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Results for “Pleiotropy”

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PubMed1993

Antagonistic pleiotropy, mutation accumulation, and human genetic disease.

The antagonistic pleiotropy theory of senescence is the most convincing theoretical explanation of the existence of aging. As yet, no locus or allele has been identified in a wild population with the features predicted by the pleiotropic theory. Human genetic diseases offer the opportunity to identify potentially pleiotropic alleles/loci. Four human genetic diseases--Huntington's disease, idiopathic hemochromatosis, myotonic dystrophy, and Alzheimer's disease--may exhibit pleiotropic effects and further study of these diseases might result in the identification of pleiotropic genes causing aging. Inability to find an early life selective benefit associated with these disease-causing alleles would favor the major alternative genetic explanation for aging, the mutation accumulation theory.

Aging↗

PubMed2003

Vascular pleiotropy of statins: clinical evidence and biochemical mechanisms.

The ability of statins to lower serum cholesterol and reduce coronary heart disease endpoints has confirmed portions of the lipid hypothesis. However, the time to benefit and increased benefit in overlapping populations have suggested that nonlipid or pleiotropic effects of statins may be present. The apparent benefit of statins in cerebrovascular disease may imply a similar final common pathway among the diverse mechanisms of vascular diseases. Statins' inhibition of isoprenoid intermediates may modify GTP binding proteins such as Rho. The augmentation of collateral blood flow downstream of activated plaque through endothelial cell nitric oxide synthase may be the biochemical basis of statins' vascular pleiotropy. Eventual clinical paradigms of statin use may include higher doses to enhance pleiotropic effects and treatment, even when lipid markers are within guidelines.

Dose-Response Relationship, Drug↗

PubMed1991

Sipple syndrome with lichen amyloidosis as a paracrinopathy: pleiotropy, heterogeneity, or a contiguous gene?

A five-generation white family with multiple endocrine neoplasia type 2A had six affected members. Two, a mother and her daughter, had interscapular cutaneous pruritic lesions resembling macular/lichen amyloidosis. In the daughter, light microscopy showed homogeneous aggregates in the papillary dermis. Crystal violet staining showed metachromasia and indicated that the deposits were amyloid. This is the fourth family with familial medullary thyroid carcinoma with cutaneous amyloidosis and as such it allowed comparative analysis. Genetic heterogeneity, a contiguous gene, and pleiotropy were considered. It appears that multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma with cutaneous amyloidosis represents the phenotypic variability of the expression of a pleiotropic gene. The condition is one of the predominantly ectodermal autosomal dominant phakomatoses and is most likely a paracrinopathy.

Adolescent↗

PubMed1995

The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15.

To understand the molecular bases for cytokine redundancy and pleiotropy, we have compared the Stat proteins activated in peripheral blood lymphocytes (PBLs) by cytokines with shared and distinct actions. Interleukin-2 (IL-2) rapidly activated Stat5 in fresh PBL, and Stat3 and Stat5 in preactivated PBL. IL-7 and IL-15 induced the same complexes as IL-2, a feature explained by the existence of similar tyrosine-phosphorylated motifs in the cytoplasmic domains of IL-2R beta and IL-7R that can serve as docking sites for Stat proteins. IL-13 Induced the same complexes as IL-4, a finding explained by our studies implicating IL-4R as a shared component of the receptors. These studies demonstrate that a single cytokine can activate different combinations of Stat proteins under different physiological conditions, and also indicate two mechanisms by which distinct cytokines can activate the same Stat protein.

Amino Acid Sequence↗

PubMed2002

Lifespan, QTLs, age-specificity, and pleiotropy in Drosophila.

We have constructed a set of 120 recombinant inbred lines for use in studies of the genetics of lifespan in Drosophila. The lines are derived from Luckinbill and Clare's (Heredity 55 (1985) 9) artificial selection experiment for increased lifespan. Inbred lines retain the relative lifespan characteristics of the experimental and control stocks from which they are derived. Mapping experiments suggest that a small number of QTLs accounts for much of the selection response. The age-specificity of genetic effects is best visualized in three-dimensional QTL maps of age-specific mortality. QTLs are shared by males and females, and have effects on age-specific mortality that are positively correlated across ages, with different times of onset. There is evidence for positively correlated pleiotropic effects of lifespan QTLs on mid-life fertility and resistance to an oxidizing chemical, and a striking lack of evidence for negative pleiotropy.

