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PubMed1998

Deleterious mutation accumulation and the regeneration of genetic resources.

The accumulation of mildly deleterious mutations accompanying recurrent regeneration of plant germ plasm was modeled under regeneration conditions characterized by different amounts of selection and genetic drift. Under some regeneration conditions (sample sizes >/=75 individuals and bulk harvesting of seed) mutation accumulation was negligible, but under others (sample sizes <75 individuals or equalization of seed production by individual plants) mutation numbers per genome increased significantly during 25-50 cycles of regeneration. When mutations also are assumed to occur (at elevated rates) during seed storage, significant mutation accumulation and fitness decline occurred in 10 or fewer cycles of regeneration regardless of the regeneration conditions. Calculations also were performed to determine the numbers of deleterious mutations introduced and remaining in the genome of an existing variety after hybridization with a genetic resource and subsequent backcrossing. The results suggest that mutation accumulation has the potential to reduce the viability of materials held in germ plasm collections and to offset gains expected by the introduction of particular genes of interest from genetic resources.

Alleles↗
PubMed1997

Genetic evidence of separate repressor and activator activities of the XylR regulator of the TOL plasmid, pWW0, of Pseudomonas putida.

The XylR protein encoded by pWW0, the TOL (toluene biodegradation) plasmid of Pseudomonas putida, activates at a distance the transcription of Pu and Ps, which are the two sigma(54)-dependent promoters of the plasmid, but it also downregulates its own sigma(70)-promoter, Pr, which divergently overlaps the upstream activating sites of Ps. All regulatory elements that control Pr activity have been faithfully reproduced in Escherichia coli, and the basis of the autoregulation of XylR transcription has been examined by monitoring the activity in vivo of different combinations of mutant proteins and promoters in rpoN+ and rpoN-genetic backgrounds. By using Ps/Pr regions bearing deleted or offset binding sites for XylR and the sigma(54)-containing RNA polymerase, we could show that formation of a nucleoprotein complex involving the polymerase bound to the divergent promoter Ps is not required for downregulation of Pr. Mutant XylR proteins, G268N and A311V (mutated within the NTP-binding region of XylR) or R453H (affected in multimerization), which are unable to activate sigma(54)-dependent transcription from Ps, were indistinguishable from the wild-type XylR in their ability to repress a reporter Pr-lacZ fusion. Autoregulation of XylR is therefore due exclusively to the binding of the protein to its target sites at the Pr promoter. This allows one to define sensu stricto XylR as a transcriptional repressor, independently of its activator role in other promoters.

Bacterial Proteins↗
PubMed2000

Genetic variation and evolutionary trade-offs for sexual and asexual reproductive modes in Allium vineale (Liliaceae).

Populations of Allium vineale commonly include individuals with very different allocation patterns to three modes of reproduction: sexual flowers, aerially produced asexual bulbils, and belowground asexual offsets. If selection is currently acting to maintain these different allocation patterns there must be a genetic basis for variation in allocation to these three reproductive modes. In addition, negative genetic correlations between reproductive traits would imply evolutionary trade-offs among reproductive strategies. We evaluated the heritability of these allocation patterns by growing 16 clones from a single population in the greenhouse at two levels of fertilization. Bulb mass and the mass and number of bulbils, offsets, and flowers were used as response variables, in addition to the proportion allocated to each reproductive mode. We found evidence of substantial heritable variation in allocation to sexual reproduction and in allocation within the two modes of asexual reproduction, indicating high sensitivity of these allocation patterns to natural selection. We also found evidence of strong negative genetic correlations between bulbil and flower traits, as well as between bulbil and offset traits, with one group of genotypes allocating greater resources to aerial asexual bulbils and the second group allocating more resources to belowground asexual offsets and aerial flowers. Phenotypic plasticity in allocation to above- vs. belowground asexual reproduction and sexual vs. asexual aerial reproduction was limited, indicating that plants are unlikely to change reproductive mode in response to nutrient availability. Together, then, we have demonstrated strong heritability for, and trade-offs in, the reproductive allocation patterns within this plant population.

Journal Article↗
PubMed2004

Long-term effects of the PPAR gamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats.

