EVOLUTION, Issue 11 2005
Lisa K. Miller
Abstract The traits thought to advertise genetic quality are often highly susceptible to environmental variation and prone to change with age. These factors may either undermine or reinforce the potential for advertisement traits to signal quality depending on the magnitude of age-dependent expression, environmental variation, and genotype-age and genotype-environment interaction. Measurements of the magnitude of these effects are thus a necessary step toward assessing the implications of age dependence and environmental variability for the evolution of signals of quality. We conducted a longitudinal study of male guppies (Poecilia reticulata) from 22 full-sibling families. Each fish was assigned at maturity to one of three treatments in order to manipulate his allocation of resources to reproduction: a control in which the male was kept alone, a courtship-only treatment in which he could see and court a female across a clear partition, and a mating treatment in which he interacted freely with a female. We measured each male's size, ornamental color patterns, courtship, attractiveness to females, and mating success at three ages. Size was influenced by treatment and age-treatment interactions, indicating that courtship and mating may impose costs on growth. Tail size and color patterns were influenced by age but not by treatment, suggesting fixed age-dependent trajectories in these advertisement traits. By contrast, display rate and attempted sneak copulation rate differed among treatments but not among ages, suggesting greater plasticity of these behavioral traits. As a result of the different patterns of variation in ornamentation and behavior, male attractiveness and mating success responded to male age, treatment, and the interaction between age and treatment. Neither age nor treatment obscured the presence of genetic variation, and the genetic relationship between male ornamentation and attractiveness remained the same among treatments. Our findings suggest that neither age-dependent variation nor environmentally induced variation in reproductive effort is likely to undermine the reliability of male signaling. [source]

GENOTYPE AND ALLELE FREQUENCIES OF N -ACETYLTRANSFERASE 2 AND GLUTATHIONE S -TRANSFERASE IN THE IRANIAN POPULATION

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2007
Anahita Torkaman-Boutorabi
SUMMARY 1.,Xenobiotic-metabolizing enzymes constitute an important line of defence against a variety of carcinogens. Many are polymorphic, constituting the basis for the wide interindividual variation in metabolic capacity and possibly a source of variation in the susceptibility to chemical-induced carcinogenesis. The aim of the present study was to determine the frequencies of important allelic variants in the N- acetyltransferase 2 (NAT2) and glutathione S- transferase (GST) genes in the Iranian population and compare them with frequencies in other ethnic populations. 2Genotyping was performed in a total of 229 unrelated healthy subjects (119 men, 110 women) for NAT2 and 170 unrelated healthy subjects (89 men, 81 women) for GST from the general Tehran population. A combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was applied for typing of NAT2 polymorphisms. Detection of GSTM1 and GSTT1 null alleles was performed simultaneously using a multiplex PCR assay. 3The frequencies of specific NAT2 alleles were 0.299, 0.314, 0.380, 0.007 and 0.000 for *4 (wild-type), *5 (C481T, M1), *6 (G590A, M2), *7 (G857A, M3) and *14 (G191A, M4), respectively. The most prevalent genotypes were NAT2 *5/*6 (29.70%) and *4/*6 (21.40%). The GSTM1 - and GSTT1 -null alleles were detected in 44.7 and 21.2% of subjects, respectively. 4We found that Iranians resemble Indians with regard to allelic frequencies of the tested variants of NAT2. The predominance of slow (49.36%) and intermediate (41.47%) acetylation status compared with wild-type rapid acetylation status (9.17%) in the study group suggests the significant prevalence of the slow acetylator (SA) phenotypes in the Iranian population. Our data confirmed that Iranians are similar to other Caucasian populations in the frequency of both GSTM1 - and GSTT1 -null alleles. [source]

DIFFERENTIAL PERFORMANCE AMONG LDH-B GENOTYPES IN RANA LESSONAE TADPOLES

EVOLUTION, Issue 5 2000
Hansjürg Hotz
Abstract The European pool frog, Rana lessonae, is widely polymorphic for two common alleles (b, e) at the lactate dehydrogenase-B (LDH-B) locus. We compared fitness-related larval life-history traits among LDH-B genotypes, which originated from segregation in heterozygous parents, in an artificial pond experiment where tadpoles of R. lessonae from a Swiss population were raised together with tadpoles of the hemiclonal hybrid R. esculenta at two densities. In R. lessonae, LDH-B e/e homozygotes at each density had a higher proportion of metamorphs among survivors, reached metamorphosis earlier, and were heavier at metamorphosis than b/b homozygotes; b/e heterozygotes had intermediate values. That e/e individuals were superior to b/b in both time to and mass at metamorphosis is surprising because these two life-history traits are thought to reflect a performance trade-off; e/e genotypes apparently compensated for shorter time to metamorphosis by a higher growth rate. The two alleles showed the same performance ranking when combined in hybrids with a R. ridibunda allele: When R. esculenta from Swiss populations reared in the same ponds had received the e allele rather than the b allele from their R. lessonae parent, they reached metamorphosis earlier, but did not differ in mass at metamorphosis. The degree of linkage disequilibrium in the source population of the eight R. lessonae used as parents of the R. lessonae tadpoles is unknown, so we cannot exclude the possibility that the performance differences are caused by some anonymous tightly linked gene, rather than the LDH-B locus, that constitutes the genomically localized target of natural selection. A causal involvement of LDH-B is plausible, nevertheless, because this enzyme takes part in the central energy-metabolizing processes and has been reported to underlie fitness differences in other animals; also, differential performance of LDH-B genotypes has been observed in R. lessonae larvae from another population. The present results suggest strong directional selection for allele e; the sum of available data, including an independent laboratory experiment, suggests that partial environment-dependent overdominance combined with balancing selection favoring e/e homozygotes under some and b/b homozygotes under other conditions may be partially responsible for the broad maintenance of the LDH-B polymorphism in R. lessonae. [source]

