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PubMed2025

A Causal Effect of Serum 25(OH)D Level on Appendicular Muscle Mass: Evidence From NHANES Data and Mendelian Randomization Analyses.

BACKGROUND: Low serum vitamin D status was reported to be associated with reduced muscle mass; however, it is inconclusive whether this relationship is causal. This study used data from the National Health and Nutrition Examination Survey (NHANES) and two-sample Mendelian randomization (MR) analyses to ascertain the causal relationship between serum 25-hydroxyvitamin D [25(OH)D] and appendicular muscle mass (AMM). METHODS: In the NHANES 2011-2018 dataset, 11 242 participants (5588 males and 5654 females) aged 18-59 years old were included, and multivariant linear regression was performed to assess the relationship between 25(OH)D and AMM measured by dual-energy X-ray absorptiometry. In two-sample MR analysis, 167 single nucleotide polymorphisms significantly associated with serum 25(OH)D at the genome-wide association level (p < 5 × 10-8) were applied as instrumental variables (IVs) to assess vitamin D effects on AMM in the UK Biobank (417 580 Europeans) using univariable and multivariable MR (MVMR) models. RESULTS: In the NHANES dataset, serum 25(OH)D concentrations were positively associated with AMM (β = 0.013, SE = 0.001, p < 0.001) in all participants, after adjustment for age, race, season of blood collection, education, income, body mass index and physical activity. In stratification analysis by sex, males (β = 0.024, SE = 0.002, p < 0.001) showed more pronounced positive associations than females (β = 0.003, SE = 0.002, p = 0.024). In univariable MR, genetically higher serum 25(OH)D levels were positively associated with AMM in all participants (β = 0.049, SE = 0.024, p = 0.039) and males (β = 0.057, SE = 0.025, p = 0.021), but only marginally significant in females (β = 0.043, SE = 0.025, p = 0.090) based on IVW models was noticed. No significant pleiotropy effects were detected for the IVs in the two-sample MR investigations. In MVMR analysis, a positive causal effect of 25(OH)D on AMM was observed in the total population (β = 0.116, SE = 0.051, p = 0.022), males (β = 0.111, SE = 0.053, p = 0.036) and females (β = 0.124, SE = 0.054, p = 0.021). CONCLUSIONS: Our results suggested a positive causal effect of serum 25(OH)D concentration on AMM; however, more researches are warranted to unveil the underlying biological mechanisms and evaluate the effects of vitamin D intervention on AMM.

Humans↗

PubMed2004

Pleiotropic effects on mandibular morphology II: differential epistasis and genetic variation in morphological integration.

The evolution of morphological modularity through the sequestration of pleiotropy to sets of functionally and developmentally related traits requires genetic variation in the relationships between traits. Genetic variation in relationships between traits can result from differential epistasis, where epistatic relationships for pairs of loci are different for different traits. This study maps relationship quantitative trait loci (QTLs), specifically QTLs that affect the relationship between individual mandibular traits and mandible length, across the genome in an F2 intercross of the LG/J and SM/J inbred mouse strains (N = 1045). We discovered 23 relationship QTLs scattered throughout the genome. All mandibular traits were involved in one or more relationship QTL. When multiple traits were affected at a relationship QTL, the traits tended to come from a developmentally restricted region of the mandible, either the muscular processes or the alveolus. About one-third of the relationship QTLs correspond to previously located trait QTLs affecting the same traits. These results comprise examples of genetic variation necessary for an evolutionary response to selection on the range of pleiotropic effects.

Animals↗

PubMed2003

Pleiotropic effects on mandibular morphology I. Developmental morphological integration and differential dominance.

Pleiotropy refers to a single genetic locus that affects more than one phenotypic trait. Pleiotropic effects of genetic loci are thought to play an important role in evolution, reflecting functional and developmental relationships among phenotypes. In a previous study, we examined pleiotropic effects displayed by quantitative trait loci (QTLs) on murine mandibular morphology in relation to mandibular structure and function. In replicating most of our previous QTLs and increasing our sample size, this study strengthens and extends our earlier results. As in our previous study, we find that QTL effects tend to be restricted to developmentally or functionally related traits. In addition, we examine patterns of differential dominance for pleiotropic QTL effects. Differential dominance occurs when dominance patterns for a single locus vary among traits. We find that multivariate overdominance is a common and substantial phenomenon, and may potentially provide an explanation for the persistence of heterozygosity in natural populations.

