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Phenotypic Consequences (phenotypic + consequence)
Selected AbstractsPhenotypic consequences of branch point substitutions,HUMAN MUTATION, Issue 8 2006Jana Královi Abstract The branch point sequence (BPS) is a conserved splicing signal important for spliceosome assembly and lariat intron formation. BPS mutations may result in aberrant pre-mRNA splicing and genetic disorders, but their phenotypic consequences have been difficult to predict, largely due to a highly degenerate nature of the BPS consensus. Here, we have examined the splicing pattern of nine reporter pre-mRNAs that have previously been shown to give rise to human hereditary diseases as a result of single-nucleotide substitutions in the predicted BPS. Increased exon skipping and intron retention observed in vivo were recapitulated for each mutated pre-mRNA, but the reproducibility of cryptic splice site activation was lower. BP mutations in reporter pre-mRNAs frequently induced aberrant 3, splice sites and also activated a cryptic 5, splice site. Systematic mutagenesis of BP adenosines showed that in most pre-mRNAs, the expression of canonical transcripts was lower for BP transitions than BP transversions. Differential splicing outcome for transitions vs. transversions was abrogated or reduced if introns were truncated to 200 nt or less, suggesting that the nature of the BP residue is less critical for interactions across very short introns. Together, these results improve prediction of phenotypic consequences of point mutations upstream of splice acceptor sites and suggest that the overrepresentation of disease-causing adenosine-to-guanosine BP substitutions observed in Mendelian disorders is due to more profound defects of gene expression at the level of pre-mRNA splicing. Hum Mutat 27(8), 803,813, 2006. © 2006 WileyLiss, Inc. [source] Incidental neurodevelopmental episodes in the etiology of schizophrenia: An expanded model involving epigenetics and developmentCLINICAL GENETICS, Issue 6 2004SM Singh Epidemiological data favors genetic predisposition for schizophrenia, a common and complex mental disorder in most populations. Search for the genes involved using candidate genes, positional cloning, and chromosomal aberrations including triplet repeat expansions have established a number of susceptibility loci and genomic sites but no causal gene(s) with a proven mechanism of action. Recent genome-wide gene expression studies on brains from schizophrenia patients and their matched controls have identified a number of genes that show an alteration in expression in the diseased brains. Although it is not possible to offer a cause and effect association between altered gene expression and disease, such observations support a neurodevelopmental model in schizophrenia. Here, we offer a mechanism of this disease, which takes into account the role of developmental noise and diversions of the neural system. It suggests that the final outcome of a neural developmental process is not fixed and exact. Rather it develops with a variation around the mean. More important, the phenotypic consequence may cross the norm as a result of fortuitous and/or epigenetic events. As a result, a normal genotype may develop as abnormal with a disease phenotype. More important, susceptible genotypes may have reduced penetrance and develop as a normal phenocopy. The incidental episodes in neurodevelopment will explain the frequency of schizophrenia in most populations and high discordance of monozygotic twins. [source] Cardiac hypertrophy and failure: lessons learned from genetically engineered miceACTA PHYSIOLOGICA, Issue 1 2001Y. Takeishi Congestive heart failure is a major and growing public health problem. Because of improved survival of myocardial infarction patients produced by thrombolytic therapy or per-cutaneous revascularization it represents the only form of cardiovascular disease with significantly increased incidence and prevalence. Clinicians view this clinical syndrome as the final common pathway of diverse pathologies such as myocardial infarction and haemodynamic overload. Insights into mechanisms for heart failure historically derived from physiological and biochemical studies which identified compensatory adaptations for the haemodynamic burden associated with the pathological condition including utilization of the Frank Starling mechanism, augmentation of muscle mass, and neurohormonal activation to increase contractility. Therapy has largely been phenomenological and designed to prevent or limit the deleterious effects of these compensatory processes. More recently insights from molecular and cell biology have contributed to a more mechanistic understanding of potential causes of