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Genetic Mechanisms (genetic + mechanism)
Kinds of Genetic Mechanisms Selected Abstractsp53 expression, K- ras gene mutation and microsatellite instability in gastric B-cell lymphomasJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2003TORU HIYAMA Abstract Background and Aims:, Genetic mechanisms involved in the development of gastric B-cell lymphomas remain unclear. The aim of the present study was to clarify the roles of mutations of the p53 and K- ras genes, and microsatellite instability (MSI) in the development of gastric B-cell lymphomas. Methods:, We investigated p53 immunoreactivity, mutations of the K- ras gene, and MSI in 27 gastric marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue type (MZBCL) and 24 diffuse large B-cell lymphomas (DLBCL). p53 immunoreactivity was examined using a monoclonal antibody, DO-7. Mutation of the K- ras gene was detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. MSI was examined at five microsatellite loci with a microsatellite assay. Cases were classified as having high-frequency MSI (MSI-H) (, 2 loci showing instability), low-frequency MSI (MSI-L) (only one locus showing instability), or as microsatellite stable. Results:, p53 immunoreactivity was detected in 1 of 16 (6%) MZBCL and 8 of 19 (42%) DLBCL. Frequency of p53 immunoreactivity in DLBCL was significantly higher than that in MZBCL (P = 0.018). MSI-H was detected only in 1 of 20 (5%) DLBCL. None of the cases examined showed mutation of the K- ras gene. Conclusions:, These data suggest that mutations of the p53 gene may play an important role in the development of gastric DLBCL, and that mutations of the K- ras gene and MSI may be involved in little part of the development of gastric B-cell lymphomas. [source] Molecular Genetic Study on Angelman Syndrome Patients without a Chromosomal DeletionEPILEPSIA, Issue 2000Shinji Saitoh Purpose: Angelman syndrome (AS) is a ncurobehavioral disorder characterized by severe mental retardation, easily cvoked laughter, ataxic gait, and epilepsy. Epilepsy associated with AS is characterized by early childhood onset gencralized seizures with profound EEG abnormalities. Therefore, AS is a good human model for genetic epilepsy syndromes. Approximately 70% of AS cases are caused by maternal deletions of chromosomc 15q I I-qI3; whereas, 30% are not associated with a chromosomal dcletion. Thcse non-deletion AS patients are caused by paternal uniparental disomy (UPD), imprinting mutation (IM), or loss-or-function mutations of the UBE3A gene, cach of which predisposes different recurrence risk. To elucidate molecular etiology of non-dclction AS patients, we investigated 34 AS patients without a chromosomal deletion. Methods: Thirty sporadic AS patients, and 4 familial AS patients (2 families of 2 sibs) were enrolled to the study. The diagnosis of AS was based on Williams' criteria (Williams et al., Am J Med Genet 1995, 56: 237). Genomic DNA was extracted from peripheral blood by a standard procedure. DNA mcthylation tcst at SNRPN locus and genotyping using 7 highly informative PCR-based polymorphisms within 15q I I - q I3 were carried out to identify UPD and IM. When both UPD and IM were ruled out, the patients were classified :LS non-UPD, non-IM. For thcsc non-UPD, non-1M paticnts, UBE3A mutations were screened by PCR-SSCP analysis using 10 sets ofprimcrs covering all coding exons. Results: Among 30 sporadic patients, I UPD and 3 IM patients were identified, and the remaining 26 patients were classified as non-UPD, non-IM. Among 4 familial patients, 2 sibs from I family were detected as IM, whcrcas 2 sibs from another family were classified as non-UPD, non-IM. No UBE3A mutations were identified within 26 sporadic and 2 familial non-UPD, non-IM patients. Conclusion: Threc molecular classes were identified for noindeletion AS patients. Therefore, the underlying genetic mechanism was dcmonstratcd to be complex for AS patients without a chromosomal deletion. Combination of the DNA methylation test and PCR-based polymorphisms was sufficient to detect UPD and IM patients. Because recurrence risk is low for UPD and high lor IM, systematic molecular investigation including the DNA methylation test and PCR-based polymorphisms should bc donc for non-delction AS paticnts for genetic counscling purpose. A majority of non-deletion patients were classified as noii-UPD, non-1M. Although, approximate 30% of non-UPD, nonIM patients arc rcportcd to have UBE3A mutations, no such mutations were identified in our study. An underlying molecular mechanism was not rcvealcd for this group of patients, and therefore, assessment of recurrence risk was difficult. Further investigation is necessary for noii-UPD, non-1M paticnts. [source] Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE-secreting cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2006Alexander Karnowski Abstract Immunoglobulin,E (IgE) is the key effector element in allergic diseases ranging from innocuous hay fever to life-threatening anaphylactic shock. Compared to other Ig classes, IgE serum levels are very low. In its membrane-bound form (mIgE), IgE behaves as a classical antigen receptor on B,lymphocytes. Expression of mIgE is essential for subsequent recruitment of IgE-secreting cells. We show that in activated, mIgE-bearing B,cells, mRNA for the membrane forms of both murine and human epsilon (,) heavy chains (HC) are poorly expressed compared to mRNA for the secreted forms. In contrast, in mIgG-bearing B,cells, mRNA for the membrane forms of murine gamma-1 (,1) and the corresponding human ,4 HC are expressed at a much higher level than mRNA for the respective secreted forms. We show that these findings correlate with the presence of deviant polyadenylation signal hexamers in the 3,,untranslated region (UTR) of both murine and human ,,genes, causing inefficient processing of primary transcripts and thus poor expression of the proteins and poor recruitment of IgE-producing cells in the immune response. Thus, we have identified a genetic steering mechanism in the regulation of IgE synthesis that represents a further means to restrain potentially dangerous, high serum IgE levels. [source] Robustness of inference on measured covariates to misspecification of genetic random effects in family studiesGENETIC EPIDEMIOLOGY, Issue 1 2003Ruth M.Pfeiffer Abstract Family studies to identify disease-related genes frequently collect only families with