Animals↗

PubMed2002

Conservation of the segmented germband stage: robustness or pleiotropy?

Gene expression patterns of the segment polarity genes in the extended and segmented germband stage are remarkably conserved among insects. To explain the conservation of these stages, two hypotheses have been proposed. One hypothesis states that the conservation reflects a high interactivity between modules, so that mutations would have several pleiotropic effects in other parts of the body, resulting in stabilizing selection against mutational variation. The other hypothesis states that the conservation is caused by robustness of the segment polarity network against mutational changes. When evaluating the empirical evidence for these hypotheses, we found strong support for pleiotropy and little evidence supporting robustness of the segment polarity network. This points to a key role for stabilizing selection in the conservation of these stages. Finally, we discuss the implications for robustness of organizers and long-term conservation in general.

Animals↗

PubMed2006

Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch.

Pleiotropism is a hallmark of cytokines and growth factors; yet, the underlying mechanisms are not clearly understood. We have identified a motif in the granulocyte macrophage-colony-stimulating factor receptor composed of a tyrosine and a serine residue that functions as a binary switch for the independent regulation of multiple biological activities. Signalling occurs either through Ser585 at lower cytokine concentrations, leading to cell survival only, or through Tyr577 at higher cytokine concentrations, leading to cell survival as well as proliferation, differentiation or functional activation. The phosphorylation of Ser585 and Tyr577 is mutually exclusive and occurs via a unidirectional mechanism that involves protein kinase A and tyrosine kinases, respectively, and is deregulated in at least some leukemias. We have identified similar Tyr/Ser motifs in other cell surface receptors, suggesting that such signalling switches may play important roles in generating specificity and pleiotropy in other biological systems.

14-3-3 Proteins↗

PubMed2006

Quantitative genetics of age at reproduction in wild swans: support for antagonistic pleiotropy models of senescence.

Why do individuals stop reproducing after a certain age, and how is this age determined? The antagonistic pleiotropy theory for the evolution of senescence predicts that increased early-life performance should be accompanied by earlier (or faster) senescence. Hence, an individual that has started to breed early should also lose its reproductive capacities early. We investigate here the relationship between age at first reproduction (AFR) and age at last reproduction (ALR) in a free-ranging mute swan (Cygnus olor) population monitored for 36 years. Using multivariate analyses on the longitudinal data, we show that both traits are strongly selected in opposite directions. Analysis of the phenotypic covariance between these characters shows that individuals vary in their inherent quality, such that some individuals have earlier AFR and later ALR than expected. Quantitative genetic pedigree analyses show that both traits possess additive genetic variance but also that AFR and ALR are positively genetically correlated. Hence, although both traits display heritable variation and are under opposing directional selection, their evolution is constrained by a strong evolutionary tradeoff. These results are consistent with the theory that increased early-life performance comes with faster senescence because of genetic tradeoffs.

Aging↗

PubMed1995

Pleiotropy in microdeletion syndromes: neurologic and spermatogenic abnormalities in mice homozygous for the p6H deletion are likely due to dysfunction of a single gene.

Variability and complexity of phenotypes observed in microdeletion syndromes can be due to deletion of a single gene whose product participates in several aspects of development or can be due to the deletion of a number of tightly linked genes, each adding its own effect to the syndrome. The p6H deletion in mouse chromosome 7 presents a good model with which to address this question of multigene vs. single-gene pleiotropy. Mice homozygous for the p6H deletion are diluted in pigmentation, are smaller than their littermates, and manifest a nervous jerky-gait phenotype. Male homozygotes are sterile and exhibit profound abnormalities in spermiogenesis. By using N-ethyl-N-nitrosourea (EtNU) mutagenesis and a breeding protocol designed to recover recessive mutations expressed hemizygously opposite a large p-locus deletion, we have generated three noncomplementing mutations that map to the p6H deletion. Each of these EtNU-induced mutations has adverse effects on the size, nervous behavior, and progression of spermiogenesis that characterize p6H deletion homozygotes. Because EtNU is thought to induce primarily intragenic (point) mutations in mouse stem-cell spermatogonia, we propose that the trio of phenotypes (runtiness, nervous jerky gait, and male sterility) expressed in p6H deletion homozygotes is the result of deletion of a single highly pleiotropic gene. We also predict that a homologous single locus, quite possibly tightly linked and distal to the D15S12 (P) locus in human chromosome 15q11-q13, may be associated with similar developmental abnormalities in humans.