APOLIPOPROTEIN E GENOTYPES IN MILD COGNITIVE IMPAIRMENT SUBTYPES

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 12 2006
Giuseppe Orsitto MD
No abstract is available for this article. [source]

SENSORY CHARACTERISTICS OF TRADITIONAL FIELD GROWN TOMATO GENOTYPES IN SOUTHERN ITALY

JOURNAL OF FOOD QUALITY, Issue 6 2007
FIORELLA SINESIO
ABSTRACT This study was conducted with the aim to characterize the diversity of fruit sensory quality of traditional tomato genotypes, grown in open fields, by means of descriptive profile analysis. It gives the results from sensory profiling of fresh tomato genotypes San Marzano, Vesuviano, Corbarino and Sorrento, originating from Southern Italy, and their respective commercial hybrids over 3 years of harvesting. The effects of genotypes, year of production (2002, 2003, 2004) and fields located in different geographical areas on sensory data were analyzed using principal component analysis and multivariate analysis of variance partial least square regression. For most sensory characteristics, the greatest variation was caused by differences in genotypes, suggesting that there was considerable level of genetic diversity. Minor effects were given to year of harvest and experimental fields. PRACTICAL APPLICATIONS Tomato is one of the most frequently consumed vegetables in many countries. Italy is one of the main tomato producers in the world, where the genetic variability among traditional tomato genotypes, hybrid and wild varieties in terms of variability in shape, dimension and sensorial attributes is enormous. A feasible area of improvement of tomato production is toward the increase or changing the original flavor. The knowledge of the effect of variety and season on sensory-perceived quality and the selection by breeding of genotypes with improved aroma and flavor profile is a tool to better orientate the tomato production. [source]

DIRECT AND CORRELATED RESPONSES TO SELECTION IN A HOST,PARASITE SYSTEM: TESTING FOR THE EMERGENCE OF GENOTYPE SPECIFICITY

EVOLUTION, Issue 8 2007
Thibault Nidelet
Genotype × environment interactions can facilitate coexistence of locally adapted specialists. Interactions evolve if adaptation to one environment trades off with performance in others. We investigated whether evolution on one host genotype traded off with performance on others in long-term experimental populations of different genotypes of the protozoan Paramecium caudatum, infected with the bacterial parasite Holospora undulata. A total of nine parasite selection lines evolving on three host genotypes and the ancestral parasite were tested in a cross-infection experiment. We found that evolved parasites produced more infections than did the ancestral parasites, both on host genotypes they had evolved on (positive direct response to selection) and on genotypes they had not evolved on (positive correlated response to selection). On two host genotypes, a negative relationship between direct and correlated responses indicated pleiotropic costs of adaptation. On the third, a positive relationship suggested cost-free adaptation. Nonetheless, on all three hosts, resident parasites tended to be superior to the average nonresident parasite. Thus genotype specificity (i.e., patterns of local adaptation) may evolve without costs of adaptation, as long as direct responses to selection exceed correlated responses. [source]

Genotype,phenotype correlation in skin fragility-ectodermal dysplasia syndrome resulting from mutations in plakophilin 1

EXPERIMENTAL DERMATOLOGY, Issue 2 2002
T. Hamada
Abstract: We report a 42-year-old Japanese man with an unusual autosomal recessive genodermatosis. The clinical features comprised normal skin at birth, loss of scalp hair at 3-months of age after a febrile illness, progressive nail dystrophy during infancy, palmoplantar keratoderma starting around the age of 18 years and trauma-induced skin fragility and blisters noted from the age of 20 years. Skin biopsy of rubbed non-lesional skin revealed widening of spaces between adjacent keratinocytes from the suprabasal layer upwards. Electron microscopy demonstrated a reduced number of hypoplastic desmosomes. Immunohistochemical labeling showed a reduction in intercellular staining for the desmosome component plakophilin 1. Mutation analysis revealed a homozygous intron 11 donor splice site mutation in the plakophilin 1 gene, 2021+1 G>A (GenBank no. Z34974). RT-PCR, using RNA extracted from the skin biopsy, provided evidence for residual low levels of the full-length wild-type transcript (,8%) as well as multiple other near full-length transcripts, one of which was in frame leading to deletion of 17 amino acids from the 9th arm-repeat unit of the plakophilin 1 tail domain. Thus, the molecular findings help explain the clinical features in the patient, who has a similar but milder phenotype to previously reported patients with skin fragility-ectodermal dysplasia syndrome associated with complete ablation of plakophilin 1 (OMIM 604536). This new ,mitis' phenotype provides further clinicopathological evidence for the role of plakophilin 1 in keratinocyte cell,cell adhesion and ectodermal development. [source]

Angiotensin-Converting Enzyme Genotype Affects the Response of Human Skeletal Muscle to Functional Overload