cardiac hypertrophy and failure. Many different analytical approaches have been employed for this purpose. These include the use of conventional animal models which permit serial observation of the onset and progression of heart failure and a sequential analysis of underlying biochemical and molecular events. Neonatal murine cardiomyocytes have been a powerful tool to examine in vitro subcellular mechanisms devoid of the confounding functional effects of multicellular preparations and heterogeneity of cell type. Finally, significant progress has been made by utilizing tissue from human cardiomyopathic hearts explanted at the time of orthotopic transplantation. Each of these methods has significant advantages and disadvantages. Arguably the greatest advance in our understanding of cardiac hypertrophy and failure over the past decade has been the exploitation of genetically engineered mice as biological reagents to study in vivo the effects of alterations in the murine genome. The power of this approach, in principle, derives from the ability to precisely overexpress or ablate a gene of interest and examine the phenotypic consequences in a cardiac specific post-natal manner. In contrast to conventional animal models of human disease which employ some form of environmental stress, genetic engineering involves a signal known molecular perturbation which produces the phenotype. [source] THE EVOLUTION OF GENETIC CANALIZATION UNDER FLUCTUATING SELECTIONEVOLUTION, Issue 1 2000Tadeusz J. Kawecki Abstract., If the direction of selection changes from generation to generation, the ability to respond to selection is maladaptive: the response to selection in one generation leads to reduced fitness in the next. Because the response is determined by the amount of genetic variance expressed at the phenotypic level, rapidly fluctuating selection should favor modifier genes that reduce the phenotypic effect of alleles segregating at structural loci underlying the trait. Such reduction in phenotypic expression of genetic variation has been named "genetic canalization." I support this argument with a series of two- and multilocus models with alternating linear selection and Gaussian selection with fluctuating optimum. A canalizing modifier gene affects the fitness of its carriers in three ways: (1) it reduces the phenotypic consequences of genetic response to previous selection; (2) it reduces the genetic response to selection, which is manifested as linkage disequilibrium between the modifier and structural loci; and (3) it reduces the phenotypic variance. The first two effects reduce fitness under directional selection sustained for several generations, but improve fitness when the direction of selection has just been reversed. The net effect tends to favor a canalizing modifier under rapidly fluctuating selection regimes (period of eight generations or less). The third effect improves fitness of the modifier allele if the fitness function is convex and reduces it if the function is concave. Under fluctuating Gaussian selection, the population is more likely to experience the concave portion of the fitness function when selection is stronger. Therefore, only weak to moderately strong fluctuating Gaussian selection favors genetic canalization. This paper considerably broadens the conditions that favor genetic canalization, which so far has only been postulated to evolve under long-term stabilizing selection. [source] Habitat-mediated size selection in endangered Atlantic salmon fry: selectional restoration assessmentEVOLUTIONARY APPLICATIONS (ELECTRONIC), Issue 4 2010Michael M. Bailey Abstract Preservation of adaptive variation is a top priority of many species restoration programs, but most restoration activities are conducted without direct knowledge of selection that might foster or impair adaptation and restoration goals. In this study, we quantified geographic variation in selection on fry size of endangered Atlantic salmon (Salmo salar) during the 6-week period immediately following stocking in the wild. We also used a model selection approach to assess whether habitat variables influence patterns of such selection. We found evidence for significant size-selection in five out of six selection trials. Interestingly, the strength and pattern of selection varied extensively among sites, and model selection suggested that this variation in phenotypic selection was related to geographic variation in the presence of large woody debris and the slope of the stream gradient. The strong selection differentials we observed should be a concern for endangered salmon restoration, whether they reflect natural processes and an opportunity to maintain adaptation, or an indicator of the potentially deleterious phenotypic