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PubMed1993

The costs of reproduction and dietary restriction: parallels between insects and mammals.

Dietary restriction increases life span in mammals. This essay connects the dietary restriction response to evolutionary life history theory and experiments related to it. Evolutionary biologists have shown mathematically that aging is an inevitable consequence of age-specific natural selection acting on species with somata separate from germ lines. Empirical tests of this prediction currently point to its general validity. Two specific genetic mechanisms are known which could underlie the evolution of aging under these conditions: age-specificity of gene effects and antagonistic pleiotropy between early and late ages. The antagonistic pleiotropy theory assumes that some genes with beneficial effects on early life fitness will have deleterious effects upon fitness in later life. Experimental work in insects, particularly selection experiments in Drosophila melanogaster, has tested these ideas. The negative genetic correlation between longevity and reproductive effort produced by selection has been shown to be paralleled, in some cases, by environmental manipulation. Thus the increase in life span caused by dietary restriction might be explained as an incidental consequence of lower reproductive effort. This response also could have been an adaptation that enhanced fitness in some species that faced uncertain food supplies, a condition that may have evolved independently in a wide variety of taxa. Several schools of research, besides that of the evolutionary biologists concerned with genetic correlations, have produced corroborations of this hypothesis in insects and mammals: the gerontological work on life span extension, reproductive physiologists concerned with factors that affect fertility, and various life history studies.

Aging↗
PubMed1996

[Cytokine redundancy--unity in diversity].

Various cytokines can induce similar biological effects in one type of cells (shared biological activity-redundancy). However, particular cytokine can also act on different tissues and cell types (multiple biological activity-pleiotropy). The functional redundancy and pleiotropy might be explained by binding of related cytokines to a common subunit of the receptor that have unique signalling capacity. Specificity of signal transduction is presumably controlled by the intracytoplasmic structure of the subunit chain, the level of activity of cytoplasmic signal molecules as well as combinations of the receptor subunits on the different type of cells.

Animals↗
PubMed1998

Calcium homeostasis and human evolution.

The maintenance of calcium homeostasis is critical to survival. The systems dependent upon the availability of calcium include the musculoskeletal, nervous, and immune systems, all of which utilize the ionic properties of divalent calcium to perform critical functions. The widespread utilization of calcium in essential biological processes across a wide range of phyla argues strongly for its adoption early in the evolution of life. In the broad context of evolution, the use of calcium in the structure of the skeleton is a relatively late, or derived trait. It is not surprising, therefore, that when conditions demand the resorption of bone to sustain normal blood calcium levels, resorption can lead to serious impairment of function. Nowhere is the force of natural selection greater than when traits essential to successful reproduction are directly involved. Thus, when the requirements of pregnancy and lactation demand it, major shifts in the endocrine regulation of calcium turnover occur. While beneficial to reproductive success, elements of these changes can have deleterious effects later in life. However, selective pressure on such traits diminishes with the years of remaining reproductive life. The genetic determinants of traits that only manifest their deleterious aspects after reproduction has ceased altogether are thus able to remain and even increase in frequency in the population's gene pool. Such traits have been designated antagonistic pleiotropies. The following discussion explores the possibilities of Type I osteoporosis, a condition experienced by many postmenopausal women being an example of antagonistic pleiotropy.

Aged↗
PubMed2026

Loss, persistence and reversal of phenotypic traits.

The irreversibility of complex trait loss has long been a tenet of evolutionary biology. However, this idea is increasingly at odds with the numerous documented exceptions across the Tree of Life. We synthesise this growing body of evidence across a diverse array of taxa and traits, exploring the evolutionary conditions that enable evolutionary reversal. By integrating macroevolutionary, genetic, and developmental information, we argue that trait reversal is commonly fostered by some form of persistence in the generative developmental pathway of the lost trait. We identify three overarching modes of trait reversal and support them with multiple case studies: by pleiotropy (the involvement of the same generative components in other traits and/or functions), by plasticity (environment-dependent expression of the trait) and by hemiplasy (persistence in another lineage, followed by reticulate evolution). We also examine important affinities between trait reversal and evolutionary novelties, undermining a neat distinction between what is old and what is new in evolution. This survey may provide a useful framework for future explorations of the developmental mechanisms underlying these still overlooked macroevolutionary dynamics.