We investigated the long-term effects of the thiazolidinedione PPARgamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats (SHRSP), a model of malignant of hypertension. Six-week-old SHRSP were treated with pioglitazone (10 mg/kg per day p.o.) for 20 weeks. The rise in systolic blood pressure (SBP) in SHRSP was only transiently and slightly attenuated by pioglitazone (P < 0.05). On one hand, cardiac hypertrophy was little affected by the pioglitazone treatment, and there was only a reduction of subepicardial interstitial fibrosis. On the other hand, left ventricular NFkappaB and AP-1 binding activities, the expression of TNFalpha, and the adhesion of molecule PECAM were significantly decreased by pioglitazone treatment. Expression of the pro-apoptotic proteins p53 and bax was significantly increased by pioglitazone. Thus, pioglitazone-attenuated cardiac inflammation in SHRSP had little effect on BP or cardiac hypertrophy. PPARgamma activation may play a preventive cardiovascular role by offsetting the cardiac inflammatory response as demonstrated in this genetic model of malignant hypertension.

Animals↗
PubMed1983

Association of heifer fertility with cow fertility and yield in dairy cattle.

Genetic correlations of heifer fertility and first-parity yield usually were negative and opposite in sign from genetic correlations of first-parity fertility and yield. Most estimates of genetic correlation between heifer and first-parity fertility were not significantly different from zero. Increasing yield may improve genetic potential for fertility, but stress of increased yield may overcome genetic potential for improved fertility. Days open and 305-day yield for first parity were considered with index selection; sires were evaluated on daughter performance. Days open had a small influence on the selection index; genetic gains in days open for first parity were largely offset by correlated losses in service period for heifers. Restricted index selection, holding days open constant, required considerable economic importance of days open.

Animals↗
PubMed2002

On a general class of conditional tests for family-based association studies in genetics: the asymptotic distribution, the conditional power, and optimality considerations.

Family-based association tests (FBATs) provide simple and powerful tests to detect association between a genetic marker and a disease-susceptibility locus, manifest in subjects by a phenotype or disease trait. Here we propose a new class of conditional tests for family-based association studies that includes most of the established tests and their generalizations. The class of tests is very general; it can be applied to longitudinal and multivariate traits or phenotypes, multiple genetic markers, and many other situations not yet discussed in the literature. For any test in this class, we derive the asymptotic distribution under the null hypothesis, the conditional power under any alternative hypothesis, and the optimal offset for single degree of freedom tests. The proposed methodology is illustrated with a genetic study of asthma.

Asthma↗
PubMed1992

Genetic disease: effects on human health.

Genetic variation (chromosomal, single gene, multifactorial) is a significant cause of morbidity and mortality in human populations. It increases in relative importance along with improvement in socioeconomic and environmental conditions and in association with prudent lifestyle. It affects longevity, development, reproductive capability, schooling, work and appearance of individuals. Its evidence is ubiquitous in the health care disciplines. Health care systems in general do not provide resources to meet the demand for genetics. Prevention of mutations, avoidance of their effects by reproductive counseling and treatment to offset mutant phenotypes are increasingly relevant scientific initiatives with broad social implications.

Adolescent↗
PubMedDate not supplied

Gene flow and genetic diversity in naturally fragmented metapopulations of deep-sea hydrothermal vent animals.

The ephemeral nature of deep-sea hydrothermal vents is expected to favor species with good colonization abilities, high dispersal rates, and rapid individual growth rates. Studies of gene flow in vent-endemic species provide glimpses into modes and patterns of dispersal. For some species, gene flow occurs without geographical bias (i.e., island model); their dispersal capabilities probably exceed the sampled geographical range. For other species, genetic differentiation increases with geographical distance (isolation-by-distance model) and suggests a stepping-stone mode of dispersal between neighboring vents. Genetic subdivision in a third group of species is associated with geographical offsets between contiguous segments of a ridge axis. These species all possess a free-living larval stage and average rates of gene flow (Nm) exceeding the critical value of one. In contrast, an amphipod that broods its young shows evidence for isolation-by-distance along a ridge axis and nearly complete isolation between distinct ridge axes. Early successional species (i.e., those that rapidly establish populations at nascent vents) also have high levels of genetic variability that probably results from a larger global population size. Bivalve species, which are restricted to a few of the known vent sites, appear at a later successional stage and have lower levels of variability. The relative successional position (early versus late) and overall abundance of a species may play significant roles in determining the retention of genetic diversity in populations inhabiting these ephemeral environments.