EXPERIMENTAL PHYSIOLOGY, Issue 5 2000
Jonathan Folland
The response to strength training varies widely between individuals and is considerably influenced by genetic variables, which until now, have remained unidentified. The deletion (D), rather than the insertion (I), variant of the human angiotensin-converting enzyme (ACE) genotype is an important factor in the hypertrophic response of cardiac muscle to exercise and could also be involved in skeletal muscle hypertrophy , an important factor in the response to functional overload. Subjects were 33 healthy male volunteers with no experience of strength training. We examined the effect of ACE genotype upon changes in strength of quadriceps muscles in response to 9 weeks of specific strength training (isometric or dynamic). There was a significant interaction between ACE genotype and isometric training with greater strength gains shown by subjects with the D allele (mean ± S.E.M.: II, 9.0 ± 1.7%; ID, 17.6 ± 2.2%; DD, 14.9 ± 1.3%, ANOVA, P 0.05). A consistent genotype and training interaction (ID DD II) was observed across all of the strength measures, and both types of training. ACE genotype is the first genetic factor to be identified in the response of skeletal muscle to strength training. The association of the ACE I/D polymorphism with the responses of cardiac and skeletal muscle to functional overload indicates that they may share a common mechanism. These findings suggest a novel mechanism, involving the renin-angiotensin system, in the response of skeletal muscle to functional overload and may have implications for the management of conditions such as muscle wasting disorders, prolonged bed rest, ageing and rehabilitation, where muscle weakness may limit function. [source]

Genotype and mating type analysis of Cryptococcus neoformans and Cryptococcus gattii isolates from China that mainly originated from non-HIV-infected patients

FEMS YEAST RESEARCH, Issue 6 2008
Xiaobo Feng
Abstract Cryptococcosis has been reported to be mostly associated with non-HIV-related patients in China. However, little is known about the molecular characteristics of clinical isolates from the Cryptococcus neoformans species complex in this country. In this study, 115 clinical isolates were included. Molecular type VNI was the most representative (n=103), followed by VGI (n=8), VNIII (n=2), VNIV (n=1), and VGII (n=1). With the exception of a serotype D mating type a isolate, all possessed the MAT, locus. Multilocus sequence typing (MLST) revealed that most Cryptococcus gattii isolates from China shared identical MLST profiles with the most common MLST genotype reported in the VGI group, and the only one VGII isolate resembled the Vancouver Island outbreak minor genotype. The C. gattii strains involved in this study were successfully grouped according to their molecular type and mating types by PCR-restriction fragment length polymorphism (RFLP) analysis of the GEF1 gene. Our results suggest that (1) in China, cryptococcosis is mostly caused by C. neoformans var. grubii (molecular type VNI), and mating type ,; (2) The most common causative agents of C. gattii infection in China are closely related to a widely distributed MLST genotype; and (3) The PCR-RFLP analysis of the GEF1 gene has the potential to identify the molecular and mating types of C. gattii simultaneously. [source]

Power calculations for likelihood ratio tests for offspring genotype risks, maternal effects, and parent-of-origin (POO) effects in the presence of missing parental genotypes when unaffected siblings are available

GENETIC EPIDEMIOLOGY, Issue 1 2007
E. Rampersaud
Abstract Genotype-based likelihood-ratio tests (LRT) of association that examine maternal and parent-of-origin effects have been previously developed in the framework of log-linear and conditional logistic regression models. In the situation where parental genotypes are missing, the expectation-maximization (EM) algorithm has been incorporated in the log-linear approach to allow incomplete triads to contribute to the LRT. We present an extension to this model which we call the Combined_LRT that incorporates additional information from the genotypes of unaffected siblings to improve assignment of incompletely typed families to mating type categories, thereby improving inference of missing parental data. Using simulations involving a realistic array of family structures, we demonstrate the validity of the Combined_LRT under the null hypothesis of no association and provide power comparisons under varying levels of missing data and using sibling genotype data. We demonstrate the improved power of the Combined_LRT compared with the family-based association test (FBAT), another widely used association test. Lastly, we apply the Combined_LRT to a candidate gene analysis in Autism families, some of which have missing parental genotypes. We conclude that the proposed log-linear model will be an important tool for future candidate gene studies, for many complex diseases where unaffected siblings can often be ascertained and where epigenetic factors such as imprinting may play a role in disease etiology. Genet. Epidemiol. © 2006 Wiley-Liss, Inc. [source]

Shift in birch leaf metabolome and carbon allocation during long-term open-field ozone exposure

GLOBAL CHANGE BIOLOGY, Issue 5 2007
SARI KONTUNEN-SOPPELA
Abstract Current and future ozone concentrations have the potential to reduce plant growth and increase carbon demand for defence and repair processes, which may result in reduced carbon sink strength of forest trees in long-term. Still, there is limited understanding regarding the alterations in plant metabolism and variation in ozone tolerance among tree species and genotypes. Therefore, this paper aims to study changes in birch leaf metabolome due to long-term realistic ozone stress and to relate these shifts in the metabolism with growth responses. Two European white birch (Betula pendula Roth) genotypes showing different ozone sensitivity were growing under 1.4,1.7 × ambient ozone in open-field conditions in Central Finland. After seven growing seasons, the trees were analysed for changes in leaf metabolite profiling, based on 339 low molecular weight compounds (including phenolics, polar and lipophilic compounds, and pigments) and related whole-tree growth responses. Genotype caused most of the variance of metabolite concentrations, while ozone concentration was the second principal component explaining the metabolome profiling. The main ozone caused changes included increases in quercetin-phenolic compounds and compounds related to leaf cuticular wax layer, whereas several compounds related to carbohydrate metabolism and function of chloroplast membranes and pigments (such as chlorophyll-related phytol derivatives) were decreasing. Some candidate compounds such as surface wax-related squalene, 1-dotriacontanol, and dotriacontane, providing growth-related tolerance against ozone were demonstrated. This study indicated that current growth-based ozone risk assessment methods are inadequate, because they ignore ecophysiological impacts due to alterations in leaf chemistry. [source]