Animals↗

PubMed1993

Molecules and cognition: the latterday lessons of levels, language, and lac. Evolutionary overview of brain structure and function in some vertebrates and invertebrates.

The characteristics of the nervous systems of a number of organisms in different phyla are examined at the recombinant DNA, protein, neuroanatomic, neurophysiological, and cognitive levels. Among the invertebrates, special attention is paid to the advantages as well as the shortcomings of the fly Drosophila melanogaster, the worm Caenorhabditis elegans, the honey bee Apis mellifera, the sea hare Aplysia californica, the octopus Octopus vulgaris, and the squid Loligo pealei. Among vertebrates, the focus is on Homo sapiens, the mouse Mus musculus, the rat Rattus norvegicus, the cat Felis catus, the macaque monkey Macaca fascicularis, the barn owl Tyto alba, and the zebrafish Brachydanio rerio. Vertebrate nervous systems have also been compared in fossil vs. extant organisms. I conclude that complex nervous systems arose in the Early Cambrian via a big bang that was underpinned by a modular method of construction involving massive pleiotropy of gene circuits. This rapidity of construction had enormous implications for the degrees of freedom that were subsequently available to evolving nervous systems. I also conclude that at the level of neuronal populations and interactions of neuropiles there is no model system between phyla except at the basic macromolecular level. Further, I argue that to achieve a significant understanding of the functions of extant nervous systems we need to concentrate on fewer organisms in greater depth and manipulate genomes via transgenic technologies to understand the behavioral outputs that are possible from an organism. Finally, I analyze the concepts of "perceptual categorization" and "information processing" and the difficulties involved in the extrapolation of computer analogies to sophisticated nervous systems.

Animals↗

PubMed1993

Interleukin 11: an overview.

Interleukin (IL)-11 is a bone marrow fibroblast derived cytokine with a wide spectrum of in vitro biological activities in the hematopoietic, lymphopoietic, hepatic, adipose, neuronal and osteoclast systems, either alone or in synergy with other hematopoietic growth factors. In vivo administration of IL-11 in mice, rats and nonhuman primates has demonstrated the thrombopoietic effects of this cytokine. The expression of the human IL-11 gene, which is localized at 19q13.3-13.4, can be controlled at both the transcriptional and post-transcriptional levels. Initial biochemical characterization has identified a 151 kD protein as the potential IL-11 binding subunit of the receptor complex. Like other cytokines such as IL-6, leukemia inhibitory factor (LIF), oncostatin M (ONC) and ciliary neurotrophic factor (CNTF), IL-11 has been shown to utilize IL-6 signal transducer, gp130. Because of the overlapping biological activities, the similarities in the predicted tertiary structures, and the sharing of common signal transducer protein, we have compared the signal transduction pathways mediated by these cytokines in various cell types. Studies of protein tyrosine phosphorylation, primary response gene expression and signaling molecules known to be important in transducing mitogenic signals have suggested that there are convergent and divergent points along the signal transduction pathways utilized by IL-11, IL-6, LIF and ONC. These observations may explain the biological pleiotropy and redundancy of this group of cytokines.

Animals↗

PubMed1985

The PET18 locus of Saccharomyces cerevisiae: a complex locus containing multiple genes.

The basis of pleiotropy shown by the pet18 mutants of Saccharomyces cerevisiae (rho-0,KIL-0 and temperature sensitive growth) was examined by cloning the fragment which complements the defect in growth at 37 degrees C of the pet18 mutants. The cloned DNA could complement the defect in the maintenance of the killer plasmid but did not give the cell the ability to maintain mitochondrial DNA. Sequence analysis of the cloned DNA revealed the presence of four open reading frames, at least two of which are necessary for the complementation activity. By using the cloned DNA as a probe, we found that two independent pet18 mutants have a deletion covering the entire sequence contained in the probe. From these results we predict that the traits of the pet18 mutants that concern temperature sensitivity and killer of the pet18 mutants are controlled by a separate gene(s) from that which participates in the maintenance of mitochondrial DNA.