Animals↗
PubMed1996

Skeletal dysplasias detectable by DNA analysis.

The emerging data of the last few years outlining the molecular basis of skeletal dysplasias has been instructive in several respects. The number of genetic loci involved appears to be much fewer than anticipated. This is offset by the identification of several instances where phenotypically distinct entities are found to be allelic variants. With respect to diagnosis by DNA, most of the conditions recognized have several different mutations described. Consequently, while mutation analysis may be possible in a given case, close liaison with the investigating laboratory is essential if optimal results are to be obtained. Achondroplasia is unusual in that there is a common mutation and the other mutations related to the phenotype appear to cluster to a few codons. This review highlights the relationship between phenotypes of skeletal malformation, their underlying loci and mutations. These mutations appear to mediate their phenotypic effects through a diverse range of genetic mechanisms.

Bone Diseases, Developmental↗
PubMed1995

Bcl-2: prevention of apoptosis as a mechanism of drug resistance.

Programmed cell death (also known as apoptosis) plays an essential role in tissue homeostasis, where it ensures that new cell production in the body is offset by a commensurate rate of cell loss. Defects in the genetic pathway that regulate the cell death process can figure prominently in the origins of cancer and also in problems with cancer treatment. Eventually, it may be possible to develop novel treatments for cancer that specifically seek to modulate the physiologic cell death pathway as opposed to nearly all currently available drugs, which are intended to interfere with some aspect of the cell division cycle.

Animals↗
PubMed1986

Decreased effectiveness of GABA-mediated inhibition in the inferior colliculus of the genetically epilepsy-prone rat.

The inferior colliculus (IC) is a critical site for induction of audiogenic seizures in the genetically epilepsy-prone rat (GEPR). Abnormal response properties observed in inferior colliculus neurons of that strain include a high incidence of onset-offset responses which may be a form of afterdischarge. These response abnormalities may involve altered actions of neurotransmitters in that region of the brain. GABA is implicated as a transmitter in endogenous sound-induced inhibition in the inferior colliculus. Endogenous inhibition and the actions of agents that affect GABA receptors were examined in inferior colliculus neurons in epileptic and normal rats. The iontophoretic dose (current) of GABA required to suppress neuronal firing in the epilepsy-prone rat was significantly greater than that required in neurons of the normal rat. A form of endogenous (binaural) inhibition in inferior colliculus neurons, which is proposed to be GABA-mediated, was also significantly reduced in the epilepsy-prone rat as compared with the normal rat. A benzodiazepine (flurazepam) which enhances the action of GABA in many brain sites including the inferior colliculus was significantly less effective than normal when applied iontophoretically onto the same neurons of the epilepsy-prone rat. The GABAA antagonist, bicuculline, which blocks the effect of GABA on inferior colliculus neurons, frequently induced the onset-offset response in neurons not previously exhibiting this pattern. These findings suggest that the reduction of GABA-mediated inhibition in the genetically epilepsy-prone rat may result in the increased incidence of afterdischarges in neurons of the inferior colliculus and may serve as an important mechanism of epileptogenesis in audiogenic seizures in this genetic form of epilepsy.

Animals↗
PubMed2024

Interspecific transfer of genetic information through polyploid bridges.