multiple cases. It is often desirable to determine if risk factors that are known to influence disease risk in the general population also play a role in the study families. If so, these factors should be incorporated into the genetic analysis to control for confounding. Pfeiffer et al. [2001 Biometrika 88: 933,948] proposed a variance components or random effects model to account for common familial effects and for different genetic correlations among family members. After adjusting for ascertainment, they found maximum likelihood estimates of the measured exposure effects. Although it is appealing that this model accounts for genetic correlations as well as for the ascertainment of families, in order to perform an analysis one needs to specify the distribution of random genetic effects. The current work investigates the robustness of the proposed model with respect to various misspecifications of genetic random effects in simulations. When the true underlying genetic mechanism is polygenic with a small dominant component, or Mendelian with low allele frequency and penetrance, the effects of misspecification on the estimation of fixed effects in the model are negligible. The model is applied to data from a family study on nasopharyngeal carcinoma in Taiwan. Genet Epidemiol 24:14,23, 2003. © 2003 Wiley-Liss, Inc. [source] Evolution of late-life fecundity in Drosophila melanogasterJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 1 2006C. L. RAUSER Abstract Late-life fecundity has been shown to plateau at late ages in Drosophila analogously to late-life mortality rates. In this study, we test an evolutionary theory of late life based on the declining force of natural selection that can explain the occurrence of these late-life plateaus in Drosophila. We also examine the viability of eggs laid by late-age females and test a population genetic mechanism that may be involved in the evolution of late-life fecundity: antagonistic pleiotropy. Together these experiments demonstrate that (i) fecundity plateaus at late ages, (ii) plateaus evolve according to the age at which the force of natural selection acting on fecundity reaches zero, (iii) eggs laid by females in late life are viable and (iv) antagonistic pleiotropy is involved in the evolution of late-life fecundity. This study further supports the evolutionary theory of late life based on the age-specific force of natural selection. [source] Petunia Germinating Pollen S/D3 Interacts with S-RNases in Petunia hybrida Vilm.JOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 5 2006Yan-Xia Guo Abstract Self-incompatibility (SI) is a genetic mechanism of self/non-self pollen recognition to prevent self-fertilization in many flowering plants and, in most cases, this is controlled by a multi-allelic S-locus. S-RNase and S-locus F box (SLF) proteins have been shown to be the female and male determinants of gametophytic self-incompatibility (GSI), respectively, in the Solanaceae, Scrophulariaceae and Rosaceae. Nevertheless, it is thought that additional factors are required for the SI response. Herein, we constructed a mature anther cDNA library from a self-incompatible Petunia hybrida Vilm. line of the S3S3 haplotype. Using AhS2-RNase from Antirrhinum hispanicum as a bait for yeast two-hybrid screening, we found that petunia germinating pollen (PGP) S/D3 was capable of interacting physically with the bait. However, the interaction lacked haplotype specificity. The PGPS/D3 gene is a single copy gene that is expressed in tissues such as the style, ovary, pollen, and leaf. The PGPS/D3::GFP (green fluorescence protein) construct was detected in both the membrane and cytoplasm. The implications of these findings in the operation of S-RNase-based SI are discussed. (Managing editor: Li-Hui Zhao) [source] Cancer incidence among persons with fragile X syndrome in Finland: a population-based studyJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 1 2009R. Sund Abstract Background Fragile X syndrome is a common inheritable cause of intellectual disability (ID) and is characterised by a large number of CGG repeats at the gene FMR1 located on the X-chromosome. It has been reported that this genetic mechanism may protect against malignant transformations. Methods We extracted from the Finnish registry on persons with ID a cohort of 302 persons with a fragile X diagnosis during 1982,1986. Follow-up for cancer incidence was performed in the Finnish Cancer Registry until the end of the year 2005. Results There were 11 reported cancers during the mean follow-up of 21.4 years per person. The expected number of cancers based on the average Finnish population was 13.8 and no statistically significant protective effect was detected [standardised incidence ratios (SIR) 0.80, confidence interval (CI) 95% 0.40,1.4]. An increased risk for lip cancer was found (SIR 23, CI 95% 2.8,85). Conclusions Confirmation of hypotheses about the mechanisms linking FXS and cancer needs further research. [source] Cleft lip with or without cleft palate and dermatoglyphic asymmetry: evaluation of a Chinese populationORTHODONTICS & CRANIOFACIAL RESEARCH, Issue 3 2002K Neiswanger Structured Abstract Authors , Neiswanger K, Cooper ME, Weinberg SM, Flodman P, Bundens Keglovits A, Liu Y, Hu D-N, Melnick M, Spence MA, Marazita ML Objective , To determine if Chinese individuals with non syndromic cleft lip with or without cleft palate (CL/P) display more dermatoglyphic asymmetry than unaffected relatives or controls. Design , Case , control study with two control groups (genetically related and unrelated). Setting and Sample Population , A total of 500 CL/P probands from Shanghai, China, 421 unaffected relatives, and 66 controls of Chinese heritage. Methods , Finger and palm prints were collected, and pattern frequencies, total ridge counts (TRC), and atd angles were calculated. Asymmetry scores between right and left hands were defined for each of the three dermatoglyphic measures. Probands' asymmetry scores were compared statistically with the scores of unaffected relatives and controls. Results , In general, the probands' asymmetry scores for TRC and atd angle did not differ significantly from the scores of either unaffected relatives or controls. However, probands with a positive family history of clefting showed significantly more asymmetry in their pattern types than either probands without a family history, unaffected relatives or controls. Conclusion , These results