consequences of hatchery practices. [source] Phenotypic consequences of branch point substitutions,HUMAN MUTATION, Issue 8 2006Jana Královi Abstract The branch point sequence (BPS) is a conserved splicing signal important for spliceosome assembly and lariat intron formation. BPS mutations may result in aberrant pre-mRNA splicing and genetic disorders, but their phenotypic consequences have been difficult to predict, largely due to a highly degenerate nature of the BPS consensus. Here, we have examined the splicing pattern of nine reporter pre-mRNAs that have previously been shown to give rise to human hereditary diseases as a result of single-nucleotide substitutions in the predicted BPS. Increased exon skipping and intron retention observed in vivo were recapitulated for each mutated pre-mRNA, but the reproducibility of cryptic splice site activation was lower. BP mutations in reporter pre-mRNAs frequently induced aberrant 3, splice sites and also activated a cryptic 5, splice site. Systematic mutagenesis of BP adenosines showed that in most pre-mRNAs, the expression of canonical transcripts was lower for BP transitions than BP transversions. Differential splicing outcome for transitions vs. transversions was abrogated or reduced if introns were truncated to 200 nt or less, suggesting that the nature of the BP residue is less critical for interactions across very short introns. Together, these results improve prediction of phenotypic consequences of point mutations upstream of splice acceptor sites and suggest that the overrepresentation of disease-causing adenosine-to-guanosine BP substitutions observed in Mendelian disorders is due to more profound defects of gene expression at the level of pre-mRNA splicing. Hum Mutat 27(8), 803,813, 2006. © 2006 WileyLiss, Inc. [source] Multi-site genetic modification of monolignol biosynthesis in alfalfa (Medicago sativa): effects on lignin composition in specific cell typesNEW PHYTOLOGIST, Issue 3 2008Jin Nakashima Summary ,,Independent antisense down-regulation of 10 individual enzymes in the monolignol pathway has generated a series of otherwise isogenic alfalfa (Medicago sativa) lines with varying lignin content and composition. These plants show various visible growth phenotypes, and possess significant differences in vascular cell size and number. ,,To better understand the phenotypic consequences of lignin modification, the distributions of lignin content and composition in stems of the various alfalfa lines at the cellular level were studied by confocal microscopy after staining for specific lignin components, and by chemical analysis of laser capture dissected tissue types. ,,Although all antisense transgenes were driven by the same promoter with specificity for vascular, fiber and parenchyma tissues, the impact of down-regulating a specific transgene varied in the different tissue types. For example, reducing expression of ferulate 5-hydroxylase reduced accumulation of syringyl lignin in fiber and parenchyma cells, but not in vascular elements. ,,The results support a model for cell type-specific regulation of lignin content and composition at the level of the monolignol pathway, and illustrate the use of laser capture microdissection as a new approach to spatially resolved lignin compositional analysis. [source] Gene expression profiling of the ageing rat vibrissa follicleBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005C-L. Yang Summary Background, The application of gene expression profiling to the study of chronological ageing has the potential to illuminate the molecular mechanisms underlying a complex and active process. For example, ageing of the skin and its constituent organs has myriad phenotypic consequences, and a better understanding of the means by which these changes arise has important corollaries for intervention strategies. Objectives, We used a transcriptional profiling approach to investigate changes in gene expression associated with ageing of the large vibrissa follicle of the Wistar rat. Methods, Follicle mRNA isolated from male Wistar rats at 1 and 18 months of age was hybridized to Clontech Atlas 1.2 Rat cDNA macroarrays. Confirmation of array results was provided by the use of Northern blotting and immunohistochemistry. Results, Seven transcripts displayed at least a 1·6-fold increase in expression with age, of which APOD (2·5-fold), GSTM2 (2·0-fold) and NPY (1·8-fold) showed the greatest increases. Decreased expression was found in 19 transcripts, most notably in ALOX12 (13·3-fold) and GAP43 (12·6-fold) expression. Conclusions, Follicular ageing is characterized by transcriptional changes associated with diverse aspects of keratinocyte metabolism, proliferation and development. [source] | ||||||||||