Hybridization blurs species boundaries and leads to intertwined lineages resulting in reticulate evolution. Polyploidy, the outcome of whole genome duplication (WGD), has more recently been implicated in promoting and facilitating hybridization between polyploid species, potentially leading to adaptive introgression. However, because polyploid lineages are usually ephemeral states in the evolutionary history of life it is unclear whether WGD-potentiated hybridization has any appreciable effect on their diploid counterparts. Here, we develop a model of cytotype dynamics within mixed-ploidy populations to demonstrate that polyploidy can in fact serve as a bridge for gene flow between diploid lineages, where introgression is fully or partially hampered by the species barrier. Polyploid bridges emerge in the presence of triploid organisms, which despite critically low levels of fitness, can still allow the transfer of alleles between diploid states of independently evolving mixed-ploidy species. Notably, while marked genetic divergence prevents polyploid-mediated interspecific gene flow, we show that increased recombination rates can offset these evolutionary constraints, allowing a more efficient sorting of alleles at higher-ploidy levels before introgression into diploid gene pools. Additionally, we derive an analytical approximation for the rate of gene flow at the tetraploid level necessary to supersede introgression between diploids with nonzero introgression rates, which is especially relevant for plant species complexes, where interspecific gene flow is ubiquitous. Altogether, our results illustrate the potential impact of polyploid bridges on the (re)distribution of genetic material across ecological communities during evolution, representing a potential force behind reticulation.

Polyploidy↗
PubMed2001

To type or not to type: the use of unaffected siblings in nonparametric linkage analysis.

Unaffected individuals are often disregarded in nonparametric linkage analysis. Because of the presumed high complexity of genetic interactions and the resulting low penetrance of any single genetic effect, the statistical contribution of unaffected sib pairs is thought to be considerably lower than that of the affected. However, in cases where a large number of unaffected family members are available for genotyping--as is the case in the simulated Genetic Analysis Workshop 12 data set--the relatively low value of the unaffected sibs may be offset by their number. In this paper, I demonstrate that unaffected siblings do contain a significant amount of statistical information, and show that the most powerful method of nonparametric analysis utilizes both affected and unaffected individuals. I also show that selecting the unaffected individuals based on their age is the most cost effective and usually the most powerful strategy.

Adult↗
PubMed1988

Genetically determined differences in ethanol sensitivity influenced by body temperature during intoxication.

The present study investigated the importance of body temperature during intoxication in mediating differences between five inbred strains of mice (C57BL/6J; BALB/cJ; DBA/2J; A/HeJ; 129/J) in their acute sensitivity to the hypnotic effects of ethanol. Mice exposed to 22 degrees C after ethanol injection became hypothermic and exhibited statistically significant differences between strains in rectal temperatures at the return of the righting reflex (RORR), duration of loss of the righting reflex (LORR), and blood and brain ethanol concentrations at RORR. Exposure to 34 degrees C after injection offset ethanol-hypothermia and markedly reduced strain-related differences in rectal temperatures and blood and brain ethanol concentrations at RORR. Brain ethanol concentrations at RORR were significantly lower in C57, BALB, DBA and A/He mice exposed to 34 degrees C compared to mice exposed to 22 degrees C during intoxication suggesting that offsetting hypothermia increased ethanol sensitivity in these strains. Taken with previous in vitro studies, these results suggest that genetically determined differences in acute sensitivity to the behavioral effects of ethanol reflect differences in body temperature during intoxication as well as differences in sensitivity to the initial actions of ethanol at the cellular level.

Acclimatization↗
PubMed2004

Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences.

BACKGROUND: Morphine-6-glucuronide (M6G) is a metabolite of morphine and a micro-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design. METHODS: Ten men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)-pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia. RESULTS: M6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 +/- 135 nm (population estimate +/- SE), the blood effect site equilibration half-life was 6.2 +/- 3.3 h, and the steepness parameter was 0.71 +/- 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency. CONCLUSIONS: A cumulative dose of 0.3 mg/kg M6G, given over 1 h, produces long-term analgesia greater than that observed with placebo, with equal dynamics (potency and speed of onset-offset) in men and women. Possible causes for the great intersubject response variability, such as genetic polymorphism of the micro-opioid receptor and placebo-related phenomena, are discussed. The predictive pharmacokinetic-pharmacodynamic model was applied successfully and was used to estimate M6G analgesia after morphine in patients with normal and impaired renal function.

Adult↗
PubMed2003

Effects of inbreeding on coastal Douglas fir growth and yield in operational plantations: a model-based approach.