Risk factors for inhibitor formation in haemophilia: a prevalent case,control study

HAEMOPHILIA, Issue 5 2009
M. V. RAGNI
Summary., Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case,control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200 U per exposure, P < 0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.0%) vs. zero of 57 (0%), P < 0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P < 0.001, and survival was shorter, 14 vs. 38 yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P > 0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. ,120 BU/mL, six vs. 16 months, P < 0.01, but unaffected by tolerizing dose regimen, P > 0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. [source]

Distinctiveness of the cagA Genotype in Children and Adults with Peptic Symptoms in South China

HELICOBACTER, Issue 4 2009
Juan Li
Abstract Background:,Helicobacter pylori infection is different between children and adults, not only in infection rate but also in virulence genotypes. However, the 3, region of CagA, important in stomach carcinogenesis, still remains unclear in children. The present study aims to compare the frequency of cagA and the distribution of its subtypes between children and adults in South China. Materials and Methods:, One hundred and twenty-eight children and 99 adults with peptic symptoms were enrolled in our research. Histology, rapid urease test, and real-time polymerase chain reaction (PCR) assay were used to diagnose H. pylori infection. vacA s1 was detected by real-time PCR, and EPIYA motifs in the 3, region of CagA by conventional PCR and DNA sequencing. Results:,H. pylori infection was diagnosed in 53 children and 62 adults. vacA s1 was identified in 90.6% and 91.9% of infected children and adults, respectively. Furthermore, cagA was identified in 73.6% and 82.3% of infected children and adults, respectively. No patient with multiple cagA subtypes was observed. A higher prevalence of more virulent cagA genotype was found in children compared to adults (p < .05). Thirty-eight of 39 (97.4%) cagA -positive children were found to have EPIYA-ABD and only one (2.6%) with EPIYA-ABC. In adults, four types of EPIYA motifs , ABC (29.4%), ABD (64.7%), ABAB (2%), and AAD (3.9%) , were identified, and the ABD type was found more commonly in severe diseases, such as atrophic gastritis (53.3%) and gastric cancer (71.4%). Conclusion:,cagA genotypes in children and in adults are different, and EPIYA-ABD may have potential clinical implication in the development of gastric cancer in South China. [source]

Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus,induced cirrhosis.

HEPATOLOGY, Issue 6 2010
A 12-year prospective follow-up study
The incidence of de novo development of esophageal varices (EV) in patients with compensated liver cirrhosis has been determined by few studies in the short term and never in the long term. The aims of the present study were to determine the incidence and the risk factors associated with the development of EV and to assess whether antiviral treatment and achievement of sustained virologic response (SVR) may prevent de novo EV development in patients with HCV-induced cirrhosis. We studied 218 patients with compensated EV-free, HCV-induced cirrhosis consecutively enrolled between 1989 and 1992 at three referral centers in Milan, Italy. Endoscopic surveillance was performed at 3-year intervals according to international guidelines. SVR was defined as undetectable serum HCV-RNA 24 weeks after treatment discontinuation. During a median follow-up of 11.4 years, 149/218 (68%) patients received antiviral treatment and 34 (22.8%) achieved SVR. None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non-SVR patients (P < 0.0001). On multivariate analysis, HCV genotype 1b (hazard ratio [HR] 2.40; 95% confidence interval [CI] 1.17-4.90) and baseline model for end-stage liver disease (MELD) score (HR 1.20; 95% CI 1.07-1.35 for 1 point increase) were independent predictors of EV. Conclusion: In the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV-induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance. Hepatology 2010 [source]

Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam,

HEPATOLOGY, Issue 6 2006
Nguyen L. Toan
Eight genotypes (A-H) of hepatitis B virus (HBV) have been identified. However, the impact of different genotypes on the clinical course of hepatitis B infection remains controversial. We investigated the frequency and clinical outcome of HBV genotypes and genotype mixtures in HBV-infected patients from Vietnam, Europe, and Africa. In addition, we analyzed the effects of genotype mixtures on alterations in in vitro viral replication. In Asian patients, seven genotypes (A-G) were detected, with A, C, and D predominating. In European and African patients, only genotypes A, C, D, and G were identified. Genotype mixtures were more frequently encountered in African than in Asian (P = .01) and European patients (P = .06). In Asian patients, the predominant genotype mixtures included A/C and C/D, compared to C/D in European and A/D in African patients. Genotype A was more frequent in asymptomatic compared with symptomatic patients (P < .0001). Genotype C was more frequent in patients with hepatocellular carcinoma (HCC; P = .02). Genotype mixtures were more frequently encountered in patients with chronic hepatitis in comparison to patients with acute hepatitis B (P = .015), liver cirrhosis (P = .013), and HCC (P = .002). Viral loads in patients infected with genotype mixtures were significantly higher in comparison to patients with a single genotype (P = .019). Genotype mixtures were also associated with increased in vitro HBV replication. In conclusion, infection with mixtures of HBV genotypes is frequent in Asia, Africa, and Europe. Differences in the replication-phenotype of single genotypes compared to genotype-mixtures suggest that co-infection with different HBV-genotypes is associated with altered pathogenesis and clinical outcome. (HEPATOLOGY 2006;43:1375,1384.) [source]

Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype,phenotype correlations,

HUMAN MUTATION, Issue 7 2009
Jordan P. Lerner-Ellis
Abstract Methylmalonic aciduria and homocystinuria, cblC type, is a rare disorder of intracellular vitamin B12 (cobalamin [Cbl]) metabolism caused by mutations in the MMACHC gene. MMACHC was sequenced from the gDNA of 118 cblC individuals. Eleven novel mutations were identified, as well as 23 mutations that were observed previously. Six sequence variants capture haplotype diversity in individuals across the MMACHC interval. Genotype,phenotype correlations of common mutations were apparent; individuals with c.394C>T tend to present with late-onset disease whereas patients with c.331C>T and c.271dupA tend to present in infancy. Other missense variants were also associated with late- or early-onset disease. Allelic expression analysis was carried out on human cblC fibroblasts compound heterozygous for different combinations of mutations including c.271dupA, c.331C>T, c.394C>T, and c.482G>A. The early-onset c.271dupA mutation was consistently underexpressed when compared to control alleles and the late-onset c.394C>T and c.482G>A mutations. The early-onset c.331C>T mutation was also underexpressed when compared to control alleles and the c.394C>T mutation. Levels of MMACHC mRNA transcript in cell lines homozygous for c.271dupA, c.331C>T, and c.394C>T were assessed using quantitative real-time RT-PCR. Cell lines homozygous for the late onset c.394C>T mutation had significantly higher levels of transcript when compared to cell lines homozygous for the early-onset mutations. Differential or preferential MMACHC transcript levels may provide a clue as to why individuals carrying c.394C>T generally present later in life. Hum Mutat 30:1,10, 2009. © 2009 Wiley-Liss, Inc. [source]

Genotype,phenotype correlations in hereditary familial retinoblastoma,

HUMAN MUTATION, Issue 3 2007
Melissa Taylor
Abstract We studied 50 unrelated pedigrees with a family history of retinoblastoma (Rb) (165 carriers of a RB1 mutation) to delineate the spectrum of RB1 germline mutations in familial Rb and to identify genotype,phenotype correlations as well as putative modifiers. Patients were followed at Institut Curie and they were examined by an ophthalmologist, a pediatrician, and a geneticist. All cases of familial Rb were determined via genetic counseling. Clinical features included disease status, laterality, age at diagnosis, mutation type, follow-up, and disease,eye ratio (DER). To eliminate mosaic cases, first-generation carriers displaying low-penetrance (LP) Rb were excluded from the analysis. Complete penetrance was the rule for nonsense and frameshift mutations (25 families) and high penetrance was observed for large rearrangements (eight families). Promoter (two families) and missense (two families) mutations displayed heterogeneous phenotypes and LP. Variable penetrance was observed for splice abnormalities (13 families) and was explained by in/out of frame mutations or respect of functional domains. Surprisingly, two families with the LP g.45867G>T/IVS6+1G>T mutation presented data that conflicted with the data reported in previous publications, as unaffected carriers had paternally inherited mutant alleles. Moreover, RNA analyses suggested that the lack of penetrance in unaffected carriers could be explained by an increase in expression levels of the wild-type allele. This observation prompted us to define a new class "3" of LP alleles. We believe this is the first large-scale study of familial Rb with a high level of homogeneity in the clinical and genetic analysis of patients and their relatives, thereby allowing for reliable intrafamilial genotype,phenotype correlations. Our analysis suggests in some cases the influence of modifier factors probably involved in mRNA level regulation and/or pRB pathway regulation. Hum Mutat 28(3), 284,293, 2007. © 2006 Wiley-Liss, Inc. [source]

Mutations in RYR1 in malignant hyperthermia and central core disease,

HUMAN MUTATION, Issue 10 2006
Rachel Robinson
Abstract The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation,contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. The majority of gene mutations reported are missense changes identified in cases of MH and CCD. In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype,phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions. Hum Mutat 27(10), 977,989, 2006. © 2006 Wiley-Liss, Inc. [source]

Genotype,phenotype correlation in von Hippel-Lindau families with renal lesions

HUMAN MUTATION, Issue 5 2004
Catherine Gallou
The original article to which this Erratum refers was published in Human Mutation 24:215,224 Human Mutation(2004) 24(3) 215,224 In the published version of this article, the key to Figure 2 was omitted. Please find Figure 2 printed here in its entirety. [source]

Novel NOD2 haplotype strengthens the association between TLR4 Asp299gly and Crohn's disease in an Australian population