Phenotype↗
PubMed2026

The Spatiotemporal Genetic Architecture of Seed Vigor in Upland Cotton.

Seed vigor underpins uniform crop establishment, but its dynamic genetics are understudied. Combining high-resolution temporal phenotyping and genomics in upland cotton, we used the SeedRanger platform to record 17 image-based traits every 30 min over 120 h, revealing stage-specific heritability and identifying 541 seed-vigor loci. These loci show extensive pleiotropy and temporal coordination, forming a genetic network that preserves developmental continuity; 8.9% overlap regions under domestication selection, indicating concurrent optimization with fiber yield. Functional validation of FLA2, a candidate gene underlying a dynamic QTL, implicates auxin-mediated control of radicle elongation and cotyledon development. This temporal framework exposes dynamic genetic architecture and breeding targets for high-vigor crops.

Gossypium↗
PubMed2026

Genetic interconnections between personality-related phenotypes and psychiatric disorders.

BACKGROUND: Personality-related phenotypes are genetically correlated with psychiatric disorders, but whether these relationships reflect shared genetic loci and differ across individual phenotypes remains unclear. We investigated their shared genetic architecture at the level of specific phenotype-disorder pairs. METHODS: We analyzed genome-wide association study summary statistics for 13 personality-related phenotypes and eight psychiatric disorders in populations of European ancestry. Genetic correlations were evaluated separately for 104 phenotype-disorder pairs using linkage disequilibrium score regression and high-definition likelihood. For pairs supported by both methods, MTAG and CPASSOC were applied separately to identify pleiotropic signals, followed by linkage disequilibrium clumping, Bayesian colocalization, gene prioritization, functional enrichment and bidirectional two-sample Mendelian randomization analyses. No composite personality or psychiatric-disorder phenotype was constructed. RESULTS: Among the 104 evaluated pairs, 77 showed significant positive genetic correlations in both analyses. Joint screening of MTAG and CPASSOC results identified pleiotropic signals in 61 pairs, comprising 1088 independent lead SNV-pair associations and 776 unique SNVs. Bayesian colocalization supported 351 signals across 42 pairs and 284 unique lead SNVs. MAGMA identified 1293 unique genes, of which 379 were prioritized by PoPS and 151 were further supported by SMR. These genes were enriched in brain tissues and biological processes involving nervous system development, synaptic organization and intercellular connectivity. Inverse-variance weighted Mendelian randomization identified 41 forward and 32 reverse associations after false-discovery-rate correction, including 21 pairs with bidirectional evidence. CONCLUSION: These item-resolved analyses identify widespread but heterogeneous genetic sharing between personality-related phenotypes and psychiatric disorders. The findings provide a pair-specific map of shared loci and prioritized genes, while the Mendelian randomization results should be interpreted cautiously because of residual heterogeneity and potential horizontal pleiotropy. Further validation in diverse populations and functional studies is required.

Colocalization↗
PubMed2025

The role of the brain-bone axis in skeletal degenerative diseases and psychiatric disorders, A genome-wide pleiotropic analysis.