In advanced generation seed orchards, tradeoffs exist between genetic gain obtained by selecting the best related individuals for seed orchard populations, and potential losses due to subsequent inbreeding between these individuals. Although inbreeding depression for growth rate is strong in most forest tree species at the individual tree level, the effect of a small proportion of inbreds in seed lots on final stand yield may be less important. The effects of inbreeding on wood production of mature stands cannot be assessed empirically in the short term, thus such effects were simulated for coastal Douglas fir [ Pseudotsuga menziesii var. menziesii (Mirb.) Franco] using an individual-tree growth and yield model TASS (Tree and Stand Simulator). The simulations were based on seed set, nursery culling rates, and 10-year-old field test performance for trees resulting from crosses between unrelated individuals and for inbred trees produced through mating between half-sibs, full-sibs, parents and offspring and self-pollination. Results indicate that inclusion of a small proportion of related clones in seed orchards will have relatively low impacts on stand yields due to low probability of related individuals mating, lower probability of producing acceptable seedlings from related matings than from unrelated matings, and a greater probability of competition-induced mortality for slower growing inbred individuals than for outcrossed trees. Thus, competition reduces the losses expected due to inbreeding depression at harvest, particularly on better sites with higher planting densities and longer rotations. Slightly higher breeding values for related clones than unrelated clones would offset or exceed the effects of inbreeding resulting from related matings. Concerns regarding the maintenance of genetic diversity are more likely to limit inclusion of related clones in orchards than inbreeding depression for final stand yield.

Analysis of Variance↗
PubMed2000

Acclimation of photosynthesis and respiration to simulated climatic warming in northern and southern populations of Acer saccharum: laboratory and field evidence.

Physiological acclimation and genotypic adaptation to prevailing temperatures may influence forest responses to future climatic warming. We examined photosynthetic and respiratory responses of sugar maple (Acer saccharum Marsh.) from two portions of the species' range for evidence of both phenomena in a laboratory study with seedlings. A field study was also conducted to assess the impacts of temperature acclimation on saplings subjected to an imposed temperature manipulation (4 degrees C above ambient temperature). The two seedling populations exhibited more evidence of physiological acclimation to warming than of ecotypic adaptation, although respiration was less sensitive to short-term warming in the southern population than in the northern population. In both seedling populations, thermal compensation increased photosynthesis by 14% and decreased respiration by 10% in the warm-acclimated groups. Saplings growing in open-top field chambers at ambient temperature and 4 degrees C above ambient temperature showed evidence of temperature acclimation, but photosynthesis did not increase in response to the 4 degrees C warming. On the contrary, photosynthetic rates measured at the prevailing chamber temperature throughout three growing seasons were similar, or lower (12% lower on average) in saplings maintained at 4 degrees C above ambient temperature compared with saplings maintained at ambient temperature. However, the long-term photosynthetic temperature optimum for saplings in the field experiment was higher than it was for seedlings in either the 27 or the 31 degrees C growth chamber. Respiratory acclimation was also evident in the saplings in the field chambers. Saplings had similar rates of respiration in both temperature treatments, and respiration showed little dependence on prevailing temperature during the growing season. We conclude that photosynthesis and respiration in sugar maple have the potential for physiological acclimation to temperature, but exhibit a low degree of genetic adaptation. Some of the potential for acclimation to a 4 degrees C increase above a background of naturally fluctuating temperatures may be offset by differences in water relations, and, in the long term, may be obscured by the inherent variability in rates under field conditions. Nevertheless, physiologically based models should incorporate seasonal acclimation to temperature and permit ecotypic differences to influence model outcomes for those species with high genetic differentiation between regions.

Journal Article↗
PubMed2006

Sexual reproduction selects for robustness and negative epistasis in artificial gene networks.

The mutational deterministic hypothesis for the origin and maintenance of sexual reproduction posits that sex enhances the ability of natural selection to purge deleterious mutations after recombination brings them together into single genomes. This explanation requires negative epistasis, a type of genetic interaction where mutations are more harmful in combination than expected from their separate effects. The conceptual appeal of the mutational deterministic hypothesis has been offset by our inability to identify the mechanistic and evolutionary bases of negative epistasis. Here we show that negative epistasis can evolve as a consequence of sexual reproduction itself. Using an artificial gene network model, we find that recombination between gene networks imposes selection for genetic robustness, and that negative epistasis evolves as a by-product of this selection. Our results suggest that sexual reproduction selects for conditions that favour its own maintenance, a case of evolution forging its own path.

Animals↗