suggest that a unique genetic mechanism of developmental instability may obtain in CL/P individuals with a positive family history of clefting. [source] Phacomatosis Pigmentokeratotica: A 20-Year Follow-up with Malignant Degeneration of Both Nevus ComponentsPEDIATRIC DERMATOLOGY, Issue 1 2005Teresa Martínez-Menchón M.D. The disorder is a consequence of the so-called twin spot genetic mechanism. We describe the first occurrence involving malignant degeneration of both nevus components, giving rise to three basal cell carcinomas over the sebaceous nevus and a malignant melanoma of the superficial spreading type over the speckled lentiginous nevus. This observation, in concert with the other instances reported in the literature, points to the need for adequate patient follow-up to ensure early detection and treatment of any possible associated malignant degeneration. [source] Caught in the trio trap?AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 4 2001Potential selection bias inherent to association studies usings parent-offspring trios Abstract During the last years, the validity of classic case control studies in psychiatric genetic research has been increasingly under question due to the risk of population stratification problems inherent to this type of association study. By consequence, the application of family-based association studies using parent-offspring trios has been strongly advocated. Recently, however, in a study comparing clinical characteristics between index patients from parent-offspring trios and singleton patients with bipolar affective disorder, the question was raised whether a systematic neglect of case control association studies could lead to a selection bias of susceptibility genes. In a similar approach, we compared demographic and clinical characteristics of 122 singleton bipolar patients with those of 54 bipolar patients derived from parent-offspring trios. The singleton patients did not only present with a higher age of onset, but also with a higher frequency of suicidal behavior and a higher familial loading for suicidality. These findings suggest that the genetic mechanism for disease might be different between trio-based and classic case control samples, where patients are examined whose parents are not available for genetic studies. Thus, giving up case control designs for the sake of family-based association studies could be at the risk of selecting against several genetically determined factors. © 2001 Wiley-Liss, Inc. [source] Brief communication: Blue eyes in lemurs and humans: Same phenotype, different genetic mechanismAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 2 2009Brenda J. Bradley Abstract Almost all mammals have brown or darkly-pigmented eyes (irises), but among primates, there are some prominent blue-eyed exceptions. The blue eyes of some humans and lemurs are a striking example of convergent evolution of a rare phenotype on distant branches of the primate tree. Recent work on humans indicates that blue eye color is associated with, and likely caused by, a single nucleotide polymorphism (rs12913832) in an intron of the gene HERC2, which likely regulates expression of the neighboring pigmentation gene OCA2. This raises the immediate question of whether blue eyes in lemurs might have a similar genetic basis. We addressed this by sequencing the homologous genetic region in the blue-eyed black lemur (Eulemur macaco flavifrons; N = 4) and the closely-related black lemur (Eulemur macaco macaco; N = 4), which has brown eyes. We then compared a 166-bp segment corresponding to and flanking the human eye-color-associated region in these lemurs, as well as other primates (human, chimpanzee, orangutan, macaque, ring-tailed lemur, mouse lemur). Aligned sequences indicated that this region is strongly conserved in both Eulemur macaco subspecies as well as the other primates (except blue-eyed humans). Therefore, it is unlikely that this regulatory segment plays a major role in eye color differences among lemurs as it does in humans. Although convergent phenotypes can sometimes come about via the same or similar genetic changes occurring independently, this does not seem to be the case here, as we have shown that the genetic basis of blue eyes in lemurs differs from that of humans. Am J Phys Anthropol, 2009. © 2009 Wiley-Liss, Inc. [source] Genetic mapping of quantitative trait loci for aseasonal reproduction in sheepANIMAL GENETICS, Issue 5 2010R. G. Mateescu Summary The productivity and economic prosperity of sheep farming could benefit greatly from more effective methods of selection for year-round lambing. Identification of QTL for aseasonal reproduction in sheep could lead to more accurate selection and faster genetic improvement. One hundred and twenty microsatellite markers were genotyped on 159 backcross ewes from a Dorset × East Friesian crossbred pedigree. Interval mapping was undertaken to map the QTL underlying several traits describing aseasonal reproduction including the number of oestrous cycles, maximum level of progesterone prior to breeding, pregnancy status determined by progesterone level, pregnancy status determined by ultrasound, lambing status and number of lambs born. Seven chromosomes (1, 3, 12, 17, 19, 20 and 24) were identified to harbour putative QTL for one or more component traits used to describe aseasonal reproduction. Ovine chromosomes 12, 17, 19 and 24 harbour QTL significant at the 5% chromosome-wide level, chromosomes 3 and 20 harbour QTL that exceeded the threshold at the 1% chromosome-wide level, while the QTL identified on chromosome 1 exceeded the 1% experiment-wide significance level. These results are a first step towards understanding the genetic mechanism of this complex trait and show that variation in aseasonal reproduction is associated with multiple chromosomal regions. [source] Identification of genetic markers associated with fatness and leg weakness traits in the pigANIMAL GENETICS, Issue 6 2009B. Fan Summary Pigs have undergone long-term selection in commercial conditions for improved rate and efficiency of lean gain. Interestingly, it has been observed in both experimental and field conditions that leg weakness has increased over time, concurrent with the selection for improved rate of lean gain, while fatter animals tend to have better leg action, and foot and leg (FL) structure. The exact molecular mechanisms or individual genes responsible for this apparent genetic correlation