Animals↗

PubMed2003

Scaling of mutational effects in models for pleiotropy.

Mutation-selection models provide a framework to relate the parameters of microevolution to properties of populations. Like all models, these must be subject to test and refinement in light of experiments. The standard mutation-selection model assumes that the effects of a pleiotropic mutation on different characters are uncorrelated. As a consequence of this assumption, mutations of small overall effect are suppressed. For strong enough pleiotropy, the result is a nonvanishing fraction of a population with the "perfect" phenotype. However, experiments on microorganisms and experiments on protein structure and function contradict the assumptions of the standard model, and Kimura's observations of heterogeneity within populations contradict its conclusions. Guided by these observations, we present an alternative model for pleiotropic mutations. The new model allows mutations of small overall effect and thus eliminates the finite fraction of the population with the perfect phenotype.

Genetics, Population↗

PubMed2005

Clinical implications for statin pleiotropy.

PURPOSE OF REVIEW: Atherosclerosis is a multi-factorial condition involving dyslipidemia that can result in cardiovascular disease. Statins are potent inhibitors of cholesterol biosynthesis, and in clinical trials, statins have been shown to be beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to occur much earlier and to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. SUMMARY OF FINDINGS: Recent studies indicate that some of the cholesterol-independent or 'pleiotropic' effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent upon isoprenylation, may play an important role in mediating the pleiotropic effects of statins. SUMMARY: The potential clinical implications of statin pleiotropy suggests that perhaps other biomarkers, in addition to lipid levels, should be used to gauge the full efficacy of statin therapy in patients with cardiovascular risks or that statin therapy may be effective in disease states, such as inflammatory conditions, ischemic stroke or cancer, where elevated cholesterol levels have not been shown to be a strong epidemiological risk for these diseases.

Atherosclerosis↗

PubMed2003

Pleiotropy, homeostasis, and functional networks based on assays of cardiovascular traits in genetically randomized populations.

A major problem in studying biological traits is understanding how genes work together to provide organismal structures and functions. Conventional reductionist paradigms attribute functions to particular proteins, motifs, and amino acids. An equally important but harder problem involves the synthesis of data at fundamental levels of biological systems to understand functionality at higher levels. We used subtle, naturally occurring, multigenic variation of cardiovascular (CV) properties in a panel of genetically randomized strains that are derived from the A/J and C57BL/6J strains of mice to perturb CV functions in nonpathologic ways. In this proof-of-concept study, computational analysis correctly identified the known relations among CV properties and revealed functionality at higher levels of the CV system. The network was then used to account for pleiotropies and homeostatic responses in single gene mutant mice and in mice treated with a pharmacologic agent (anesthesia). The CV network accounted for functional dependencies in complementary ways to the insights obtained from genetic networks and biochemical pathways. These networks are therefore an important approach for defining and characterizing functional relations in complex biological systems in health and disease.

Animals↗

PubMed2000

Single QTL effects, epistasis, and pleiotropy account for two-thirds of the phenotypic F(2) variance of growth and obesity in DU6i x DBA/2 mice.

