pgd-1 was significantly higher in infected (41% of 85) than in uninfected (17% of 83) adult T. infestans, although no such difference was found among nymphs (n = 347). From other localities, only insects infected with T. cruzi were subjected to isozyme analysis. Populations of T. infestans within villages showed panmixia, while genetic differentiation of T. infestans between villages was correlated with the distance between them. The genetic structure of T. infestans natural populations followed an 'isolation by distance' model, involving a series of founder effects followed by genetic drift, rather than adaptation in response to differential selection pressures. This conforms with circumstantial evidence that T. infestans spread, mainly in association with recent human migrations, from a source, probably in southern Bolivia. Isoenzyme characterization of populations of T. infestans could be used to infer sources of re-infestation during the surveillance phase of control programs.

Animals↗
PubMed2002

The Baltic Sea as a model system for studying postglacial colonization and ecological differentiation, exemplified by the red alga Ceramium tenuicorne.

The Baltic Sea provides a unique model system for studying genetic effects of postglacial colonization and ecological differentiation, because all marine organisms must have immigrated after the opening of the Danish Straits 8000 years ago and responded to the development of the steep Skagerrak-Baltic salinity gradient. The red alga Ceramium tenuicorne shows conspicuous variation in growth and reproduction along this gradient. Herein we obtained reproductive data coupled with two types of molecular markers, one organellar (cox2-3 spacer sequences of mitochondrial DNA; mtDNA) and one mainly nuclear (random amplified polymorphic DNAs; RAPDs). Nine main populations were sampled in a nested spatial hierarchy including three salinity regions (Oslofjorden, Kattegat, and the Baltic Sea), and nine additional populations were sampled for the mtDNA analysis. Asexuality was frequent at low (Baltic) and medium (Kattegat) salinities but virtually absent at the highest salinity (Oslofjorden). Five mtDNA haplotypes were observed, of which two highly divergent ones were common. One was restricted to and fixed in Oslofjorden, and the other, which was closely related to the three rare haplotypes, was found from southernmost Norway via Kattegat into the Baltic. The RAPD data revealed, on the other hand, a continuous cline corresponding to the salinity gradient, with 27.4% divergence among salinity regions and most of the variation stored at the smallest spatial scale analysed (64.2%; within 1 m2 subpopulations). The combined data suggest colonization from a diverse Atlantic glacial gene pool followed by (1) lineage sorting of ancestral mtDNA polymorphisms and (2) strong differential selection among nuclear genotypes along the salinity gradient, including selection for nonrecombinant multiplication of those best fit to the marginal low-salinity habitats.

Adaptation, Physiological↗
PubMed2003

Transcriptome analysis of sulfur depletion in Arabidopsis thaliana: interlacing of biosynthetic pathways provides response specificity.

Higher plants assimilate inorganic sulfate into cysteine, which is subsequently converted to methionine, and into a variety of other sulfur-containing organic compounds. To resist sulfur deficiency, plants must demonstrate physiological flexibility: the expression of an extensive set of genes and gene regulators that act in the affected pathways or signalling cascades must be delicately tuned in response to environmental challenges. To elucidate this network of interactions, we have applied an array hybridisation/transcript profiling method to Arabidopsis plants subjected to 6, 10 and 13 days of constitutive and induced sulfur starvation. The temporal expression behaviour of approximately 7200 non-redundant genes was analysed simultaneously. The experiment was designed in a way to identify statistically significant changes of gene expression based on sufficient numbers of repeated hybridisations performed with five uniform pools of plant material. The expression profiles were processed to select differentially expressed genes. Among the 1507 sulfur-responsive clones implicated in this way, 632 genes responded specifically to sulfur deficiency by significant over-expression. The sulfur-responsive genes were grouped according to functional categories or biosynthetic pathways. As expected, genes of the sulfur assimilation pathway were altered in expression. Furthermore, genes involved in flavonoid, auxin, and jasmonate biosynthesis pathways were upregulated in conditions of sulfur deficiency. Based on the correlative analysis of gene expression patterns, we suggest that a complex co-ordination of systematic responses to sulfur depletion is provided via integration of flavonoid, auxin and jasmonate pathway elements. Plait concept for transduction of specificity via the main non-specific signalling stream is proposed.