between fatness and leg weakness and other physical adaptability traits have been less well reported. Based on our recent studies involving candidate genes and leg weakness traits, the present investigation has identified 30 SNPs from 26 genes that were found to be associated with 10th rib backfat in a sow population consisting of 2066 animals. The specific alleles associated with increased backfat tended to be associated with better overall leg action, as shown for the genes including MTHFR, WNT2, APOE, BMP8, GNRHR and OXTR, while inconsistent associations with the single FL structure trait and backfat were observed for other genes. This study suggests that in some cases there may be a common genetic mechanism or linked genes regulating fatness and leg weakness. Such relationships are clearly complex, and the utilization of genetic markers associated with both traits should be treated cautiously. [source] A Mutation that Creates a Pseudoexon in SOD1 Causes Familial ALSANNALS OF HUMAN GENETICS, Issue 6 2009Paul N. Valdmanis Summary Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease which targets motor neurons of the cortex, brainstem and spinal cord. About 5,10% of all amyotrophic lateral sclerosis cases are familial (FALS), and 15,20% of FALS cases are caused by mutations in the zinc-copper superoxide dismutase gene (SOD1). We identified a large family from France with ten members affected with ALS. Linkage was established to the SOD1 locus on chromosome 21 and genomic and cDNA sequencing was performed for the SOD1 gene. This revealed an activated pseudoexon between exons 4 and 5 that was present in two tested members of the family. Translation of this 43 base pair exon results in the introduction of seven amino acids before a stop codon is present, leading to a prematurely truncated SOD1 protein product of 125 amino acids. Sequencing intron 4 in a patient revealed a heterozygous change 304 bp before exon 5 (c.358 , 304C > G), but only 5 bp after the cryptic exon, thus causing this alternative splice product. This mutation segregated in all affected individuals of the family. This adds an additional genetic mechanism for developing SOD1 -linked ALS and is one which can be more readily targeted by gene therapy. [source] A Partially Linear Tree-based Regression Model for Multivariate OutcomesBIOMETRICS, Issue 1 2010Kai Yu Summary In the genetic study of complex traits, especially behavior related ones, such as smoking and alcoholism, usually several phenotypic measurements are obtained for the description of the complex trait, but no single measurement can quantify fully the complicated characteristics of the symptom because of our lack of understanding of the underlying etiology. If those phenotypes share a common genetic mechanism, rather than studying each individual phenotype separately, it is more advantageous to analyze them jointly as a multivariate trait to enhance the power to identify associated genes. We propose a multilocus association test for the study of multivariate traits. The test is derived from a partially linear tree-based regression model for multiple outcomes. This novel tree-based model provides a formal statistical testing framework for the evaluation of the association between a multivariate outcome and a set of candidate predictors, such as markers within a gene or pathway, while accommodating adjustment for other covariates. Through simulation studies we show that the proposed method has an acceptable type I error rate and improved power over the univariate outcome analysis, which studies each component of the complex trait separately with multiple-comparison adjustment. A candidate gene association study of multiple smoking-related phenotypes is used to demonstrate the application and advantages of this new method. The proposed method is general enough to be used for the assessment of the joint effect of a set of multiple risk factors on a multivariate outcome in other biomedical research settings. [source] Estimating a Multivariate Familial Correlation Using Joint Models for Canonical Correlations: Application to Memory Score Analysis from Familial Hispanic Alzheimer's Disease StudyBIOMETRICS, Issue 2 2009Hye-Seung Lee Summary Analysis of multiple traits can provide additional information beyond analysis of a single trait, allowing better understanding of the underlying genetic mechanism of a common disease. To accommodate multiple traits in familial correlation analysis adjusting for confounders, we develop a regression model for canonical correlation parameters and propose joint modeling along with mean and scale parameters. The proposed method is more powerful than the regression method modeling pairwise correlations because it captures familial aggregation manifested in multiple traits through maximum canonical correlation. [source] Association between leptin receptor gene polymorphisms and early-onset prostate cancerBJU INTERNATIONAL, Issue 1 2003Z. Kote-Jarai Significant tissue loss is a consistent feature of ureteric obstruction with, most studies showing increased programmed cell death or apoptosis of kidney epithelial cells. The study by Chuang et al. showed that there is also muscular damage during obstruction, specifically of the ureteric myocytes. More importantly they show for the first time that this induction of cell death is associated with the increased expression of cytochrome c and the caspases, key proteins that drive the induction of apoptosis. Admittedly they do not show whether cytochrome c is released from the mitochondria or that the caspases are truly activated, important events in the cell death pathway, but an increase in their expression does indicate their role in this process. Understanding the pathways leading to tissue loss during ureteric obstruction has important implications in the development of novel treatments for this condition. OBJECTIVE To report a case-control study examining the relationship between polymorphisms in the leptin receptor (OBR) gene and the development of young-onset prostate cancer, because epidemiological studies report that prostate cancer risk is associated with animal fat intake, and thus we investigated if this association occurs via this genetic mechanism. PATIENTS, SUBJECTS AND METHODS The Lys109Arg (OBR1) and Gln223Arg (OBR2) polymorphisms in the coding region of OBR were studied in blood DNA from 271 patients with prostate cancer aged < 56 years at diagnosis and 277 geographically