Genes influencing body weight and composition and serum concentrations of leptin, insulin, and insulin-like growth factor I (IGF-I) in nonfasting animals were mapped in an intercross of the extreme high-growth mouse line DU6i and the inbred line DBA/2. Significant loci with major effects (F > 7.07) for body weight, obesity, and muscle weight were found on chromosomes 1, 4, 5, 7, 11, 12, 13, and 17, for leptin on chromosome 14, for insulin on chromosome 4, and for IGF-I on chromosome 10 at the Igf1 gene locus itself and on chromosome 18. Significant interaction between different quantitative trait loci (QTL) positions was observed (P < 0.01). Evidence was found that loci having small direct effect on growth or obesity contribute to the obese phenotype by gene-gene interaction. The effects of QTLs, epistasis, and pleiotropy account for 64% and 63% of the phenotypic variance of body weight and fat accumulation and for over 32% of muscle weight and serum concentrations of leptin, and IGF-I in the F(2) population of DU6i x DBA/2 mice. [The quantitative trait loci described in this paper have been submitted to the Mouse Genome Database.]

Animals↗

PubMed2003

Antagonistic pleiotropy, mortality source interactions, and the evolutionary theory of senescence.

Most theoretical work on the evolution of senescence has assumed that all individuals within a population are equally susceptible to extrinsic sources of mortality. An influential qualitative prediction based on this assumption is Williams's hypothesis, which states that more rapid senescence is expected to evolve when the magnitude of such extrinsic mortality sources is increased. Much evidence suggests, however, that for many groups of organisms externally imposed mortality risk is a function of an organism's internal condition and hence susceptibility to such hazards. Here we use a model of antagonistic pleiotropy to investigate the consequences that such interactions (between environmental hazard and internal condition) can have for Williams's hypothesis. As with some previous theory examining noninteractive extrinsic mortality sources, we find that an increase in interactive extrinsic sources of mortality makes it less likely that an individual will survive from birth to any given age, weakening selection against physiological deterioration at all ages and thus favoring more rapid senescence. However, an increase in interactive mortality sources also typically strengthens selection against physiological deterioration at any age, given an individual has survived to that age, because it reduces the fitness of poor-condition individuals more than good-condition individuals. These opposing effects are not felt equally at all ages, with the latter predominating at early ages. The combined effects can therefore result in the novel prediction that an increase in interactive extrinsic mortality sources can select for slower senescent deterioration early in life but more rapid deterioration late in life.

Age Factors↗

PubMed2005

Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines.

The leptin receptor (LEPR) is a class I cytokine receptor signalling via both the janus kinase/signal transducer and activator of transcription (JAK/STAT) and the MAP kinase pathways. In addition, leptin has been shown previously to activate AMP-activated kinase (AMPK) in skeletal muscle. To enable a detailed analysis of leptin signalling in pancreatic beta cells, LEPR point mutants with single or combined exchanges of the three intracellular tyrosines were expressed in HIT-T15 insulinoma cells. Western blots with activation state-specific antibodies recognizing specific signalling molecules revealed that the wild-type receptor activated STAT1, STAT3, STAT5 and ERK1/2 but failed to alter the phosphorylation of AMPK. Each of the three intracellular tyrosine residues in LEPR exhibited different signalling capacities: Tyr985 was necessary and sufficient for leptin-induced activation of ERK1/2; Tyr1077 induced tyrosyl phosphorylation of STAT5; and Tyr1138 was capable of activating STAT1, STAT3 and STAT5. Consistent results were obtained in reporter gene assays with STAT3 or STAT5-responsive promoter constructs, respectively. Furthermore, the sequence motifs surrounding the three tyrosine residues are conserved in LEPR from mammals, birds and in a LEPR-like cytokine receptor from pufferfish. Mutational analysis of the box3 motif around Tyr1138 identified Met1139 and Gln1141 as important determinants that define specificity towards the different STAT factors. These data indicate that all three conserved tyrosines are involved in LEPR function and define the pleiotropy of signal transduction via STAT1/3, STAT5 or ERK kinases. Activation and inhibition of AMPK appears to require additional components of the signalling pathways that are not present in beta cells.

Amino Acid Sequence↗

PubMed2000

The relationship between loci for mating system and fitness-related traits in Mimulus (Scrophulariaceae): a test for deleterious pleiotropy of QTLs with large effects.

