Selection-mutation balance models with epistatic selection

We present an application of birth-and-death processes on configuration spaces to a generalized mutation4 selection balance model. The model describes the aging of population as a process of accumulation of mu5 tations in a genotype. A rigorous treatment demands that mutations correspond to points in abstract spaces. 6 Our model describes an infinite-population, infinite-sites model in continuum. The dynamical equation which 7 describes the system, is of Kimura-Maruyama type. The problem can be posed in terms of evolution of states 8 (differential equation) or, equivalently, represented in terms of Feynman-Kac formula. The questions of interest 9 are the existence of a solution, its asymptotic behavior, and properties of the limiting state. In the non-epistatic 10 case the problem was posed and solved in [Steinsaltz D., Evans S.N., Wachter K.W., Adv. Appl. Math., 2005, 11 35(1)]. In our model we consider a topological space X as the space of positions of mutations and the influence of epistatic potentials

An intronic growth hormone receptor mutation causing activation of a pseudoexon is associated with a broad spectrum of growth hormone insensitivity phenotypes

Context: Inherited GH insensitivity (GHI) is usually caused by mutations in the GH receptor (GHR). Patients present with short stature associated with high GH and low IGF-I levels and may have midfacial hypoplasia ( typical Laron syndrome facial features). We previously described four mildly affected GHI patients with an intronic mutation in the GHR gene (A.(1) -> G.(1) substitution in intron 6), resulting in the activation of a pseudoexon (6 Psi) and inclusion of 36 amino acids. Objective: The study aimed to analyze the clinical and genetic characteristics of additional GHI patients with the pseudoexon (6 Psi) mutation. Design/Patients: Auxological, biochemical, genetic, and haplotype data from seven patients with severe short stature and biochemical evidence of GHI were assessed. Main Outcome Measures: We assessed genotype-phenotype relationship. Results: One patient belongs to the same extended family, previously reported. She has normal facial features, and her IGF-I levels are in the low-normal range for age. The six unrelated patients, four of whom have typical Laron syndrome facial features, have heights ranging from -3.3 to -6.0 SD and IGF-I levels that vary from normal to undetectable. We hypothesize that the marked difference in biochemical and clinical phenotypes might be caused by variations in the splicing efficiency of the pseudoexon. Conclusions: Activation of the pseudoexon in the GHR gene can lead to a variety of GHI phenotypes. Therefore, screening for the presence of this mutation should be performed in all GHI patients without mutations in the coding exons.

Interactions between age and apoE genotype on fasting and postprandial triglycerides levels

Objective The influences of genetic determinants on the magnitude of postprandial lipaemia are presently unclear. Here the impact of the common apolipoprotein (apo)E epsilon mutation on the postprandial triglyceride (TG) response is determined, along with an assessment of genotype penetrance according to age, body mass index and gender. Methods and results Healthy adults (n = 251) underwent a postprandial investigation, in which blood samples were taken at regular intervals after a test breakfast (0 min, 49 g fat) and lunch (330 min, 29 g fat) until 480 min after the test breakfast. There was a significant impact of apoE genotype on fasting total cholesterol (TC), (P = 0.027), LDL-cholesterol (LDL-C), (P = 0.008), and %LDL3 (P = 0.001), with higher and lower levels in the E4 and E2 carriers respectively relative to the E3/E3 genotype. Reflective of a higher fasting TG (P = 0.001), a significantly higher area under the curve for the postprandial TG response (TG AUC) was evident in the E4 carriers relative to the E3/E3 group (P = 0.038). In the group as a whole, a significant age × genotype interaction was observed for fasting TC (P = 0.021). In the participants >50 years there was a significant impact of genotype on TC (P = 0.005), LDL-C (P = 0.001) and TAG AUC (P = 0.028). Conclusions It is possible that an exaggerated postprandial lipaemia contributes to the increased coronary heart disease risk associated with carriers of the E4 allele; an effect which is more evident in older adults.

The impact of catechol-O-methyltransferase genotype on the acute responsiveness of vascular reactivity to a green tea extract

