The thrifty phenotype hypothesis: thrifty offspring or thrifty mother?

Medical research is increasingly focusing on the contribution of nutritional programming to disease in later life. Programming is a process whereby a stimulus during a critical window of time permanently affects subsequent structure, function or developmental schedule of the organism. The thrifty phenotype hypothesis is widely used to interpret such studies, with early growth restriction seen as adaptation to environmental deprivation. However, such permanent adjustment is less beneficial than maintaining flexibility so as to recover from early growth deficits if the environment improves. Thus, the existing thrifty phenotype hypothesis fails to explain why plasticity is lost so early in development in species with extended growth. One explanation is that the developing organism simply cannot maintain phenotypic plasticity throughout the period of organ growth. This article adds a life history perspective, arguing that programming of the offspring may in some species benefit maternal fitness more than it does that of individual offspring. Closing the critical window early in development allows the preservation of maternal strategy in offspring phenotype, which in humans benefits the mother by constraining offspring demand after weaning. The offspring gains by being buffered against environmental fluctuations during the most sensitive period of development, allowing coherent adaptation of organ growth to the state of the environment. The critical window is predicted to close when offspring physiology becomes independent of maternal physiology, the timing of which depends on offspring trait. Because placental nutrition and lactation buffer against short-term environmental fluctuations, maternal strategy is predicted to derive from long-term experience, encapsulated in maternal size and nutritional status. Such an approach implies that public health programmes for improving birth weight may be more effective if they target maternal development rather than nutrition during pregnancy. Equally, aggressive nutritional management of infants born small or pre-term may induce the very environmental fluctuations that are naturally softened by maternal nutrition.     

Otiorhynchus sulcatus, an autopolyploid general-purpose genotype species?

The weevil Otiorhynchus sulcatus is a pest species that has spread rapidly to large parts of the world due to human activities. O. sulcatus is extremely polyphagous and found to attack a large number of agricultural and horticultural plant species despite that all individuals are clonal triploid females. I here compare the genetical variation in specimens from various parts of the distribution using both mtDNA and nuclear DNA. The genetical markers employed indicate O. sulcatus to be an evolutionary young clonal species of non-hybrid origin. The extreme polyphagy and ecological success indicate that these weevils may well be a prime example of general purpose genotypes.     

Does age, sex, or ACE genotype affect glucose and insulin responses to strength training?

The purpose of the present study was to determine whether age, sex, or angiotensin I-converting enzyme (ACE) genotype influences the effects of strength training (ST) on glucose homeostasis. Nineteen sedentary young (age = 20-30 yr) men (n = 10) and women (n = 9) were studied and compared with 21 sedentary older (age = 65-75 yr) men (n = 12) and women (n = 9) before and after a 6-mo total body ST program. Fasting insulin concentrations were reduced in young men and in older men with ST (P < 0.05 in both). In addition, total insulin area under the curve decreased by 21% in young men (P < 0.05), and there was a trend for a decrease (11%) in older men (P = 0.06). No improvements in insulin responses were observed in young or older women. The ACE deletion/deletion genotype group had the lowest fasting insulin and insulin areas under the oral glucose tolerance test (OGTT) curve before training (all P < 0.05), but those with at least one insertion allele had a trend for a greater reduction in total insulin area than deletion homozygotes (P = 0.07). These results indicate that ST has a more favorable effect on insulin response to an OGTT in men than in women and offer some support for the hypothesis that ACE genotype may influence insulin responses to ST.     

ß-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients

?-ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-?-alanine and N-carbamyl-?-aminoisobutyric acid to ?-alanine and ?-aminoisobutyric acid, ammonia and CO(2). To date, only five genetically confirmed patients with a complete ?-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified ?-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-?-alanine and N-carbamyl-?-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding ?-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant ?-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human ?-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated ?-ureidopropionase patients, indicating that ?-ureidopropionase deficiency may be more common than anticipated.     

Comparative analysis of Tritrichomonas foetus (Riedmüller, 1928) cat genotype,T. foetus (Riedmüller, 1928) cattle genotype and Tritrichomonas suis (Davaine, 1875) at 10 DNA loci