matched control subjects. Cases were collected through the Cancer Research UK/British Prostate Group Familial Prostate Cancer Study. Blood DNA was genotyped using the polymerase chain reaction and a restriction enzyme digest. RESULTS There was no statistically significant association between the OBR genotype and prostate cancer risk; men homozygous for 109Arg genotype had a slightly increased risk for prostate cancer, with a relative risk (95% confidence interval) of 1.36 (0.65,2.85), and those homozygous for the 223Arg allele had some reduction in prostate cancer risk, at 0.82 (0.58,1.26), but neither was statistically significant. CONCLUSION This case-control study showed no significant association between leptin receptor gene polymorphisms and the risk of young-onset prostate cancer, suggesting that genetic variations in OBR are unlikely to have a major role in the development of early-onset prostate cancer in the UK. [source] Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysisCLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2009S-H. Kim Summary Background Toluene diisocyanate (TDI) is the most important cause of occupational asthma, but the genetic mechanism of TDI-induced asthma is still unknown. Objective The objective of the study was to identify susceptibility alleles associated with the TDI-induced asthma phenotype. Methods We conducted a genome-wide association study in 84 patients with TDI-induced asthma and 263 unexposed healthy normal controls using Affymetrix 500K SNPchip. We also investigated the relationships between genetic polymorphisms and transcript levels in Epstein,Barr virus-transformed lymphoblastoid cell lines from patients with TDI-induced asthma enrolled in this study. Results Genetic polymorphisms of CTNNA3 (catenin alpha 3, alpha-T catenin) were significantly associated with the TDI-induced asthma phenotype (5.84 × 10,6 for rs10762058, 1.41 × 10,5 for rs7088181, 2.03 × 10,5 for rs4378283). Carriers with the minor haplotype, HT2 [GG], of two genetic polymorphisms (rs10762058 and rs7088181) showed significantly lower PC20 methacholine level (P=0.041) and lower mRNA expression of CTNNA3 than non-carriers (P=0.040). A genetic polymorphism in the 3, downstream region of CTNNA3 (rs1786929), as identified by DNA direct sequencing, was significantly associated with the TDI-induced asthma phenotype (P=0.015 in recessive analysis model) and the prevalence of serum-specific IgG to cytokeratin 19 (P=0.031). Conclusion These findings suggested that multiple genetic polymorphisms of CTNNA3 may be determinants of susceptibility to TDI-induced asthma. [source] Molecular analysis of congenital goitres with hypothyroidism caused by defective thyroglobulin synthesis.CLINICAL ENDOCRINOLOGY, Issue 1 2010Identification of a novel c.7006C>T [p.R2317X] mutation, expression of minigenes containing nonsense mutations in exon Summary Background, Thyroglobulin (TG) deficiency is an autosomal-recessive disorder that results in thyroid dyshormonogenesis. A number of distinct mutations have been identified as causing human hypothyroid goitre. Objectives, The purpose of this study was to identify and characterize new mutations in the TG gene in an attempt to increase the understanding of the genetic mechanism responsible for this disorder. A total of six patients from four nonconsanguineous families with marked impairment of TG synthesis were studied. Methods, Single-strand conformation polymorphism (SSCP) analysis, sequencing of DNA, genotyping, expression of chimeric minigenes and bioinformatic analysis were performed. Results, Four different inactivating TG mutations were identified: one novel mutation (c.7006C>T [p.R2317X]) and three previously reported (c.886C>T [p.R277X], c.6701C>A [p.A2215D] and c.6725G>A [p.R2223H]). Consequently, one patient carried a compound heterozygous for p.R2223H/p.R2317X mutations; two brothers showed a homozygous p.A2215D substitution and the remaining three patients, from two families with typical phenotype, had a single p.R277X mutated allele. We also showed functional evidences that premature stop codons inserted at different positions in exon 7, which disrupt exonic splicing enhancer (ESE) sequences, do not interfere with exon definition and processing. Conclusions, In this study, we have identified a novel nonsense mutation p.R2317X in the acetylcholinesterase homology domain of TG. We have also observed that nonsense mutations do not interfere with the pre-mRNA splicing of exon 7. The results are in accordance with previous observations confirming the genetic heterogeneity of TG defects. [source] What drives cell morphogenesis: A look inside the vertebrate photoreceptorDEVELOPMENTAL DYNAMICS, Issue 9 2009Breandán Kennedy Abstract Vision mediating photoreceptor cells are specialized light-sensitive neurons in the outer layer of the vertebrate retina. The human retina contains approximately 130 million of such photoreceptors, which enable images of the external environment to be captured at high resolution and high sensitivity. Rod and cone photoreceptor subtypes are further specialized for sensing light in low and high illumination, respectively. To enable visual function, these photoreceptors have developed elaborate morphological domains for the detection of light (outer segments), for changing cell shape (inner segments), and for communication with neighboring retinal neurons (synaptic terminals). Furthermore, rod and cone subtypes feature unique morphological variations of these specialized characteristics. Here, we review the major aspects of vertebrate photoreceptor morphology and key genetic mechanisms that drive their formation. These mechanisms are necessary for cell differentiation as well as function. Their defects lead to cell death. Developmental Dynamics 238:2115,2138, 2009. © 2009 Wiley-Liss, Inc. [source] Evolutionary conservation and divergence of the segmentation process in arthropodsDEVELOPMENTAL DYNAMICS, Issue 6 2007Wim G. M. Damen Abstract A fundamental characteristic of the arthropod body plan is its organization in metameric units along the anterior,posterior axis. The segmental organization is laid down during early embryogenesis. Our view on arthropod segmentation is still strongly influenced by the huge amount of data available from the fruit fly Drosophila melanogaster (the Drosophila paradigm). However, the simultaneous formation of the segments in Drosophila is a derived mode of segmentation. Successive