INFLAMMATORY BOWEL DISEASES, Issue 5 2008
Georgia E. Hume MD
Abstract Background: The first major Crohn's disease (CD) susceptibility gene, NOD2, implicates the innate intestinal immune system and other pattern recognition receptors in the pathogenesis of this chronic, debilitating disorder. These include the Toll-like receptors, specifically TLR4 and TLR5. A variant in the TLR4 gene (A299G) has demonstrated variable association with CD. We aimed to investigate the relationship between TLR4 A299G and TLR5 N392ST, and an Australian inflammatory bowel disease cohort, and to explore the strength of association between TLR4 A299G and CD using global meta-analysis. Methods: Cases (CD = 619, ulcerative colitis = 300) and controls (n = 360) were genotyped for TLR4 A299G, TLR5 N392ST, and the 4 major NOD2 mutations. Data were interrogated for case-control analysis prior to and after stratification by NOD2 genotype. Genotype,phenotype relationships were also sought. Meta-analysis was conducted via RevMan. Results: The TLR4 A299G variant allele showed a significant association with CD compared to controls (P = 0.04) and a novel NOD2 haplotype was identified which strengthened this (P = 0.003). Furthermore, we identified that TLR4 A299G was associated with CD limited to the colon (P = 0.02). In the presence of the novel NOD2 haplotype, TLR4 A299G was more strongly associated with colonic disease (P < 0.001) and nonstricturing disease (P = 0.009). A meta-analysis of 11 CD cohorts identified a 1.5-fold increase in risk for the variant TLR4 A299G allele (P < 0.00001). Conclusions:TLR 4 A299G appears to be a significant risk factor for CD, in particular colonic, nonstricturing disease. Furthermore, we identified a novel NOD2 haplotype that strengthens the relationship between TLR4 A299G and these phenotypes. (Inflamm Bowel Dis 2007) [source]

Multidrug resistance 1 gene polymorphism and susceptibility to inflammatory bowel disease

INFLAMMATORY BOWEL DISEASES, Issue 5 2007
S. Ardizzone MD
Abstract Background: Several studies have evaluated the role of the multidrug resistance 1 gene (MDR1) polymorphism, which encodes the membrane-bound efflux transporter P-glycoprotein 170, in determining susceptibility to and disease behavior in inflammatory bowel disease (IBD), but with conflicting results. Methods: A total of 211 patients with Crohn's disease (CD), 97 patients with ulcerative colitis (UC), and 212 control subjects were investigated for the presence of MDR1 G2677T/A and C3435T polymorphisms. Genotype frequencies of CD and UC patients were compared to those observed in a control population. Genotype,phenotype correlations with major clinical features were also established and estimated risks (odds ratio [OR] with 95% confidence interval [CI]) for the mutations were calculated by a logistic regression analysis and multiple correspondent analysis. Results: No significant difference was observed for genotype frequencies for both MDR1 G2677T/A and C3435T polymorphisms on overall disease susceptibility for either CD or UC patients compared with control subjects. A significant association was found between the MDR1 C3435T polymorphism and patients with ileo-colonic CD (OR = 3.34; 95% CI: 1.34,8.27). Interestingly, a negative association was found between MDR1 C3435T polymorphism in patients with a positive family history for IBD (OR = 0.44; 95% CI: 0.20,0.95) and articular manifestations (OR = 0.29; 95% CI: 0.13,0.68). Both susceptible and protective effects were identified. No significant association between G2677T/A polymorphism and any specific subphenotypes was found, nor was there any association with subphenotypic categories of UC and both single nucleotide polymorphisms. Conclusions: The results of our study suggest that MDR1 gene polymorphism could have a role in determining susceptibility to IBD. The variability of this possible effect in the several studies reported so far may be the indirect expression of the complex role played by the MDR1 gene and its product, P-glycoprotein 170, in the regulation of host,bacteria interactions and in the pathogenesis of IBD. (Inflamm Bowel Dis 2007) [source]

Short/long heterozygotes at 5HTTLPR and white matter lesions in geriatric depression

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 3 2008
David C. Steffens
Abstract Objective We examined the relationship between 5HTTLPR genotype and volume of magnetic resonance imaging (MRI) brain lesions. Method We studied 217 older depressed patients and 141 individuals in the comparison group using a standard brain MRI protocol to calculate lesion volumes. Genotype at 5HTTLPR was determined for each subject. Results In age-adjusted models, the l/s genotype was associated with increased volume of total and white-matter lesions among depressed patients. This relationship lost significance in models controlling for reported hypertension. Conclusions The finding that 5HTTLPR heterozygotes have higher vascular lesion volumes may be related to development of hypertension. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Morphological Traits above the Flag Leaf Node as Indicators of Drought Susceptibility Index in Durum Wheat

JOURNAL OF AGRONOMY AND CROP SCIENCE, Issue 2 2007
D. Villegas
Abstract Selection criteria for drought tolerance would be helpful tools for wheat breeding programmes. To assess the usefulness of some morphological traits above the flag leaf node as indicators of yield and the susceptibility index (SI) of Fischer and Maurer, 10 durum wheat genotypes were used in experiments conducted under two water regimes at two latitudes in Spain during 3 years. Morphological traits were measured at anthesis, and yield, yield components and quality traits were evaluated at ripening. Principal components analysis showed associations between morphological traits and yield, yield components and quality, most of them caused by differences between environments. Peduncle weight, spike weight and length and awn length were significantly related to SI within environments. Spike and peduncle weight were the traits more related to yield and SI in all the experiments together and in the rainfed sites, while in the irrigated sites spike length was better. The spike weight and length were negatively associated with SI, while peduncle weight was positively associated to SI. Genotype means across all experiments were associated with SI values. These morphological traits could be selection criteria in breeding programmes to obtain varieties with good yield stability. The genetic variability found suggests opportunity for selection. [source]