The parasitic protists in the genus Tritrichomonas cause significant disease in domestic cattle and cats. To assess the genetic diversity of feline and bovine isolates of Tritrichomonas foetus (Riedmüller, 1928) Wenrich and Emmerson, 1933, we used 10 different genetic regions, namely the protein coding genes of cysteine proteases 1, 2 and 4–9 (CP1, 2, 4–9) involved in the pathogenesis of the disease caused by the parasite. The cytosolic malate dehydrogenase 1 (MDH1) and internal transcribed spacer region 2 of the rDNA unit (ITS2) were included as additional markers. The gene sequences were compared with those of Tritrichomonas suis (Davaine, 1875) Morgan and Hawkins, 1948 and Tritrichomonas mobilensis Culberson et al., 1986. The study revealed 100% identity for all 10 genes among all feline isolates (=T. foetus cat genotype), 100% identity among all bovine isolates (=T. foetus cattle genotype) and a genetic distinctness of 1% between the cat and cattle genotypes of T. foetus. The cattle genotype of T. foetus was 100% identical to T. suis at nine loci (CP1, 2, 4–8, ITS2, MDH1). At CP9, three out of four T. suis isolates were identical to the T. foetus cattle genotype, while the T. suis isolate SUI-H3B sequence contained a single unique nucleotide substitution. Tritrichomonas mobilensis was 0.4% and 0.7% distinct from the cat and cattle genotypes of T. foetus, respectively. The genetic differences resulted in amino acid changes in the CP genes, most pronouncedly in CP2, potentially providing a platform for elucidation of genotype-specific host-pathogen interactions of T. foetus. On the basis of this data we judge T. suis and T. foetus to be subjective synonyms. For the first time, on objective nomenclatural grounds, the authority of T. suis is given to Davaine, 1875, rather than the commonly cited Gruby and Delafond, 1843. To maintain prevailing usage of T. foetus, we are suppressing the senior synomym T. suis Davaine, 1875 according to Article 23.9, because it has never been used as a valid name after 1899 and T. foetus is widely discussed as the cause of bovine trichomonosis. Thus bovine, feline and porcine isolates should all be given the name T. foetus. This promotes the stability of T. foetus for the veterinary and economically significant venereal parasite causing bovine trichomonosis.     

Personalizing foods: is genotype necessary?

The inescapable conclusion of a just a decade of nutrigenomics research must now be brought to practice. Humans differ in their responses to diet and many of these differences are being assigned to genetic polymorphisms. However, differences in the varying responses to diet between humans are not solely because of genetic variation. Lifestage, lifestyle, prior nutritional and physiological variables and even your mother's microflora all influence the differences between humans. The question becomes: are all of these inputs to an individual's health measurable as part of a nutritional phenotype assessment? The answer to this question is increasingly, yes. As variations in humans can be both measured and even more importantly understood, the implications of those measures to dietary guidance become actionable. More accurate assessment of the inputs to human health and the consequences of those inputs measured as accurate proteomic and metabolomic analyses would bring personalized health to practice far faster than waiting for a predictive knowledge of genetic variation.     

Effects of drought, temperature, herbivory, and genotype on plant–insect interactions in soybean (Glycine max)

Climate change is predicted to cause continued increases in global temperatures, greater variability in precipitation and in some cases, more frequent insect pest outbreaks. Here we seek to understand how abiotic and biotic stresses associated with climate change can affect plant-herbivore interactions in a model crop species (soybean, Glycine max (L.) Merr.) by answering three questions: (1) Do the combined effects of abiotic and biotic stresses associated with climate change cause synergistic negative effects on plant biomass? (2) Can abiotic stress affect resistance of plants to insect herbivores? (3) Does genetic variation in plant traits modify a plant’s response to stress? We performed three experiments in controlled growth environments using up to 51 soybean genotypes selected to vary in numerous traits associated with drought and resistance against pests (e.g., insect herbivores, nematodes, and pathogenic fungi), and up to 3 generalist-feeding herbivorous noctuid moth species (Helicoverpa zea, Heliothis virescens, and Spodoptera exigua) that commonly feed on soybean in North America. Drought and herbivory had the largest and the most consistent negative effects on plant performance, reducing the above- and below-ground biomass by 10-45 %, whereas increased temperature had little to no effect on plants. Drought also increased susceptibility to generalist noctuid herbivores, but these results varied dramatically in magnitude and direction among plant genotypes. Our experiments show that the effects of abiotic and biotic stress on soybean biomass were largely due to the additive effects of these stresses, and there exists substantial genetic variation in the soybean germplasm pool we studied that could be used as a source of parental stock in breeding new crops that can more effectively tolerate and resist the combined negative effects of insect herbivory and drought.     

Fatty acid–genotype interactions and cardiovascular risk

Cardiovascular disease (CVD) risk and rate of progression is determined by genetic, environmental and behavioural factors. Majority of genotype–diet–CVD phenotype research till date has focussed on the interactive impact of single nucleotide polymorphisms (SNP) and dietary fat composition, on blood lipids levels, with strong evidence of the existence of hypo- and hyper-responders. However, a recognised concern in the field of nutrigenetics is a lack of consistency between findings of different studies. This apparent lack of consistency is likely to be attributable to the impact of factors such as ethnicity and gender on the ‘size’ of nutrigenetic interactions, a clear understanding of which needs to be gained. Although not yet ready for widespread use, in the future a greater use of genetic profiling is likely to enhance current strategies of CVD prediction, and improve the design of more personalised approaches to minimise risk in the individual.     