INTRODUCTION: Skeletal degenerative diseases and psychiatric disorders often coexist clinically. However, the genetic correlations and underlying biological mechanisms between these two types of diseases remain unclear. OBJECTIVES: To investigate the genetic correlations between skeletal degenerative diseases and psychiatric disorders and to identify shared genomic loci, genes, and pathways. METHODS: This comprehensive genome-wide pleiotropic association study utilized summary statistics from publicly available genome-wide association data. Various statistical genetic correlation methods were employed, including LDSC, HDL, PLACO, Coloc, Hyprcoloc, and Mendelian randomization (MR) analysis, along with immune cell colocalization analysis. The study aimed to identify potential shared genetic factors among three skeletal degenerative diseases (osteoarthritis, intervertebral disc degeneration, and osteoporosis) and three psychiatric disorders (schizophrenia, anxiety disorder, and major depressive disorder). RESULTS: Analyses using LDSC, HDL, and Bonferroni corrections revealed significant genetic correlations between intervertebral disc degeneration (IVDD) and anxiety disorder (ANX); fractures, IVDD, and arthritis with major depressive disorder (MDD); and arthritis with schizophrenia (SCZ). Significant genetic correlations were also observed between VDD and ANX, fractures, IVDD, hip osteoarthritis (HipOA), knee osteoarthritis (KneeOA) and MDD, and KneeOA and SCZ. Pleiotropy analysis using PLACO, MAGMA, and multitrait colocalization Hyprcoloc identified 65 pleiotropic loci, 27 shared causal loci, and 9 shared risk loci involving immune cells related to both psychiatric and bone-related diseases. Additionally, tissue-specific enrichment analysis showed that genes mapped to these loci were enriched in brain, cardiovascular, pancreatic, and other tissues. The IVW method demonstrated that MDD increased the risk of IVDD and KneeOA, while IVDD increased the risk of ANX and MDD. Conversely, SCZ was associated with a reduced risk of KneeOA. Multiple sensitivity analyses further supported a positive causal effect of IVDD on MDD. CONCLUSION: These findings suggest significant genetic correlations between skeletal degenerative diseases and psychiatric disorders, highlighting multiple shared comorbid genes and key immune cell types. Importantly, the study supports the role of the brain-bone axis in the regulation of skeletal degenerative diseases and psychiatric disorders, which could provide valuable insights for potential therapeutic targets and interventions for these conditions.

Humans↗
PubMed2025

Saturating the eQTL map in Drosophila: Genome-wide patterns of cis and trans regulation of transcriptional variation in outbred populations.

Most genetic polymorphisms associated with complex traits are found in non-coding regions of the genome. Characterizing their effect presents a formidable challenge, and expression quantitative trait locus (eQTLs) mapping has been a key approach to do so. As comprehensive eQTL maps are available only for a few species, here we developed the Drosophila outbred synthetic population (Dros-OSP) and used it to characterize the landscape of transcriptional regulation in Drosophila melanogaster. We collected head and body transcriptomes and genomes from 1,286 outbred flies and mapped local and distant eQTLs for 98% of the genes. We characterized the network organization of the transcriptome across tissues and described the properties of local and distal eQTLs in terms of genetic diversity, heritability, connectivity, and pleiotropy. These results provide new insights into the genetic basis of transcriptional regulation in the fruit fly and offer a new mapping resource that will expand the possibilities currently available for the Drosophila community.

Animals↗
PubMed2026

Dissecting the shared genetic architecture between migraine subtypes and cardiovascular diseases: a multi-layered genomic analysis.

BACKGROUND: Epidemiological studies have linked migraine to an increased risk of cardiovascular disease (CVD); however, the shared genetic basis and putative causal relationships between migraine subtypes and cardiovascular traits remain poorly understood. METHODS: Leveraging large-scale GWAS summary statistics for migraine phenotypes (overall migraine, migraine with aura [MA], and migraine without aura [MO]) from FinnGen R12, along with seven cardiovascular diseases from publicly available consortia, we conducted a multi-layered genetic analysis. This integrative framework encompassed genetic correlation [linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL)], cross-trait meta-analysis (CPASSOC and PLACO), Bayesian colocalization, summary-data-based Mendelian randomization (SMR) using GTEx v8 eQTL data, and bidirectional two-sample Mendelian randomization (MR). RESULTS: Significant genetic correlations were identified between migraine and multiple cardiovascular traits, with hypertension and coronary artery disease (CAD) showing the most robust associations. MA exhibited broader genetic overlap with cardiovascular diseases than MO, including a notably stronger correlation with ischemic stroke, whereas MO demonstrated a stronger correlation with hypertension. Cross-trait meta-analysis identified 160 pleiotropic loci across 17 of 21 trait pairs. Colocalization analysis confirmed 32 loci harboring shared causal variants, mapped to 13 candidate genes, of which 7 (PHACTR1, LRP1, SOX7, ABO, FHOD3, MEI1, XKR6) were further validated by SMR as exhibiting tissue-specific regulatory effects. Among these, PHACTR1 displayed the broadest pleiotropic profile across migraine phenotypes and vascular diseases. After MR-PRESSO outlier removal, bidirectional MR identified 10 MR-supported associations, two of which (genetic liability to hypertension on overall migraine, and CAD on MA) survived Bonferroni correction, all free of detectable horizontal pleiotropy. Genetic liability to hypertension was associated with increased migraine risk (OR = 1.90, 95% CI 1.25-2.90, P = 2.64 × 10⁻³), atherosclerotic diseases showed subtype-specific effects (inverse for MO, positive for MA), and, in the reverse direction, migraine was associated with increased ischemic stroke risk. CONCLUSIONS: This study provides a comprehensive and systematic characterization of the shared genetic architecture between migraine subtypes and cardiovascular diseases. By identifying pleiotropic genes and bidirectional putative causal relationships with subtype-specific patterns, our findings carry implications for the development of targeted therapeutics and subtype-specific cardiovascular risk stratification.