Apolipoprotein E Genotype and Mortality: Findings from the Cache County Study

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 6 2005
Kathleen M. Hayden PhD
Objectives: To evaluate the association between apolipoprotein E (apo E) ,4 and mortality, the population attributable risk for mortality with ,4, and relative contributions of cardiovascular disease (CVD) and Alzheimer's disease (AD). Design: Population-based cohort study. Setting: Community-based. Participants: Permanent residents of Cache County, Utah, aged 65 and older as of January 1, 1995. Measurements: Participants were genotyped at the apo E locus using buccal-swab deoxyribonucleic acid. Cardiovascular health was ascertained using self- or proxy-report interviews at participants' residences. AD was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, and National Institute of Neurological and Communicative Disorders and Stroke,Alzheimer's Disease and Related Disorders criteria. Utah Department of Vital Statistics quarterly reports were reviewed to identify participants who died. Results: Crude evaluations showed nonsignificantly greater risk of death for ,2/2 (hazard ratio (HR)=1.66, 95% confidence interval (CI)=0.92,2.76) and ,3/4 (HR=1.11, 95% CI=0.97,1.26) genotypes and significantly greater risk for ,4/4 (HR=1.48, 95% CI=1.09,1.96). After adjustment for age, age2, sex, and education, risks increased to 1.98 (95% CI=1.08,3.35), 1.28 (95% CI=1.12,1.46), and 2.02 (95% CI=1.47,2.71), respectively, compared with ,3/3 genotypes. Adjustment for presence of any CVD did not change the risk of death for ,3/4 and ,4/4. Adjustment for AD reduced the risk of death for ,3/4 (HR=1.13, 95% CI=0.99,1.30) and ,4/4 (HR=1.59, 95% CI=1.15,2.14). The population attributable risk of death for ,3/4 and ,4/4 genotypes combined is estimated at 9.6%. Conclusion: These findings suggested that the ,2/2, ,3/4, and ,4/4 genotypes have greater early mortality risks. Further analyses showed that AD partially mediates the association between ,3/4, ,4/4, and death. [source]

Association Between Exercise and Pubertal BMD Is Modulated by Estrogen Receptor , Genotype,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2004
Miia Suuriniemi MSc
Abstract Genetic and environmental factors contribute to bone mass, but the ways they interact remain poorly understood. This study of 245 pre- and early pubertal girls found that the PvuII polymorphism in the ER -, gene modulates the effect of exercise on BMD at loaded bone sites. Introduction: Impaired achievement of bone mass at puberty is an important risk factor for the development of osteoporosis in later life. Genetic, as well as environmental, factors contribute to bone mass, but the ways they interact with each other remain poorly understood. Materials and Methods: We investigated the interaction between a PvuII polymorphism at the ER -, gene and physical activity (PA) on the modulation of bone mass and geometry in 245 10- to 13-year-old pre- and early pubertal Finnish girls. Level of PA was assessed using a questionnaire. Bone properties were measured using DXA and pQCT. The analyses were controlled for the effects of Tanner stage and body size index. Results: Girls with heterozygote ER-, genotype (Pp) and high PA had significantly higher bone mass and BMD, as well as thicker cortex, at loaded bone sites than their low-PA counterparts. No differences were found in bone properties of the distal radius, which is not a weight-bearing bone. Bone properties did not differ in either homozygote groups (PP and pp) regardless of the PA level. Conclusions: These findings suggest that the PvuII polymorphism in the ER -, gene may modulate the effect of exercise on BMD at loaded bone sites. The heterozygotes may benefit most from the effect of exercise, whereas neither of the homozygote groups received any significant improvement from high PA. Furthermore, high PA may hide the genetic influence on bone. Indeed, it seems that one may compensate one's less favorable Pp genotype by increasing leisure PA at early puberty. [source]

Idiopathic Hyperphosphatasia and TNFRSF11B Mutations: Relationships Between Phenotype and Genotype,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2003
Belinda Chong
Abstract Homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin, were found in affected members from six of nine families with idiopathic hyperphosphatasia. The severity of the phenotype was related to the predicted effects of the mutations on osteoprotegerin function. Introduction: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption. Materials and Methods: We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined. Results: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype. Conclusion: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships. [source]

The Association Between Heel Ultrasound and Hormone Replacement Therapy Is Modulated by a Two-Locus Vitamin D and Estrogen Receptor Genotype

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2000
Yves Giguère
Abstract Evidence supports the role of estrogen deprivation in the process of bone remodeling and increased risk of fracture in postmenopausal women but little is known about the genetic basis of individual differences in response to therapy. In a cross-sectional study, 425 ambulatory postmenopausal French-Canadian women from Quebec (age range, 42,85 years old) were genotyped for a common Bsm I polymorphism at the vitamin D receptor (VDR) gene as well as a Pvu II polymorphism in the estrogen receptor (ESR1) gene. Heel ultrasound was determined by right calcaneal quantitative ultrasound (QUS) and results were expressed as an age- and-weight-adjusted stiffness index (heel SI z score). Our aim was to investigate the interaction between hormone-replacement therapy (HRT) and receptor genotypes in an effect on heel SI. Notably, a two-locus genotype (VDR-bb/ESR-PP) present in 9.5% of women was responsible for over 30% of the total HRT-related heel SI difference in the whole sample. Women bearing this combined VDR/ESR1 genotype who received HRT for more than 5 years had a 21% (1.25 SD) greater heel SI (p = 0.002) than those bearing the same genotype but who received HRT for <5 years. This may translate into a 2- to 3-fold difference in the risk of fracture. Although follow-up studies are needed, our findings suggest that QUS of the heel in postmenopausal women taking HRT is affected by variation in VDR and ESR1 loci, jointly. [source]