The beneficial effects of green tea catechins, such as the proposed improvement in endothelial function, may be influenced by phase II metabolism during and after absorption. The methylation enzyme, catechol-O-methyltransferase (COMT), has a missense mutation rs4680 (G to A), proposed to result in a 40 % reduction in enzyme activity. In the present pilot study, twenty subjects (ten of each homozygous COMT genotype) were recruited. Green tea extract capsules (836 mg green tea catechins) were given in a fasted state, and a high-carbohydrate breakfast was given after 60 min. Blood samples and vascular function measurements were taken at regular intervals. The change in digital volume pulse stiffness index (SI) from baseline was shown to be different between genotype groups at 120 and 240 min, with a lower SI in the GG individuals (P ≤ 0·044). The change in blood pressure from baseline also differed between genotype groups, with a greater increase in systolic (P = 0·023) and diastolic (P = 0·034) blood pressure at 120 min in the GG group. The AA group was shown to have a greater increase in insulin concentrations at 120 min (P = 0·019) and 180 min (P = 0·008) compared with baseline, despite similar glucose profiles. No genotypic differences were found in vascular reactivity measured using laser Doppler iontophoresis, total nitrite, lipids, plasma total antioxidant capacity or inflammatory markers after ingestion of the green tea extract. In conclusion, SI and insulin response to the glucose load differed between the COMT genotype groups, and this may be suggestive of a green tea extract and genotype interaction.

Genotype x environment interaction in the uptake of Cs and Sr from soils by plants

The soil-plant transfer factors for Cs and Sr were analyzed in relationship to soil properties, crops, and varieties of crops. Two crops and two varieties of each crop: lettuce (Lactuca sativa L.), cv. Salad Bowl Green and cv. Lobjoits Green Cos, and radish (Raphanus sativus L.), cv. French Breakfast 3 and cv. Scarlet Globe, were grown on five different soils amended with Cs and Sr to give concentrations of 1 mg kg(-1) and 50 mg kg(-1) of each element. Soil-plant transfer coefficients ranged between 0.12-19.10 (Cs) and 1.48-146.10 (Sr) for lettuce and 0.09-13.24 (Cs) and 2.99-93.00 (Sr) for radish. Uptake of Cs and Sr by plants depended on both plant and soil properties. There were significant (P less than or equal to 0.05) differences between soil-plant transfer factors for each plant type at the two soil concentrations. At each soil concentration about 60% of the variance in the uptake of the Cs and Sr was due to soil properties. For a given concentration of Cs or Sr in soil, the most important factor effecting soil-plant transfer of these elements was the soil properties rather than the crops or varieties of crops. Therefore, for the varieties considered here, soil-plant transfer of Cs and Sr would be best regulated through the management of soil properties. At each concentration of Cs and Sr, the main soil properties effecting the uptake of Cs and Sr by lettuce and radish were the concentrations of K and Ca, pH and CEC. Together with the concentrations of contaminants in soils, they explained about 80% of total data variance, and were the best predictors for soil-plant transfer. The different varieties of lettuce and radish gave different responses in soil-plant transfer of Cs and Sr in different soil conditions, i.e. genotype x environment interaction caused about 30% of the variability in the uptake of Cs and Sr by plants. This means that a plant variety with a low soil-plant transfer of Cs and Sr in one soil could have an increased soil-plant transfer factor in other soils. The broad implications of this work are that in contaminated agricultural lands still used for plant growing, contaminant-excluding crop varieties may not be a reliable method for decreasing contaminant transfer to foodstuffs. Modification of soil properties would be a more reliable technique. This is particularly relevant to agricultural soils in the former USSR still affected by fallout from the Chernobyl disaster.

Metal bioaccumulation and cellular fractionation in an epigeic earthworm (Lumbricus rubellus): the interactive influences of population exposure histories, site-specific geochemistry and mitochondrial genotype

Subcellular fractionation techniques were used to describe temporal changes (at intervals from T0 to T70 days) in the Pb, Zn and P partitioning profiles of Lumbricus rubellus populations from one calcareous (MDH) and one acidic (MCS) geographically isolated Pb/Zn-mine sites and one reference site (CPF). MDH and MCS individuals were laboratory maintained on their native field soils; CPF worms were exposed to both MDH and MCS soils. Site-specific differences in metal partitioning were found: notably, the putatively metal-adapted populations, MDH and MCS, preferentially partitioned higher proportions of their accumulated tissue metal burdens into insoluble CaPO4-rich organelles compared with naive counterparts, CPF. Thus, it is plausible that efficient metal immobilization is a phenotypic trait characterising metal tolerant ecotypes. Mitochondrial cytochrome oxidase II (COII) genotyping revealed that the populations indigenous to mine and reference soils belong to distinct genetic lineages, differentiated by 13%, with 7 haplotypes within the reference site lineage but fewer (3 and 4, respectively) in the lineage common to the two mine sites. Collectively, these observations raise the possibility that site-related genotype differences could influence the toxico-availability of metals and, thus, represent a potential confounding variable in field-based eco-toxicological assessments.