Humans↗
PubMed1997

Arrhythmogenic right ventricular dysplasia and anterior polar cataract.

Arrythmogenic right ventricular dysplasia (ARVD) is an autosomal dominant inherited cardiomyopathy with incomplete penetrance and variable expressivity. Recently, the gene was mapped to 14q23-24. It is being increasingly investigated as a major cause of sudden death at a young age. Anterior polar cataract (APC) is a rare hereditary form of lens opacity. The locus for an APC gene was located tentatively on 14q24qter. We describe a patient with a severe form of ARVD in whom asymptomatic APC was detected by an ophthalmologic examination. His sister had ARVD and similar cataracts. Parents were second cousins but were healthy. This is the first report of possible autosomal recessive inheritance of ARVD. This is also the first time that the combination of ARVD and APC is reported. Three possibilities may explain this concurrence: pleiotropy, contiguous gene syndrome, or coincidence. Our findings suggest placement of an APC gene at 14q23-24.

Adult↗
PubMed1998

Linkage and association.

Methods of both linkage analysis and association analysis may be model-based or model-free. The former are useful for initial exploratory analysis, the latter for more detailed multivariate genometric analysis. Linkage leads to an association, but that association may be solely intrafamilial. Allelic association may be due to pleiotropy, linkage disequilibrium, meiotic drive, selection, or population stratification. Using non-transmitted parental alleles as controls for alleles transmitted to cases, in conjunction with a McNemar-type test, does not detect association in the absence of linkage. Model-based analyses should use models that approximate the complexity of the disease being studied in order to be both robust and powerful.

Case-Control Studies↗
PubMed1999

Genetics of abdominal visceral fat levels.

The purpose of this review is to explore the evidence accumulated thus far that suggests a genetic component to the observed variation in abdominal visceral fat (AVF) levels. The precise determination of AVF levels in humans is limited to methods such as computerized tomography and magnetic resonance imaging; thus, few studies have examined the role of genetic factors on this phenotype. Evidence from the Québec Family Study (QFS) and the HERITAGE Family Study indicates that between 50-55% of the variance in AVF levels, adjusted for total fatness, is attributable to genetic factors. Additionally, a major gene hypothesis for AVF was supported in the both the QFS and HERITAGE Family Study. However, after adjustment for total fat mass the support for a major gene was reduced, suggesting that a major gene which affects fat mass may also affect AVF either directly (pleiotropy), or indirectly. The search for candidate genes that may impact AVF levels is in its infancy, and few candidate genes have been identified. However, the glucocorticoid receptor (GRL), ss3 adrenergic receptor (ADRB3), and fatty acid binding protein 2 (FABP2) genes have been significantly associated with AVF or intra-abdominal fat levels in humans. In addition, three quantitative trait loci obtained from crosses of mice, the Do2, Mob4, and Qbw1 loci have been linked with mesenteric or abdominal fat and are thus considered positional candidate genes for AVF levels. The search for candidate genes or random genetic markers associated with AVF levels is a challenging prospect. However, given the significant heritability of this phenotype, the quest remains promising. Am. J. Hum. Biol. 11:225-235, 1999. Copyright 1999 Wiley-Liss, Inc.

Journal Article↗
PubMed2000

How can psychological adaptations be heritable?

