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Regulatory Mutations (regulatory + mutation)
Selected AbstractsToday's multiple choice exam: (a) gene duplication; (b) structural mutation; (c) co-option; (d) regulatory mutation; (e) all of the aboveEVOLUTION AND DEVELOPMENT, Issue 6 2007Todd H. Oakley No abstract is available for this article. [source] RD Lawrence Lecture 2009 Old genes, new tricks: learning about blood glucose regulation from naturally occurring genetic variation in humansDIABETIC MEDICINE, Issue 11 2009A. L. Gloyn Abstract The study of rare monogenic forms of diabetes and pancreatic B-cell dysfunction provides an unrivalled opportunity to link a specific change in gene function with precise cellular consequences and clinical phenotype in humans. Over the past 20 years there has been considerable success in determining the genetic aetiology of a number of rare monogenic forms of diabetes, which has had a significant impact on both our understanding of normal physiology and on translational medicine. The impact of these discoveries has been substantial, with insights into both developmental biology and normal physiology. There are clear examples where determining the genetic aetiology for individuals with rare monogenic subtypes of diabetes has led to improved treatment. Although formerly in the shadow of the monogenic diabetes field, over the past 3 years there has been staggering progress in our understanding of the genetic basis of Type 2 diabetes. This has been largely as a result of genome-wide association studies and has seen the list of ,diabetes susceptibility genes' increase from three to close to 20. There is now encouraging evidence to support a potential role for genetics in determining the response of individuals with Type 2 diabetes to different therapeutic options. One of the challenges that lies ahead is determining how the non-coding genetic variants exert their pathogenicity. It is possible that parallels can be drawn from functional work on rare regulatory mutations causing monogenic forms of diabetes. However, it is more likely that comprehensive approaches will be necessary. [source] THE LOCI OF EVOLUTION: HOW PREDICTABLE IS GENETIC EVOLUTION?EVOLUTION, Issue 9 2008David L. Stern Is genetic evolution predictable? Evolutionary developmental biologists have argued that, at least for morphological traits, the answer is a resounding yes. Most mutations causing morphological variation are expected to reside in the cis -regulatory, rather than the coding, regions of developmental genes. This "cis -regulatory hypothesis" has recently come under attack. In this review, we first describe and critique the arguments that have been proposed in support of the cis -regulatory hypothesis. We then test the empirical support for the cis -regulatory hypothesis with a comprehensive survey of mutations responsible for phenotypic evolution in multicellular organisms. Cis -regulatory mutations currently represent approximately 22% of 331 identified genetic changes although the number of cis -regulatory changes published annually is rapidly increasing. Above the species level, cis -regulatory mutations altering morphology are more common than coding changes. Also, above the species level cis -regulatory mutations predominate for genes not involved in terminal differentiation. These patterns imply that the simple question "Do coding or cis -regulatory mutations cause more phenotypic evolution?" hides more interesting phenomena. Evolution in different kinds of populations and over different durations may result in selection of different kinds of mutations. Predicting the genetic basis of evolution requires a comprehensive synthesis of molecular developmental biology and population genetics. [source] THE LOCUS OF EVOLUTION: EVO DEVO AND THE GENETICS OF ADAPTATIONEVOLUTION, Issue 5 2007Hopi E. Hoekstra An important tenet of evolutionary developmental biology ("evo devo") is that adaptive mutations affecting morphology are more likely to occur in the cis -regulatory regions than in the protein-coding regions of genes. This argument rests on two claims: (1) the modular nature of cis -regulatory elements largely frees them from deleterious pleiotropic effects, and (2) a growing body of empirical evidence appears to support the predominant role of gene regulatory change in adaptation, especially morphological adaptation. Here we discuss and critique these assertions. We first show that there is no theoretical or empirical basis for the evo devo contention that adaptations involving morphology evolve by genetic mechanisms different from those involving physiology and other traits. In addition, some forms of protein evolution can avoid the negative consequences of pleiotropy, most notably via gene duplication. In light of evo devo claims, we then examine the substantial data on the genetic basis of adaptation from both genome-wide surveys and single-locus studies. Genomic studies lend little support to the cis -regulatory theory: many of these have detected adaptation in protein-coding regions, including transcription factors, whereas few have examined regulatory regions. Turning to single-locus studies, we note that the most widely cited examples of adaptive cis -regulatory mutations focus on trait loss rather than gain, and none have yet pinpointed an evolved regulatory site. In contrast, there are many studies that have both identified structural mutations and functionally verified their contribution to adaptation and speciation. Neither the theoretical arguments nor the data from nature, then, support the claim for a predominance of cis -regulatory mutations in evolution. Although this claim may be true, it is at best premature. Adaptation and speciation probably proceed through a combination of cis -regulatory and structural mutations, with a substantial contribution of the latter. [source] Mutation and evolutionary analyses identify NR2E1- candidate-regulatory mutations in humans with severe cortical malformationsGENES, BRAIN AND BEHAVIOR, Issue 6 2007R. A. Kumar Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain,behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1,/, mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain,behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role. [source] Mechanistic understanding of the fermentative L -glutamic acid overproduction by Corynebacterium glutamicum through combined metabolic flux profiling and transmembrane transport characteristicsJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 12 2004Theodora Tryfona Abstract Since the 1950s when Micrococcus glutamicus later renamed Corynebacterium