Invasibility or invasiveness? Effects of habitat, genotype, and their interaction on invasive Rhododendron ponticum populations

The extent and nature of biological invasions are mainly influenced by either the genotype of the invading species, the suitability of the new habitat or by genotype-habitat interactions expressed in adaptations to the new environment. The relevance of these factors was assessed for the invasive evergreen shrub Rhododendron ponticum. Habitat characteristics of soil, climate and community properties were analysed in six native populations in both Georgia (Caucasus) and Spain and in six invasive ones in Ireland. Growth variables of rhododendron individuals and seedling occurrences in the field served as response variables. We performed a reciprocal transplant experiment with rhododendron cuttings and determined survival of transplants in all countries. Due to low survival rates in Georgia and Spain, vegetative increase was only analysed for Ireland. The Irish sites benefited from significantly higher nutrient supply than the Spanish and Georgian sites. We found both strong positive correlations of nutrient supply and negative correlations of seasonal temperature amplitude with growth variables of shoots and seedling density. Origin, target site and interaction effects were significant in the survival of transplanted rhododendron individuals. The Irish site was more favorable for all genotypes, but the invasive genotypes did not perform better than the native ones. The total increase in shoot length of transplants in Ireland was highest in the Irish genotypes, which might suggest adaptation of the Irish populations to their new area. In conclusion, we found evidence for invasiveness of Irish Rhododendron ponticum populations, but only in the invaded habitat. Nonetheless, habitats in the new range also seem to be well suited to native Spanish populations, supporting the idea that invasibility of these new sites also contributes to rhododendron invasion success.     

The thrifty epigenotype: An acquired and heritable predisposition for obesity and diabetes?

Obesity and type 2 diabetes arise from a set of complex gene-environment interactions. Explanations for the heritability of these syndromes and the environmental contribution to disease susceptibility are addressed by the "thrifty genotype" and the "thrifty phenotype" hypotheses. Here, the merits of both models are discussed and elements of them are used to synthesize a "thrifty epigenotype" hypothesis. I propose that: (1) metabolic thrift, the capacity for efficient acquisition, storage and use of energy, is an ancient, complex trait, (2) the environmentally responsive gene network encoding this trait is subject to genetic canalization and thereby has become robust against mutational perturbations, (3) DNA sequence polymorphisms play a minor role in the aetiology of obesity and type 2 diabetes-instead, disease susceptibility is predominantly determined by epigenetic variations, (4) corresponding epigenotypes have the potential to be inherited across generations, and (5) Leptin is a candidate gene for the acquisition of a thrifty epigenotype.     

Does the fetal genotype affect maternal physiology during pregnancy?

Conventional wisdom states that associations between fetal growth and diseases in pregnancy, such as pregnancy-induced hypertension (PIH) and gestational diabetes (GDM), result from effects of the mother's genotype or environment acting on her physiology which subsequently affect the fetus. However, recent evidence from human mothers carrying macrosomic offspring with Beckwith Wiedemann syndrome and pregnant mice carrying p57(kip2)-null offspring suggest that variation in the fetal genome can modify maternal physiology to increase fetal nutrient delivery and optimise growth. These are some of the first documented examples of such effects, whereby the genome of one individual directly affects the physiology of another related individual from the same species. We propose that this mechanism is involved in the aetiology of PIH and GDM.     

Evidence for non-random distribution of Fcγ receptor genotype combinations

Human IgG receptors (FcR) display considerable heterogeneity, and are crucial immune response modulating molecules. FcRIIA, FcRIIIA, and FcRIIIB display functional biallelic polymorphisms. FcR polymorphisms have been found associated with susceptibility to infectious and autoimmune diseases. Linked transmission of FcR alleles was studied by determining the distribution of FcRIIA-FcRIIIA-FcRIIIB genotype combinations in 514 Dutch Caucasian, and 149 Japanese blood donors. The structure of the FcR locus was studied by radiation hybrid mapping of FcRIA, FcRIIA, FcRIIB, FcRIIIA, FcRIIIB, and adjacent genes from the pentraxin family. In addition, crossing-over frequencies within the FcR locus were determined in 63 Dutch Caucasian families, encompassing 183 individuals. FcRII and FcRIII subclasses were mapped in close proximity (0.47–3.14 cR). Accordingly, crossing-over frequencies within the FcRII-III locus in Dutch families were low. Analysis of combined FcR genotypes strongly suggested non-random distribution of FcRIIA-FcRIIIA-, and FcRIIIA-FcRIIIB genotypes in Dutch donors (P<0.001 and P<0.00001, respectively), and of FcRIIA-FcRIIIb genotypes in Japanese blood donors (P<0.02). Frequencies of FcRII-FcRIII haplotypes differed significantly between Dutch and Japanese (P<0.00001). This study provides important information for the interpretation of studies reporting associations of FcR alleles with disease, and underscores the apparent differences in FcR heterogeneity between ethnic groups.     