Loci with large phenotypic effects are generally not thought to be important in the evolution of quantitative traits because of their deleterious pleiotropic effects, yet empirical studies of such pleiotropic effects are lacking. Here I use molecular markers to test the extent of deleterious pleiotropy of quantitative trait loci (QTLs) that have large effects on mating system differences between the wild plants Mimulus guttatus and M. platycalyx (Scrophulariaceae). Six fitness-related traits, namely germination rate (GR), number of nodes (NN), number of flowers (NF), plant height (HT), above-ground biomass (WT), and flowering time (FT) were examined in a growth chamber for a backcross population between M. guttatus and M. platycalyx (with M. platycalyx as recurrent parent). Interval mapping based upon a linkage map consisting of isozyme and random amplified polymorphic DNA (RAPD) markers detected no QTL for fitness-related traits near the mating system QTLs. Single-marker analysis based upon 13 markers flanking the mating system QTLs detected three significant marker-fitness trait associations, and these associations indicate beneficial effects of mating system loci. This suggests that QTLs with large effects on mating system traits do not have significant deleterious pleiotropic effects, and that they could be important factors in adaptive evolution of Mimulus.

Alleles↗

PubMed2004

Functional allelic heterogeneity and pleiotropy of a repeat polymorphism in tyrosine hydroxylase: prediction of catecholamines and response to stress in twins.

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, has a common tetranucleotide repeat polymorphism, (TCAT)(n). We asked whether variation at (TCAT)(n) may influence the autonomic nervous system and its response to environmental stress. To understand the role of heredity in such traits, we turned to a human twin study design. Both biochemical and physiological autonomic traits displayed substantial heritability (h(2)), up to h(2) = 56.8 +/- 7.5% (P < 0.0001) for norepinephrine secretion, and h(2) = 61 +/- 6% (P < 0.001) for heart rate. Common (TCAT)(n) alleles, particularly (TCAT)(6) and (TCAT)(10i), predicted such traits (including catecholamine secretion, as well as basal and poststress heart rate) in allele copy number dose-dependent fashion, although in directionally opposite ways, indicating functional allelic heterogeneity. (TCAT)(n) diploid genotypes (e.g., [TCAT](6)/[TCAT](10i)) predicted the same physiological traits but with increased explanatory power for trait variation (in contrast to allele copy number). Multivariate ANOVA documented genetic pleiotropy: joint effects of the (TCAT)(10i) allele on both biochemical (norepinephrine) and physiological (heart rate) traits. (TCAT)(6) allele frequencies were lower in normotensive twins at genetic risk of hypertension, consistent with an effect to protect against later development of hypertension, and suggesting that the traits predicted by these variants in still-normotensive subjects are early, heritable, "intermediate phenotypes" in the pathogenetic scheme for later development of sustained hypertension. We conclude that common allelic variation within the tyrosine hydroxylase locus exerts a powerful, heritable effect on autonomic control of the circulation and that such variation may have implications in later development of cardiovascular disease traits such as hypertension.

Adenine↗

PubMed2001

Functional pleiotropy of an intramolecular triplex-forming fragment from the 3'-UTR of the rat Pigr gene.

A microsatellite-containing 359-bp restriction fragment, isolated from the rat Pigr gene (murine polymeric immunoglobulin receptor gene) 3'-untranslated region (3'-UTR) and inserted into 3'-UTR or 3' flanking positions in transcription units of supercoiled plasmids, attenuates luciferase reporter gene expression in orientation- and position-dependent ways following transient transfection of human 293 cells. The same fragment stimulates orientation-dependent gene expression in a 5' flanking position. Plasmid linearization abrogates both orientation- and position-dependent responses. Cell-free translation reveals that 5' and 3' flanking expression responses are proportional to increased and decreased luciferase mRNA levels, whereas 3'-UTR expression is associated with control mRNA levels. Hypersensitivity to nucleases S1 and P1, gel mobility differences between supercoiled plasmids carrying opposing microsatellite orientations, and anomalous melting profiles of this fragment are also observed. These results suggest that functional pleiotropy of this fragment depends on the DNA context of its purine-rich microsatellite strand and on DNA supercoiling. Intramolecular triplexes stabilized by supercoiling and secondary structures of purine repeat-rich mRNAs may also confer regulatory properties to similar genomic elements.

3' Untranslated Regions↗