glutamicum was discovered, the production of amino acids by fermentative methods has become an important aspect of industrial microbiology. Numerous studies to understand and improve the metabolic conditions leading to amino acid overproduction have been carried out. Most amino acids are currently produced by use of mutants that contain combinations of auxotrophic and regulatory mutations. L -Glutamic acid is the amino acid produced in the greatest quantities (106 tonnes per year) and Corynebacteria are central to its industrial production. However, further improvements to strain performance are difficult to obtain by empirical optimization and a more rational approach is required. The use of metabolic flux analysis provides valuable information regarding bottlenecks in the formation of desired metabolites. Such techniques have found application in elucidating flux control, provided insight into metabolic network function and developed methods to amplify or redirect fluxes in engineered bioprocesses. Hence, branch points in biosynthesis, precursor supply in fuelling reactions and export of metabolites can be manipulated, resulting in high glutamic acid overproduction by Corynebacterium glutamicum fermentations. In this review, in addition to reviewing the state of play in metabolic flux analysis for glutamate overproduction, the metabolic pathways involved in the production of L -glutamic acid, the mechanisms mediating its efflux and secretion as well as their manipulation to achieve higher glutamate production, are discussed. The link between metabolic flux and transmembrane transport of glutamic acid are also considered. Copyright © 2004 Society of Chemical Industry [source] Nerve Tissue-Specific (GLUD2) and Housekeeping (GLUD1) Human Glutamate Dehydrogenases Are Regulated by Distinct Allosteric MechanismsJOURNAL OF NEUROCHEMISTRY, Issue 5 2000Implications for Biologic Function Abstract: Human glutamate dehydrogenase (GDH), an enzyme central to the metabolism of glutamate, is known to exist in housekeeping and nerve tissue-specific isoforms encoded by the GLUD1 and GLUD2 genes, respectively. As there is evidence that GDH function in vivo is regulated, and that regulatory mutations of human GDH are associated with metabolic abnormalities, we sought here to characterize further the functional properties of the two human isoenzymes. Each was obtained in recombinant form by expressing the corresponding cDNAs in Sf9 cells and studied with respect to its regulation by endogenous allosteric effectors, such as purine nucleotides and branched chain amino acids. Results showed that L-leucine, at 1.0 mM, enhanced the activity of the nerve tissue-specific (GLUD2-derived) enzyme by ,1,600% and that of the GLUD1-derived GDH by ,75%. Concentrations of L-leucine similar to those present in human tissues (,0.1 mM) had little effect on either isoenzyme. However, the presence of ADP (10-50 ,M) sensitized the two isoenzymes to L-leucine, permitting substantial enzyme activation at physiologically relevant concentrations of this amino acid. Nonactivated GLUD1 GDH was markedly inhibited by GTP (IC50 = 0.20 ,M), whereas nonactivated GLUD2 GDH was totally insensitive to this compound (IC50 > 5,000 ,M). In contrast, GLUD2 GDH activated by ADP and/or L-leucine was amenable to this inhibition, although at substantially higher GTP concentrations than the GLUD1 enzyme. ADP and L-leucine, acting synergistically, modified the cooperativity curves of the two isoenzymes. Kinetic studies revealed significant differences in the Km values obtained for ,-ketoglutarate and glutamate for the GLUD1- and the GLUD2-derived GDH, with the allosteric activators differentially altering these values. Hence, the activity of the two human GDH is regulated by distinct allosteric mechanisms, and these findings may have implications for the biologic functions of these isoenzymes. [source] Adapting to winter in wheat: a long-term study follows parallel phenotypic and genetic changes in three experimental wheat populationsMOLECULAR ECOLOGY, Issue 3 2008JARED L. STRASBURG Abstract Drawing a direct connection between adaptive evolution at the phenotypic level and underlying genetic factors has long been a major goal of evolutionary biologists, but the genetic characterization of adaptive traits in natural populations is notoriously difficult. The study of evolution in experimental populations offers some help , initial conditions are known and changes can be tracked for extended periods under conditions more controlled than wild populations and more realistic than laboratory or greenhouse experiments. In this issue of Molecular Ecology, researchers studying experimental wheat populations over a 12-year period have demonstrated evolution in a major adaptive trait, flowering time, and parallel changes in underlying genetic variation (Rhonéet al. 2008). Their work suggests that cis -regulatory mutations at a single gene may explain most of the flowering time variation in these populations. [source] Tissue-dependent limited pleiotropy affects gene expression in barleyTHE PLANT JOURNAL, Issue 2 2008Elena Potokina Summary Non-synonymous coding mutations in a gene change the resulting protein, no matter where it is expressed, but the effects of cis -regulatory mutations could be spatially or temporally limited , a phenomenon termed limited pleiotropy. Here, we report the genome-wide occurrence of limited pleiotropy of cis -regulatory mutations in barley (Hordeum vulgare L.) using Affymetrix analysis of 22 840 genes in a population of 139 doubled haploid lines derived from a cross between the cultivars Steptoe (St) and Morex (Mx). We identified robust cis -acting expression regulators that segregate as major genes in two successive ontogenetic stages: germinating embryo tissues and seedling leaves from the embryonic axis. We show that these polymorphisms may be consistent in both tissues or may cause a dramatic change in transcript abundance in one tissue but not in another. We also show that the parental allele that increases expression can vary with the tissue, suggesting nucleotide polymorphism in enhancer sequences. Because of the limited pleiotropy of cis -regulating mutations, the number of cis expression quantitative trait loci (cis -eQTLs) discovered by ,genetical genomics' is strongly affected by the particular tissue or developmental stage studied. Given that limited pleiotropy is a common feature of cis -regulatory mutations in barley, we predict that the phenomenon would be relevant to developmental and/or tissue-specific interactions across wide taxonomic boundaries in both plants and animals. [source] | ||||||||||||||||||||||