terminal addition of segments from a posteriorly localized presegmental zone is the ancestral mode of arthropod segmentation. This review focuses on the evolutionary conservation and divergence of the genetic mechanisms of segmentation within arthropods. The more downstream levels of the segmentation gene network (e.g., segment polarity genes) appear to be more conserved than the more upstream levels (gap genes, Notch/Delta signaling). Surprisingly, the basally branched arthropod groups also show similarities to mechanisms used in vertebrate somitogenesis. Furthermore, it has become clear that the activation of pair rule gene orthologs is a key step in the segmentation of all arthropods. Important findings of conserved and diverged aspects of segmentation from the last few years now allow us to draw an evolutionary scenario on how the mechanisms of segmentation could have evolved and led to the present mechanisms seen in various insect groups including dipterans like Drosophila. Developmental Dynamics 236:1379,1391, 2007. © 2007 Wiley-Liss, Inc. [source] Spontaneous mutation in mice provides new insight into the genetic mechanisms that pattern the seminal vesicles and prostate glandDEVELOPMENTAL DYNAMICS, Issue 4 2003Paul C. Marker Abstract The seminal vesicles and prostate gland are anatomically adjacent male sex-accessory glands. Although they arise from different embryonic precursor structures and express distinct sets of secretory proteins, these organs share common features in their developmental biology. A key shared developmental feature is the elaboration of complex secretory epithelia with tremendous surface area from simple precursor structures with juxtaposed epithelial and mesenchymal cells. In this study, new insight into the nature of the biological processes that underlie glandular morphogenesis is achieved by analyzing the phenotypes present in mice that harbor a spontaneous mutation, seminal vesicle shape (svs), previously identified for causing altered seminal vesicle morphology in adults. An examination of seminal vesicle development in svs mice provides the first evidence that the concurrent processes of epithelial branching and epithelial infolding are distinct processes under separate genetic control. It also provides the first direct evidence that the thickness and topology of the smooth muscle layer in the seminal vesicles are determined by interaction with the glandular epithelium during the branching process. In addition, the seminal vesicle phenotype in svs mice is shown to phenocopy the morphologic form present in certain other mammals such as the guinea pig, raising the possibility that the svs mutation is the sort of variant that arises during evolution. By also including an investigation of the prostate gland, this study also identifies previously unrecognized phenotypes in svs prostates, including increased gland size and dramatically reduced levels of branching morphogenesis. Finally, this study advances the goal of identifying the svs gene by mapping the svs mutation relative to known molecular markers and testing Fgfr2 as a candidate gene. The finding that the svs mutation maps to a genomic region syntenic to a region frequently deleted in human prostate tumors, together with the prostatic phenotype present in svs mice, further raises the interesting possibility that the svs mutation will identify a candidate prostate tumor suppressor gene. Developmental Dynamics 226:643,653, 2003. © 2003 Wiley-Liss, Inc. [source] Hedgehog and Fgf signaling pathways regulate the development of tphR -expressing serotonergic raphe neurons in zebrafish embryosDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2004H. Teraoka Abstract Serotonin (5HT) plays major roles in the physiological regulation of many behavioral processes, including sleep, feeding, and mood, but the genetic mechanisms by which serotonergic neurons arise during development are poorly understood. In the present study, we have investigated the development of serotonergic neurons in the zebrafish. Neurons exhibiting 5HT-immunoreactivity (5HT-IR) are detected from 45 h postfertilization (hpf) in the ventral hindbrain raphe, the hypothalamus, pineal organ, and pretectal area. Tryptophan hydroxylases encode rate-limiting enzymes that function in the synthesis of 5HT. As part of this study, we cloned and analyzed a novel zebrafish tph gene named tphR. Unlike two other zebrafish tph genes (tphD1 and tphD2), tphR is expressed in serotonergic raphe neurons, similar to tph genes in mammalian species. tphR is also expressed in the pineal organ where it is likely to be involved in the pathway leading to synthesis of melatonin. To better understand the signaling pathways involved in the induction of the serotonergic phenotype, we analyzed tphR expression and 5HT-IR in embryos in which either Hh or Fgf signals are abrogated. Hindbrain 5HT neurons are severely reduced in mutants lacking activity of either Ace/Fgf8 or the transcription factor Noi/Pax2.1, which regulates expression of ace/fgf8, and probably other genes encoding signaling proteins. Similarly, serotonergic raphe neurons are absent in embryos lacking Hh activity confirming a conserved role for Hh signals in the induction of these cells. Conversely, over-activation of the Hh pathway increases the number of serotonergic neurons. As in mammals, our results are consistent with the transcription factors Nk2.2 and Gata3 acting downstream of Hh activity in the development of serotonergic raphe neurons. Our results show that the pathways involved in induction of hindbrain serotonergic neurons are likely to be conserved in all vertebrates and help establish the zebrafish as a model system to study this important neuronal class. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 275,288, 2004 [source] The evolutionary psychology of left and right: Costs and benefits of lateralizationDEVELOPMENTAL PSYCHOBIOLOGY, Issue 6 2006Giorgio VallortigaraArticle first published online: 2 AUG 200 Abstract Why do the left and right sides of the vertebrate brain play different functions? Having a lateralized brain, in which each hemisphere carries out different functions, is ubiquitous among vertebrates. The different specialization of the left and right side of the brain may increase brain efficiency,and some evidence for that is reported here. However, lateral biases due to brain lateralization (such as preferences in the use of a limb or, in animals with laterally placed eyes, of a visual hemifield) usually occur at the population level, with most individuals showing similar direction of bias. Individual brain efficiency does not require the alignment of lateralization in the population. Why then are not left- and right-type individuals equally common? Not only humans, but most vertebrates show a similar pattern. For instance, in the paper I report evidence that most toads, chickens, and fish react faster when a predator approaches from the left. I argue that invoking individual brain efficiency (lateralization may increase fitness), evolutionary chance or direct genetic mechanisms cannot explain this widespread pattern. Instead, using concepts from mathematical theory of games, I show that alignment of lateralization at the population level may arise as an "evolutionarily stable strategy" when individually asymmetrical organisms must coordinate their behavior with that of other asymmetrical organisms. Thus, the population structure of lateralization may result from genes specifying the direction of asymmetries which have been selected under "social" pressures. © 2006 Wiley Periodicals, Inc. Dev Psychobiol 48: 418,427, 2006. [source] Genetic analysis of larval survival and larval growth of two populations of Leptinotarsa decemlineata on tomatoENTOMOLOGIA EXPERIMENTALIS ET APPLICATA, Issue 2 2001Wenhua Lu Abstract The genetics of adaptation to tomato in Leptinotarsa decemlineata (Say) were investigated in reciprocal F1, F2, and backcross populations generated from crosses between beetles from a tomato adapted population and from a population that was poorly adapted to tomato. Larvae from the parent and test populations were reared on tomato for four days, after which survivorship and larval weights were recorded. Most results indicate that differences in larval growth and survival on tomato between the parent populations are largely determined by autosomal, polygenic mechanisms, the inheritance of which involves a significant dominance component. However, results from F2 crosses are not consistent with this conclusion. A significant difference in larval weights, but not in survival, between reciprocal F1 populations in an analysis of combined data from four separate experiments suggests that maternal cytoplasmic effects may contribute to differences in larval performance on tomato between the adapted and unadapted populations. The unusual results obtained from F2 crosses in this study are not atypical of results from previous studies of the genetics of adaptation to host plants by the Colorado potato beetle. Host plant adaptation by Colorado potato beetles may therefore involve unusual genetic mechanisms that are not easily assessed by classical Mendelian analysis. [source] Secreted factors from ventral telencephalon induce the differentiation of GABAergic neurons in cortical culturesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2006H.-h. Trinh Abstract It is widely believed that the pyramidal cells and interneurons of the cerebral cortex are distinct in their origin, lineage and genetic make up. In view of these findings, the current thesis is that the phenotype determination of cortical neurons is primarily directed by genetic mechanisms. Using in vitro assays, the present study demonstrates that secreted factors from ganglionic eminence (GE) of the ventral telencephalon have the potency to induce the differentiation of a subset of cortical neurons towards ,-aminobutyric acid (GABA)ergic lineage. Characterization of cortical cultures that were exposed to medium derived from GE illustrated a significant increase in the number of GABA-, calretinin- and calbindin-positive neurons. Calcium imaging together with pharmacological studies showed that the application of exogenous medium significantly elevated the intracellular calcium transients in cortical neurons through the activation of ionotropic glutamate receptors. The increase in GABA+ neurons appeared to be associated with the elevated calcium activity; treatment with blockers specific for glutamate receptors abolished both the synchronized transients and reduced the differentiation of GABAergic neurons. Such studies demonstrate that although intrinsic mechanisms determine the fate of cortical interneurons, extrinsic factors have the potency to influence their neurochemical differentiation and contribute towards their molecular diversity. [source] The evolutionary genetics of personality,EUROPEAN JOURNAL OF PERSONALITY, Issue 5 2007Lars Penke Abstract Genetic influences on personality differences are ubiquitous, but their nature is not well understood. A theoretical framework might help, and can be provided by evolutionary genetics. We assess three evolutionary genetic mechanisms that could explain genetic variance in personality differences: selective neutrality, mutation-selection balance, and balancing selection. Based on evolutionary genetic theory and empirical results from behaviour genetics and personality psychology, we conclude that selective neutrality is largely irrelevant, that mutation-selection balance seems best at explaining genetic variance in intelligence, and that balancing selection by environmental heterogeneity seems best at explaining genetic variance in personality traits. We propose a general model of heritable personality differences that conceptualises intelligence as fitness components and personality traits as individual reaction norms of genotypes across environments, with different fitness consequences in different environmental niches. We also discuss the place of mental health in the model. This evolutionary genetic framework highlights the role of gene-environment interactions in the study of personality, yields new insight into the person-situation-debate and the structure of personality, and has practical implications for both quantitative and molecular genetic studies of personality. Copyright © 2007 John Wiley & Sons, Ltd. [source] INDEPENDENT EVOLUTION OF COMPLEX LIFE HISTORY ADAPTATIONS IN TWO FAMILIES OF FISHES, LIVE-BEARING HALFBEAKS (ZENARCHOPTERIDAE, BELONIFORMES) AND POECILIIDAE (CYPRINODONTIFORMES)EVOLUTION, Issue 11 2007David Reznick We have previously documented multiple, independent origins of placentas in the fish family Poeciliidae. Here we summarize similar analyses of fishes in the family Zenarchopteridae. This family includes three live-bearing genera. Earlier studies documented the presence of superfetation, or the ability