Single-nucleotide polymorphisms in the IL-4 and IL-13 promoter region in aggressive periodontitis

JOURNAL OF CLINICAL PERIODONTOLOGY, Issue 6 2007
J. R. Gonzales
Abstract Introduction: IL-4 and IL-13 polymorphisms have been shown to influence the susceptibility to systemic diseases. In this study, possible associations between the IL-4 ,590 C,T, IL-4 ,34 C,T, IL-13 ,1112 C,T and IL-13 ,1512 A,C promoter polymorphisms were investigated in subjects with generalized aggressive periodontitis (AgP) compared with healthy individuals. Material and Methods: Fifty-eight patients with diagnosis of generalized AgP and 51 matched healthy controls participated in the study. Blood samples were collected and DNA isolated. Molecular analyses were performed by PCR-RFLP in a blind fashion. Genotype and allele frequencies among study groups were compared using Fisher's exact test (, value: 0.05). Pearson's ,2 test was used for analysis of Hardy,Weinberg equilibrium. Results: The frequency of the IL-4 ,590 T/T and IL-4 ,34 T/T genotypes differed significantly between groups (p=0.05, 0.02, respectively), although the allele frequencies were similar. There was a higher frequency of the IL-4 ,590 T/T and IL-4 ,34 T/T genotypes in patients with AgP compared with controls. The genotype and allele frequencies of the IL-13 polymorphisms did not differ between groups. Conclusions: This study demonstrated an association between the IL-4 ,590 T/T and IL-4 ,34 T/T genotypes and AgP. Further research is necessary to prove if there is an association of these polymorphisms with AgP, and if the polymorphisms have a functional effect. [source]

The role of genotypic diversity in determining grassland community structure under constant environmental conditions

JOURNAL OF ECOLOGY, Issue 5 2007
RAJ WHITLOCK
Summary 1A recent experiment varied the genetic diversity of model grassland communities under standardized soil and management conditions and at constant initial species diversity. After 5 years' growth, genetically diverse communities retained more species diversity and became more similar in species composition than genetically impoverished communities. 2Here we present the results of further investigation within this experimental system. We proposed that two mechanisms , the first invoking genetically determined and constant differences in plant phenotypes and the second invoking genotype,environment interactions , could each underpin these results. This mechanistic framework was used as a tool to interpret our findings. 3We used inter-simple sequence repeat (ISSR) DNA markers to confirm which of the individuals of six study species initially included in the model communities were unique genotypes. We then used the molecular markers to assess the survival and abundance of each genotype at the end of the 5-year experimental period. 4The DNA marker data were used to create, for the first time, a genotype abundance hierarchy describing the structure of a community at the level of genotypes. This abundance hierarchy revealed wide variation in the abundance of genotypes within species, and large overlaps in the performance of the genotypes of different species. 5Each genotype achieved a consistent level of abundance within genetically diverse communities, which differed from that attained by other genotypes of the same species. The abundance hierarchy of genotypes within species also showed consistency across communities differing in their initial level of genetic diversity, such that species abundance in genetically impoverished communities could be predicted, in part, by genotypic identity. 6Three species (including two canopy-dominants) experienced shifts in their community-level genotype abundance hierarchies that were consistent with an increased influence of genotype,environment interactions in genetically impoverished communities. 7Our results indicate that under relatively constant environmental conditions the species abundance structure of plant communities can in part be predicted from the genotypic composition of their component populations. Genotype,environment interactions also appear to shape the structure of communities under such conditions, although further experiments are needed to clarify the magnitude and mechanism of these effects. [source]

Caligus elongatus Nordmann genotypes on wild and farmed fish

JOURNAL OF FISH DISEASES, Issue 2 2007
Ø Øines
Abstract Two mitochondrial genotypes have been described for Caligus elongatus Nordmann in Norway. This article reports on the distribution of C. elongatus mitochondrial cytochrome C oxidase 1 genotypes from wild fish hosts from the SE Norwegian coast. For comparison, lice from areas with fish farming were included in the study. The genotype distribution of 841 lice from wild coastal (n = 535), wild North Sea pelagic (n = 26), farmed (n = 160) and wild hosts in areas of fish farming (n = 89) is presented. The genotype frequencies of C. elongatus on wild coastal hosts varied significantly between spring and autumn. Lice from these fish show a large proportion of genotype 1 lice in March,June every year. Genotype 2 lice were found more frequently in autumn. Genotype 1 was clearly associated with the lumpfish, Cyclopterus lumpus L. The genotype frequency appeared to be different in areas with aquaculture. Caligus elongatus from farmed fish and wild fish caught close to Atlantic salmon fish farms in Norway were predominantly genotype 1 in autumn. Genotypes of C. elongatus on the SE coast of Norway vary according to season and fish species. Factors involved in the encounter between fish and lice are important for the establishment of lice on their hosts. [source]