Adaptation, Physiological↗
PubMed2005

[The voice evaluation protocol of the European Laryngological Society (ELS) -- first results of a multicenter study].

INTRODUCTION: A multidimensional protocol has been established by the ELS in order to reach better agreement and standardisation for functional assessment of pathologic voices. In order to evaluate the validity, practicability and applicability of this protocol the experiences of 6 european voice centres have been analysed in a retrospective study. MATERIAL AND METHODS: The ELS protocol comprises 5 dimensions: perceptual voice evaluation, videostroboscopy, acoustics, aerodynamics and subjective rating by the patient. Results obtained in 94 patients with benign voice disorders were evaluated retrospectively in a multicenter study. RESULTS: According to our results, the validity, practicability and applicability of the ELS protocol was largely satisfactory. This was true for all "common" voice disorders, but not for extreme voice alterations (e. g. spasmodic dysphonia, aphonia, substitution voices). The 5 dimension proofed to be not redundant and were able to selectively differentiate pre- post changes among various etiologies of voice disorders, various types of treatment and genders.

Adolescent↗
PubMed2004

Comparing the dynamical effects of symmetric and antisymmetric stretch excitation of methane in the Cl+CH4 reaction.

The effects of two nearly isoenergetic C-H stretching motions on the gas-phase reaction of atomic chlorine with methane are examined. First, a 1:4:9 mixture of Cl(2), CH(4), and He is coexpanded into a vacuum chamber. Then, either the antisymmetric stretch (nu(3)=3019 cm(-1)) of CH(4) is prepared by direct infrared absorption or the infrared-inactive symmetric stretch (nu(1)=2917 cm(-1)) of CH(4) is prepared by stimulated Raman pumping. Photolysis of Cl(2) at 355 nm generates fast Cl atoms that initiate the reaction with a collision energy of 1290+/-175 cm(-1) (0.16+/-0.02 eV). Finally, the nascent HCl or CH(3) products are detected state-specifically via resonance enhanced multiphoton ionization and separated by mass in a time-of-flight spectrometer. We find that the rovibrational distributions and state-selected differential cross sections of the HCl and CH(3) products from the two vibrationally excited reactions are nearly indistinguishable. Although Yoon et al. [J. Chem. Phys. 119, 9568 (2003)] report that the reactivities of these two different types of vibrational excitation are quite different, the present results indicate that the reactions of symmetric-stretch excited or antisymmetric-stretch excited methane with atomic chlorine follow closely related product pathways. Approximately 37% of the reaction products are formed in HCl(v=1,J) states with little rotational excitation. At low J states these products are sharply forward scattered, but become almost equally forward and backward scattered at higher J states. The remaining reaction products are formed in HCl(v=0,J) and have more rotational excitation. The HCl(v=0,J) products are predominantly back and side scattered. Measurements of the CH(3) products indicate production of a non-negligible amount of umbrella bend excited methyl radicals primarily in coincidence with the HCl(v=0,J) products. The data are consistent with a model in which the impact parameter governs the scattering dynamics.

Journal Article↗
PubMed1984

Cytomegalovirus infects human lymphocytes and monocytes: virus expression is restricted to immediate-early gene products.

In this investigation, we studied the ability of human cytomegalovirus to infect peripheral blood mononuclear cells. With monoclonal antibody technology, we demonstrated that cytomegalovirus could infect human lymphocytes of T- and B-cell lineage, natural killer cells, and monocytes. Furthermore, virus expression was limited to the synthesis of immediate-early cytomegalovirus polypeptides. These peripheral blood mononuclear cells did not produce infectious virus, nor were mature virions visualized by electron microscopy. This abortive infection of mononuclear cells was most convincingly shown with stocks of cytomegalovirus that had been recently isolated from infected patients and passaged minimally in fibroblasts. This argues for an increased lymphotropic effect of some isolates of cytomegalovirus, compared to strains of virus that are extensively adapted to growth in fibroblasts. Furthermore, immunocompetent cells that were shown to be abortively infected with cytomegalovirus lost selected differentiated functions.