Genotype and fungicide effects on late-season root growth of winter wheat

The aim of this work was to investigate differences among genotypes in post-anthesis root growth and distribution of modern UK winter wheat cultivars, and the effects of fungicide applications. Post-anthesis root growth of up to six cultivars of winter wheat (Triticum aestivum L.), given either one or three applications of fungicide, was studied in field experiments during two seasons. Total root mass remained unchanged between GS63 (anthesis) and GS85, but root length increased significantly from 14.7 to 31.4 km m(2) in one season. Overall, there was no evidence for a decline in either root mass or length during grain filling. Root mass as a proportion of total plant mass was about 0.05 at GS85. There were significant differences among cultivars in root length and mass especially below 30 cm. Malacca had the smallest root length and Savannah the largest, and Shamrock had a significantly larger root system below 40 cm in both seasons. Fungicide applied at ear emergence had no significant effect on root mass in either season but increased root length (P < 0.01) in the more disease-prone season. By maintaining a green canopy for longer, fungicide applied at flag leaf emergence may have resulted in delayed senescence of the root system and contributed to the post-anthesis maintenance of root mass and length.

Influence of porcine genotype on the abundance of thyroid hormones and leptin in sow milk and its impact on growth, metabolism and expression of key adipose tissue genes in offspring

Neonatal mortality is greater in commercial porcine genotypes, compared with the ancient Meishan breed that rapidly lay down adipose tissue; this may be related to hormones, such as triiodothyronine (T3) or leptin. Leptin is present in maternal milk; however, the extent to which this supply provides the neonate with leptin is unknown, but may play a role in growth and development. We investigated whether thyroid hormones and leptin concentrations in maternal milk differed between genotypes; and whether this influenced piglet concentrations or expression of genes involved in adipose tissue regulation. Eight Meishan and six commercial sows were entered into the study and milk samples from the day of parturition to day 4 postpartum was taken daily. The median birth weight piglet in each litter had a daily venous blood sample taken and was euthanised on day 4. Gene expressions of IGF-I, IGF-binding protein 3 (IGFBP-3), peroxisome proliferators activated receptor (PPAR) and glucocorticoid receptor (GR) were measured in adipose tissue using real-time PCR. T3 was increased in Meishan milk, but not in piglet plasma. Milk thyroxine was similar between breeds but commercial piglet levels were significantly higher. Leptin was higher in commercial sow milk throughout the study. Milk leptin was strongly correlated to plasma leptin during the first postnatal days and also to organ and body weight in Meishan piglets that also had significantly higher expression of GR, but not IGF-I, IGFBP-3 or PPAR. In conclusion, we have found a significant disparity in the provision of thyroid hormones in Meishan and commercial sow’s milk. These changes are not always translated to plasma concentrations of hormone in the piglet. Leptin appears to have a stronger role in growth and development in the Meishan genotype compared with commercial; along with the increased GR expression, this may also represent a potential mechanism behind the rapid accumulation of adipose tissue in Meishan piglets.

Effect of species and genotype on the efficiency of enrichment of poultry meat with n-3 polyunsaturated fatty acids

The effect of poultry species (broiler or turkey) and genotype (Wrolstad or BUT T8 turkeys and Ross 308 or Cobb 500 broilers) on the efficiency with which dietary longchain n-3 PUFA were incorporated into poultry meat was determined. Broilers and turkeys of both genotypes were fed one of six diets varying in FA composition (two replicates per genotype x diet interaction). Diets contained 50 g/kg added oil, which was either blended vegetable oil (control), or partially replaced with linseed oil (20 or 40 g/kg diet), fish oil (20 or 40 g/kg diet), or a mixture of the two (20 g linseed oil and 20 g fish oil/kg diet). Feeds and samples of skinless breast and thigh meat were analyzed for FA. Wrolstad dark meat was slightly more responsive than BUT T8 (P = 0.046) to increased dietary 18:3 concentrations (slopes of 0.570 and 0.465, respectively). The Ross 308 was also slightly more responsive than the Cobb 500 (P= 0.002) in this parameter (slopes of 0.557 and 0.449). There were no other significant differences between the genotypes. There was some evidence (based on the estimates of the slopes and their associated standard errors) that white turkey meat was more responsive than white chicken meat to 20:5 (slopes of 0.504 and 0.289 for turkeys and broilers, respectively). There was no relationship between dietary 18:3 n-3 content and meat 20:5 and 22:6 contents. If birds do convert 18:3 to higher FA, these acids are not then deposited in the edible tissues.