Base Sequence↗

PubMed2001

Non-alpha-helical elements modulate polytopic membrane protein architecture.

In "all alpha-fold" transmembrane proteins, including ion channels, G-protein-coupled receptors (GPCRs), bacterial rhodopsins and photosynthetic reaction centers, relatively long alpha-helices, straight, curved or kinked, pack into compact elliptical or circular domains. Using both existing and newly developed tools to analyze transmembrane segments of all available membrane protein three-dimensional structures, including that very recently elucidated for the GPCR, rhodopsin, we report here the finding of frequent non-alpha-helical components, i.e. 3(10)-helices ("tight turns"), pi-helices ("wide turns") and intrahelical kinks (often due to residues other than proline). Often, diverse helical types and kinks concatenate over long segments and produce complex inclinations of helical axis, and/or diverse frame shifts in the "canonical", alpha-helical side-chain pattern. Marked differences in transmembrane architecture exist even between seemingly structurally related proteins, such as bacteriorhodopsin and rhodopsin. Deconvolution of these non-canonical features into their composite elements is essential for understanding the pleiotropy of polytopic protein structure and function, and must be considered in developing valid macromolecular models.

Amino Acid Sequence↗

PubMed1993

Evolution of optimal behaviour in networks of Boolean automata.

This paper describes the response to selection for optimal behaviour in networks of Boolean automata. The networks considered are "open" in the sense that they receive an input and produce an output. The task that the nets are selected to solve is to maximize the mean "height" attained in a fixed number of iterations in "landscapes" that vary in their ruggedness. This is analogous to an organism with a fixed time budget that attempts to maximize its food intake in an environment where the food concentration varies in space. The results suggest that it is possible to select simple Boolean nets to respond adaptively to their inputs. Selection on simple environments produces a near "optimal" response. The response to complex environments is worse. The results suggest that nets selected on complex environments perform better on environments of different degrees of complexity than those selected on simple environments. Although nets with larger numbers of automata do not respond markedly better to selection, the variability in the response to selection is reduced. It appears to be difficult to predict the movements of nets from a study of the attractors of net with sensory units clamped at particular values. The cycle of bits in clamped nets can vary greatly with small changes in the inputs to the nets. The actual movement of nets does not, however, reflect this instability. It is concluded that networks of Boolean automata may be useful models with which to investigate different genetic algorithms. Furthermore, perturbations in such systems may give insights into the nature of pleiotropy and epistasis.

Algorithms↗

PubMed1996

Dominance--one hundred and fifteen years after Mendel's paper.

In The Molecular Basis of Dominance, Kacser & Burns (1981) demonstrated that dominance in diploids and polyploids, and pleiotropy in all organisms, were biochemical phenomena; they were the consequences of the response of a metabolic system to a genetically specified change in the activity of any one enzyme within the system. Epistasis was similarly explicable when each of at least two enzyme activities suffered a change. The significance of this achievement by Kacser & Burns (1981) for biochemistry, genetics, molecular biology, medicine and bio-technology is best seen against the background of 115 years of attempts to explain the origins of dominance.

Animals↗

PubMed2001

Complex adaptive systems, aging and longevity.

Mortality and reproduction are intimately entwined in the study of aging and longevity. I apply the modern theory of complex adaptive systems (nonlinear, stochastic, dynamic methods) to questions of aging and longevity. I begin by highlighting major questions that must be answered in order to obtain a deeper understanding of aging. These are: (i) What should (in an evolutionary sense) mortality trajectories look like? (ii) Why does caloric restriction slow aging? (iii) Why does reproduction cause delayed mortality? (iv) Why does compensatory growth cause delayed mortality? I show how dynamic state variable models based on stochastic dynamic programming (Clark & Mangel, 2000) can be used to embed genetic theories of senescence (either mutation accumulation or antagonistic pleiotropy) in the somatic environment, as George Williams called for in 1957, and how they make the disposable soma theory of aging operational. Such models will allow unification of genetic and phenotypic theories of aging.

Adaptation, Physiological↗

PubMed2002

The regulatory anatomy of honeybee lifespan.