Antibodies, Monoclonal↗
PubMed1995

Three gonadotropin-releasing hormone genes in one organism suggest novel roles for an ancient peptide.

Gonadotropin-releasing hormone (GnRH) is known and named for its essential role in vertebrate reproduction. Release of this decapeptide from neurons in the hypothalamus controls pituitary gonadotropin levels which, in turn, regulate gonadal state. The importance of GnRH is underscored by its widespread expression and conservation across vertebrate taxa: five amino acids are invariant in all nine known forms, whereas two others show only conservative changes. In most eutherian mammals, only one form, expressed in the hypothalamus, is thought to exist, although in a recent report, antibody staining in developing primates suggests an additional form. In contrast, multiple GnRH forms and expression loci have been reported in many non-mammalian vertebrates. However, evidence based on immunological discrimination does not always agree with analysis of gene expression, since GnRH forms encoded by different genes may not be reliably distinguished by antibodies. Here we report the expression of three distinct GnRH genes in a teleost fish brain, including the sequence encoding a novel GnRH preprohormone. Using in situ hybridization, we show that this form is found only in neurons that project to the pituitary and exhibit changes in soma size depending on social and reproductive state. The other two GnRH genes are expressed in other, distinct cell populations. All three genes share the motif of encoding a polypeptide consisting of GnRH and a GnRH-associated peptide. Whereas the GnRH moiety is highly conserved, the GnRH-associated peptides are not, reflecting differential selective pressure on different parts of the gene. GnRH forms expressed in nonhypothalamic regions may serve to coordinate reproductive activities of the animal.

Amino Acid Sequence↗
PubMed1996

Reversible immortalization of mammalian cells mediated by retroviral transfer and site-specific recombination.

A procedure of reversible immortalization of primary cells was devised by retrovirus-mediated transfer of an oncogene that could be subsequently excised by site-specific recombination. This study focused on the early stages of immortalization: global induction of proliferation and life span extension of cell populations. Comparative analysis of Cre/LoxP and FLP/FRT recombination in this system indicated that only Cre/LoxP operates efficiently in primary cells. Pure populations of cells in which the oncogene is permanently excised were obtained, following differential selection of the cells. Cells reverted to their preimmortalized state, as indicated by changes in growth characteristics and p53 levels, and their fate conformed to the telomere hypothesis of replicative cell senescence. By permitting temporary and controlled expansion of primary cell populations without retaining the transferred oncogene, this strategy may facilitate gene therapy manipulations of cells unresponsive to exogenous growth factors and make practical gene targeting by homologous recombination in somatic cells. The combination of retroviral transfer and site-specific recombination should also extend gene expression studies to situations previously inaccessible to experimentation.

3T3 Cells↗
PubMed1996

Organization and expression of canine olfactory receptor genes.

Four members of the canine olfactory receptor gene family were characterized. The predicted proteins shared 40-64% identity with previously identified olfactory receptors. The four subfamilies identified in Southern hybridization experiments had as few as 2 and as many as 20 members. All four genes were expressed exclusively in olfactory epithelium. Expression of multiple members of the larger subfamilies was detected, suggesting that most if not all of the cross-hybridizing bands in genomic Southern blots represented actively transcribed olfactory receptor genes. Analysis of large DNA fragments using Southern blots of pulsed-field gels indicated that subfamily members were clustered together, and that two of the subfamilies were closely linked in the dog genome. Analysis of the four olfactory receptor gene subfamilies in 26 breeds of dog provided evidence that the number of genes per subfamily was stable in spite of differential selection on the basis of olfactory acuity in scent hounds, sight hounds, and toy breeds.

Amino Acid Sequence↗