Identification of potential inhibitors for HCV NS3 genotype 4a by combining protein–ligand interaction fingerprint, 3D pharmacophore,docking, and dynamic simulation

HCV NS3 protease domain has been one of the most attractive targets for developing new drugs for HCV infection and many drugs were successfully developed, but all of them were designed for targeting HCV genotype 1 infection. HCV genotype 4a dominant in Egypt has paid less attention. Here, we describe our protocol of virtual screening in identification of novel potential potent inhibitors for HCV NS3 of genotype 4a using homology modeling, PLIF (protein–ligand interaction fingerprint), docking, pharmacophore, and dynamic simulation. A high-quality 3D model of HCV NS3 protease of genotype 4a was constructed using crystal structure of HCV NS3 protease of genotype 1b (PDB ID: 4u01) as a template. PLIF was generated using five crystal structures of HCV NS3 (PDB ID: 4u01, 3kee, 4ktc, 4i33, and 5epn) which revealed the most important residues and their interactions with the co-crystalized ligands. A 3D pharmacophore model consisting of six features was developed from the generated PLIF data and then used as a screening filter for 11,244 compounds. Only 423 compounds passed the pharmacophore filter and entered the docking-based virtual screening stage. The highest ranked five hits from docking result (compound (C1–C5)) were selected for further analysis. They exhibited stronger interaction and higher binding affinity than HCV NS3 protease ligands. Dynamic simulation of the protein–best lead complex was performed to validate and augment the virtual screening results and it showed that these compounds have a strong binding affinity and could be very effective in treating HCV genotype 4a infections.     

Phenotype–genotype analysis in two Chinese families with Liddle syndrome

The families with Liddle syndrome show marked phenotypic variation in blood pressure, serum potassium and other clinical manifestations. Here we analyzed the correlation of genotype–phenotype in two Chinese families with Liddle syndrome. The sequence of C-terminus of SCNN1B and SCNN1G were screened in the two families with likely Liddle syndrome. In addition to hypertension and hypokalemia, one of the two pedigrees had sudden death in their family members, so the exons of 428 reported genes-related to cardiovascular diseases were screened as well in the family. A heterozygous βR566X nonsense mutation was found in the proband-1 in the first pedigree, and the proband’s sister and father. They showed mild phenotype with hypertension under control. In contrast, two of the four previous studies report that the mutation causes severe phenotype. A heterozygous βR597PfrX607 frameshift mutation was identified in the proband-2 in the second pedigree, showing malignant phenotype including resistant hypertension, hypokalemia, higher PRA and plasma angiotensin II levels. Both the proband-2 and the proband-2’s father had sudden death in their twenties, but no meaningful mutations were found by screening of the exons in 428 cardiovascular disease-related genes. However, the same mutation has been related to moderate phenotype in previous studies. Our results confirmed that the phenotypes of Liddle syndrome are varied significantly even with the same mutation. The mechanisms why the same mutation causes very different phenotype need to be explored because intervention of these modifiers may change the disease course and prognosis accordingly.     

An improved reverse genetics system for Newcastle disease virus genotype Ⅶ

正Dear Editor,Newcastle disease virus(NDV),also known as avian paramyxovirus serotype 1(APMV-1),is a member of the genus Avulavirus within the family Paramyxoviridae,order Mononegavirales(Miller et al.,2010).Although all isolated NDV strains belong to a single serotype,epidemiological studies have revealed that the genotype Ⅶ     

Leishmania infantum tropism: strain genotype or host immune status?

In apparently immunocompetent patients, Leishmania infantum provokes a spectrum of disease, ranging from simple skin lesion to severe visceral leishmaniasis, that is determined mainly by the protozoan genotype. In HIV-positive individuals, leishmanial infection results almost exclusively in visceral disease. In this review, Luigi Grodoni and Marina Gromiccia discuss the role o f the intrinsic virulence of L. infantum strains and the immune condition of the host, and focus on recently described mechanisms of immunological control of leishmanial infection.