Honeybee workers (Apis mellifera) may be classified as either short-lived summer bees or long-lived winter bees in temperate zones. The protein status appears to be a major determinant of honeybee lifespan, and the lipoprotein vitellogenin seems to play a crucial role. Here, we give a review of the role of the vitellogenin in honeybee workers, and present a data-driven mathematical model describing the dynamics of this representative protein in the individual bee as a function of its task profile under various regimes. The results support the hypothesis that vitellogenin is a true storage protein that is utilized for various metabolic purposes including the synthesis of brood food. Except for workers having been foragers for many days, they also suggest that the previous life histories of workers do not constrain them from becoming winter bees as long as they get ample food and time to build up their protein reserves before wintering. The results also indicate that it may not be necessary to introduce the ovary as a storage organ for vitellogenin in order to generate normal winter bees. The insights gained from these results are then discussed in a broader gerontological and life history context. Remarkably similar features concerning regulation of ageing in Caenorhabditis elegans, Drosophila melanogaster and honeybees are pointed out and discussed. Furthermore, we show that in contrast to the "mutation accumulation" and the "antagonistic pleiotropy" evolutionary theories of ageing, the "disposable soma" theory is capable of explaining the bimodal longevity distribution of honeybees when interpreted in a group selection context. Finally, by showing that depletion of nutrient stores can be actively controlled by pathways connected to regulation of ageing, we strengthen the claim that age-based division of labour, with performance of risky tasks delayed until late in life by workers with depleted nutrient stores, may have evolved as an energy-saving mechanism in insect colonies.

Aging↗

PubMedDate not supplied

Genetic and epigenetic regulation schemes: need for an alternative paradigm.

Self-organization of living cells results from the tangle of positive and negative feedback developed to ensure their homeostasis and/or their differentiation. There are three major means cellular regulation operates: the genetic, the epigenetic, and the metabolic ones. The regulation type in each of them has been overviewed. Further examination of relations between complexity and developmental stability points out sui generis properties of feedback loops, which are redundancy and pleiotropy. Prototypical schemes for positive and negative regulation with redundant and pleiotropic (including multifunctional) proteins are presented. They stress a theoretical shift from the analytical to the systemic framework. The systemic paradigm appears to be of increasing interest and importance in the study of concepts for the representation of genetic and epigenetic regulations.

Animals↗

PubMed1998

Molecules, developmental modules, and phenotypes: a combinatorial approach to homology.

Most traditional views of homology rely on two unwarranted premises: the pervasively hierarchical nature of biology, inclusive of the levels of genes, development, and morphology and the linear mapping of genes onto developmental schedules and of developmental schedules onto phenotypes. These premises are only occasionally verified. Hierarchical behavior is negated by gene duplication and exon shuffling at the level of genes, by the coexistence of autonomous vs nonautonomous gene expression at the level of development, by ontogenetic repatterning at the level of morphology. The linearity of mapping of genes onto development is disturbed by genetic piracy, uncoupling of positional vs spatial control, and pleiotropy. The independence of developmental modules affects the mapping of development onto morphology and, finally, the peculiar topology of the epigenetic code affects the linearity of the gene to phenotype mapping. To cope with this complex behavior, a combinatorial approach to homology is recommended.

Animals↗

PubMed1999

Evolutionary preservation of redundant duplicated genes.

Gene duplication events produce both perfect and imperfect copies of genes. Perfect copies are said to be functionally redundant when knockout of one gene produces no 'scoreable', phenotypic effects. Preserving identical, duplicate copies of genes is problematic as all copies are prone to accumulate neutral mutations as pseudogenes, or more rarely, evolve into new genes with novel functions. We summarise theoretical treatments for the invasion and subsequent evolutionary modification of functionally redundant genes. We then consider the preservation of functionally identical copies of a gene over evolutionary time. We present several models for conserving redundancy: asymmetric mutation, asymmetric efficacy, pleiotropy, developmental buffering, allelic competition and regulatory asymmetries. In all cases, some form of symmetry breaking is required to maintain functional redundancy indefinitely.

Animals↗

PubMed1977

Altered drug permeability in mammalian cell mutants.