A model of seed dormancy in wild oats (Avena fatua) for investigating genotype x environment interactions

Dormancy is an adaptive trait in seed populations that helps ensure that seed germination is distributed over time and occurs in environmental conditions suitable for seedling growth. Several genes.. associated with seed dormancy in various plant species, have been integrated into a hypothetical dormancy model for Avena fatua L. (wild oats). Generally, the synthesis of, and sensitivity to, abscisic acid (ABA) during imbibition determines whether genes similar to those during maturation are expressed leading to a maintenance of dormancy during extended imbibition. Alternatively, there may be a shift towards expression of genes associated with gibberellins leading to germination. Environmental factors during maturation, after-ripening and imbibition are likely to interact with the genotype to affect gene expression and hence whether or not a seed germinates. In spite of the difficulties of working on a hexaploid species, A. fatua was selected for study because of its worldwide importance as a weed. Dormant and non-dormant genotypes of this species were also available. Gene expression studies are being carried out on three A.fatua genotypes produced tinder different environmental conditions to investigate the role of specific genes in dormancy and genotype X environment interactions in relation to dormancy.

The influence of winter oilseed rape (Brassica napus ssp oleifera var. biennis) cultivar and grass genotype on the competitive balance between crop and grass weeds

Three experiments conducted over two years (2002-04) at the Crops Research Unit, University of Reading, investigated competition between autumn sown oilseed rape cultivars (Brassica napus L. ssp. oleifera var. biennis (DC.) Metzg.) and Lolium multiflorum Lam., L. x boucheanum Kunth and Alopecurus myosuroides Huds., sown as indicative grass weeds. Rape cultivar (cv.) had a substantial effect on grass weed seed return. Over the six cultivars tested, L. multiflorum spikelet production ranged from just under 400 spikelets/m(2) in the presence of cv. Winner to nearly 5800 in competition with cv. Lutin. Cultivar competitiveness was associated with high biomass, large dense floral layers and early stem extension. There was some evidence of differential competitive tolerance between rape cultivars. The results suggested that rape cultivars could be screened for competitiveness by measuring floral layer interception of photosynthetic active radiation. L. x boucheanum cultivars varied in ability to compete with rape. In the absence of inter-specific competition, spikelet density was similar for Aberecho and Polly (circa 31000 spikelets/m(2)) but when grown with rape Polly outyielded Aberecho (i.e. 12 090 and 7990 spikelets/m(2) respectively).

Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study

Background: The lipid-modulatory effects of high intakes of the fish-oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well established and likely to contribute to cardioprotective benefits. Objectives: We aimed to determine the effect of moderate EPA and DHA intakes (< 2 g EPA + DHA/d) on the plasma fatty acid profile, lipid and apolipoprotein concentrations, lipoprotein subclass distribution, and markers of oxidative status. We also aimed to examine the effect of age, sex, and apolipoprotein E (APOE) genotype on the observed responses. Design: Three hundred twelve adults aged 20-70 y, who were prospectively recruited according to age, sex, and APOE genotype, completed a double-blind placebo-controlled crossover study. Participants consumed control oil, 0.7 g EPA + DHA/d (0.7FO), and 1.8 g EPA + DHA/d (1.8FO) capsules in random order, each for an 8-wk intervention period, separated by 12-wk washout periods. Results: In the group as a whole, 8% and 11% lower plasma triacylglycerol concentrations were evident after 0.7FO and 1.8FO, respectively (P < 0.001): significant sex x treatment (P = 0.038) and sex x genotype x treatment (P = 0.032) interactions were observed, and the greatest triacylglycerol-lowering responses (reductions of 15% and 23% after 0.7FO and 1.8FO, respectively) were evident in APOE4 men. Furthermore, lower VLDL-cholesterol (P = 0.026) and higher LDL-cholesterol (P = 0.010), HDL-cholesterol (P < 0.001), and HDL2 (P < 0.001) concentrations were evident after fish-oil intervention. Conclusions: Supplements providing EPA + DHA at doses as low as 0.7 g/d have a significant effect on the plasma lipid profile. The results of the current trial, which used a prospective recruitment approach to examine the responses in population subgroups, are indicative of a greater triacylglycerol-lowering action of long-chain n-3 polyunsaturated fatty acids in males than in females.

Rare and fleeting: an example of interspecific recombination in animal mitochondrial DNA

Recombination is thought to occur only rarely in animal mitochondrial DNA ( mtDNA). However, detection of mtDNA recombination requires that cells become heteroplasmic through mutation, intramolecular recombination or ' leakage' of paternal mtDNA. Interspecific hybridization increases the probability of detecting mtDNA recombinants due to higher levels of sequence divergence and potentially higher levels of paternal leakage. During a study of historical variation in Atlantic salmon ( Salmo salar) mtDNA, an individual with a recombinant haplotype containing sequence from both Atlantic salmon and brown trout ( Salmo trutta) was detected. The individual was not an F1 hybrid but it did have an unusual nuclear genotype which suggested that it was a later-generation backcross. No other similar recombinant haplotype was found from the same population or three neighbouring Atlantic salmon populations in 717 individuals collected during 1948 - 2002. Interspecific recombination may increase mtDNA variability within species and can have implications for phylogenetic studies.