to carry multiple litters of young in different stages of development in the same ovary, in some species in all three genera. There is also one earlier report of matrotrophy, or extensive postfertilization maternal provisioning, in two of these genera. We present detailed life-history data for approximately half of the species in all three genera and combine them with the best available phylogeny to make inferences about the pattern of life-history evolution within this family. Three species of Hemirhamphodon have superfetation but lack matrotrophy. Most species in Nomorhamphus and Dermogenys either lack superfetation and matrotrophy or have both superfetation and matrotrophy. Our phylogenetic analysis shows that matrotrophy may have evolved independently in each genus. In Dermogenys, matrotrophic species produce fewer, larger offspring than nonmatrotrophic species. In Nomorhamphus; matrotrophic species instead produce more and smaller offspring than lecithotrophic species. However, the matrotrophic species in both genera have significantly smaller masses of reproductive tissue relative to their body sizes. All aspects of these results are duplicated in the fish family Poeciliidae. We discuss the possible adaptive significance of matrotrophy in the light of these new results. The two families together present a remarkable opportunity to study the evolution of a complex trait because they contain multiple, independent origins of the trait that often include close relatives that vary in either the presence or absence of the matrotrophy or in the degree to which matrotrophy is developed. These are the raw materials that are required for either an analysis of the adaptive significance of the trait or for studies of the genetic mechanisms that underlie the evolution of the trait. [source] WHEN ONTOGENY REVEALS WHAT PHYLOGENY HIDES: GAIN AND LOSS OF HORNS DURING DEVELOPMENT AND EVOLUTION OF HORNED BEETLESEVOLUTION, Issue 11 2006Armin P. Moczek Abstract How ecological, developmental and genetic mechanisms interact in the genesis and subsequent diversification of morphological novelties is unknown for the vast majority of traits and organisms. Here we explore the ecological, developmental, and genetic underpinnings of a class of traits that is both novel and highly diverse: beetle horns. Specifically, we focus on the origin and diversification of a particular horn type, those protruding from the pronotum, in the genus Onthophagus, a particularly speciose and morphologically diverse genus of horned beetles. We begin by documenting immature development of nine Onthophagus species and show that all of these species express pronotal horns in a developmentally transient fashion in at least one or both sexes. Similar to species that retain their horns to adulthood, transient horns grow during late larval development and are clearly visible in pupae. However, unlike species that express horns as adults, transient horns are resorbed during pupal development. In a large number of species this mechanisms allows fully horned pupae to molt into entirely hornless adults. Consequently, far more Onthophagus species appear to possess the ability to develop pronotal horns than is indicated by their adult phenotypes. We use our data to expand a recent phylogeny of the genus Onthophagus to explore how the widespread existence of developmentally transient horns alters our understanding of the origin and dynamics of morphological innovation and diversification in this genus. We find that including transient horn development into the phylogeny dramatically reduces the number of independent origins required to explain extant diversity patters and suggest that pronotal horns may have originated only a few times, or possibly only once, during early Onthophagus evolution. We then propose a new and previously undescribed function for pronotal horns during immature development. We provide histological as well as experimental data that illustrate that pronotal horns are crucial for successful ecdysis of the larval head capsule during the larval-to-pupal molt, and that this molting function appears to be unique to the genus Onthophagus and absent in the other scarabaeine genera. We discuss how this additional function may help explain the existence and maintenance of developmentally transient horns, and how at least some horn types of adult beetles may have evolved as exaptations from pupal structures originally evolved to perform an unrelated function. [source] Sulfur assimilation and glutathione metabolism under cadmium stress in yeast, protists and plantsFEMS MICROBIOLOGY REVIEWS, Issue 4 2005David Mendoza-Cózatl Abstract Glutathione (,-glu-cys-gly; GSH) is usually present at high concentrations in most living cells, being the major reservoir of non-protein reduced sulfur. Because of its unique redox and nucleophilic properties, GSH serves in bio-reductive reactions as an important line of defense against reactive oxygen species, xenobiotics and heavy metals. GSH is synthesized from its constituent amino acids by two ATP-dependent reactions catalyzed by ,-glutamylcysteine synthetase and glutathione synthetase. In yeast, these enzymes are found in the cytosol, whereas in plants they are located in the cytosol and chloroplast. In protists, their location is not well established. In turn, the sulfur assimilation pathway, which leads to cysteine biosynthesis, involves high and low affinity sulfate transporters, and the enzymes ATP sulfurylase, APS kinase, PAPS reductase or APS reductase, sulfite reductase, serine acetyl transferase, O -acetylserine/O -acetylhomoserine sulfhydrylase and, in some organisms, also cystathionine ,-synthase and cystathionine ,-lyase. The biochemical and genetic regulation of these pathways is affected by oxidative stress, sulfur deficiency and heavy metal exposure. Cells cope with heavy metal stress using different mechanisms, such as complexation and compartmentation. One of these mechanisms in some yeast, plants and protists is the enhanced synthesis of the heavy metal-chelating molecules GSH and phytochelatins, which are formed from GSH by phytochelatin synthase (PCS) in a heavy metal-dependent reaction; Cd2+ is the most potent activator of PCS. In this work, we review the biochemical and genetic mechanisms involved in the regulation of sulfate assimilation-reduction and GSH metabolism when yeast, plants and protists are challenged by Cd2+. [source] | |||||||||||||||||||||||||||||||||||||