The properties of colchicine uptake into Chinese hamster ovary cells were examined and found to be consistent with an unmediated diffusion mode. This uptake was stimulated several fold by metabolic inhibitors. The activation energy of colchicine uptake was found to be 19 kcal per mole; a similar value was obtained in cells stimulated by cyanide. Drug resistant mutants with greatly reduced colchicine permeability have been isolated. They displayed a pleiotropic phenotype, being cross-resistant to a variety of unrelated compounds. The basis of this pleiotropy was due also to reduced drug permeability. Examination of the lipids and fatty acids of parental and mutant cell membranes revealed no major differences. However, a 170,000 dalton surface glycoprotein was observed to be associated with colchicine resistance. This glycoprotein was postulated to be a modulator of drug permeability. All these data are consistent with the concept that mammalian cells are able to regulate the permeation of drugs entering by an unmediated diffusion process.

Animals↗

PubMed1996

IL-6 cytokine family and signal transduction: a model of the cytokine system.

The interleukin 6 (IL-6) cytokine family, which includes IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), IL-11 and cardiotrophin-1 (CT-1), exhibits pleiotropy and redundancy in biological activities. The IL-6 family cytokines exhibit a helical structure. Their receptors belong to the type 1 cytokine receptor family. The receptors of the IL-6 family cytokines share a receptor subunit, which explains one of the mechanisms of functional redundancy. In this review, we describe the general features of the IL-6 cytokine family and its signal transduction mechanisms. Many functional properties of the IL-6 family of cytokines and their receptors are general features of the cytokine system.

Amino Acid Sequence↗

PubMed1994

QTL mapping of naturally-occurring variation in flowering time of Arabidopsis thaliana.

A segregating F2 population of Arabidopsis thaliana derived from a cross between the late-flowering ecotype Hannover/Münden (HM) and the early-flowering ectoype Wassilewskija (WS) was analyzed for flowering time and other morphological traits. Two unlinked quantitative trait loci (QTLs) affecting days to first flower (DFF-a and DFF-b) mapped to chromosome 5. QTLs which affect node number (NN), leaf length at flowering (LLF), and lead length at 35 days (LL35) also mapped to chromosome 5; LLF-a, LL35-a, NN-a map to the same region of chromosome 5 as DFF-a; LLF-b and LL35-bmap to the same region of chromosome 5 as DFF-b. Another QTL affecting leaf length at flowering (LLF-c) maps to chromosome 3. The proximity of DFF-a, LLF-a, LL35-a and NN-a, as well as the similarity in gene action among these QTLs (additivity), suggest that they may be pleiotropic consequences of a single gene at this locus. Similarly, LL35-b and LLF-b map near each other and both display recessive gene action, again suggesting the possibility of pleiotropy. DFF-b, which also maps near LL35-b and LLF-b, displays largely additive gene action (although recessive gene action could not be ruled out). This suggests that DFF-b may represent a different gene from LL35-b and/or LLF-b. DFF-a maps near two previously identified mutants: co (which also affects flowering time and displays gene action consistent with additivity) and flc.(ABSTRACT TRUNCATED AT 250 WORDS)

Arabidopsis↗

PubMed1986

Amplification of the amyE-tmrB region on the chromosome in tunicamycin-resistant cells of Bacillus subtilis.

In a class of tunicamycin-resistant mutants (tmrA7) of Bacillus subtilis, the production of extracellular alpha-amylase is increased by about five fold. The tmrA7 characteristics (tunicamycin resistance and hyperproduction of extracellular alpha-amylase) can be transferred to recipient cells by transformation. In the transformants and the original tmrA7 mutant, typical amplification of the region from 4 kb upstream of the amyE gene to the tmrB gene on the chromosome was detected. The repeating unit, 16 kb in size, repeats tandemly about five and ten times in the mutant and transformants, respectively, and the alpha-amylase production is proportional to the copy number of the amyE gene. Simultaneous amplification of the tmrB gene, which is responsible for tunicamycin resistance in the multicopy state, and the alpha-amylase structural gene (amyE) seems to be the cause of the pleiotropy of the tmrA7 mutation.

Bacillus subtilis↗