By Fisher's fundamental theorem, selection depletes additive genetic variation. However, moderate heritabilities are invariably obtained for psychological traits, even those that have been under intense selection. Examples include sociosexuality (interest in emotionally uncommitted sex), schizophrenia and sexual orientation, which have all been subject to strong sexual selection. A number of factors can help maintain (or at least slow depletion of) genetic variation. These include antagonistic pleiotropy; geographic or temporal variability in optimal phenotypes (and hence genotypes); mutational pressure (especially in the context of parasite resistance dynamics); and existence of heritable strategic variation or morphs. I discuss the likelihood that these factors maintain heritable variation for intelligence. I then review some evolutionary hypotheses regarding variation in some specific psychological traits.

Adaptation, Psychological↗
PubMed1992

Distribution and binding properties of receptors for leukaemia inhibitory factor.

The pleiotropic biological actions of leukaemia inhibitory factor (LIF) on haemopoietic cells (macrophages and megakaryocytes), hepatocytes, osteoblasts, pre-adipocytes, embryonic stem cells, myoblasts and neuronal cells must be mediated through the interactions of LIF with specific cellular receptors. The demonstration by equilibrium binding analysis and autoradiography of LIF receptors on all of the above cells and cell lines suggests that each of these pleiotropic effects of LIF is mediated by direct interactions with the responding cells rather than by the indirect release of secondary cytokines. Despite the differing biological effects of LIF on these cells, equilibrium binding, kinetic analyses and receptor internalization studies have all suggested that these cells display essentially identical high affinity LIF receptors. Nevertheless, there is evidence on some cell types (granulocyte-macrophage colony-stimulating factor [GM-CSF] transgenic peritoneal cells and F9 embryonal carcinoma cells) for a second class of low affinity LIF receptors (Kd = 1.5 nM versus Kd = 30 pM for high affinity receptors) which, LIF receptors (Kd = 1.5 nM versus Kd = 30 pM for high affinity receptors) which differ from the high affinity receptors only in kinetic dissociation rate. Moreover, the evidence suggests that low and high affinity receptors are structurally related and interconvertible, because detergent solubilization of LIF receptors from any cell type results in the quantitative conversion of high affinity receptors into low affinity receptors. As is the case for other related cytokine receptors, these data suggest that high affinity LIF receptors may be composed of two protein subunits--one responsible for LIF-specific low affinity binding and the other responsible for affinity conversion and cell signalling by the receptor. Such a model provides a possible explanation for the pleiotropy of LIF's biological actions.

Animals↗
PubMed1997

Human ageing and telomeres.

Telomerase expression is repressed early in development in all normal somatic human tissues investigated to date, whereas activity and the expression of the RNA component for this enzyme are upregulated in almost all cases of malignant transformation and late-stage cancer. The telomere hypothesis of ageing and immortalization postulates that sufficient telomere loss on one or more chromosomes in normal somatic cells triggers cell senescence, whereas reactivation of the enzyme is necessary for cell immortalization. Measurements of telomere length and telomerase activity in cancer and during normal and accelerated human ageing in skin, blood, haemopoietic, skeletal muscle, vascular and CNS tissues support this model. Tissue culture studies of cell ageing and transformation have added to our understanding of telomere dynamics in these processes. Evolution of telomerase repression and mortality in somatic cells of long-lived organisms is consistent with antagonistic pleiotropy models in which cell senescence is a tumour suppressor mechanism: stringent repression of telomerase has a beneficial early effect in reducing the probability of cancer, but a deleterious, unselected late effect in its contributions to age-related disease.

Aging↗
PubMed1999

On the homology of structures and Hox genes: the vertebral column.

Research on expression patterns of Hox genes has revealed a surprisingly high conservation among vertebrates. In agreement with this conservation, a correlation has been found between the anterior limits of expression areas of certain Hox genes and the borders between morphological regions of the vertebral axis. These similarities are striking and important, but also counterintuitive, unless there are strong selection pressures to protect this conservatism. It is important to identify the selective forces that maintain these conservative networks. These selective forces can be due to pleiotropy or to internal selection. Discussed are the selective factors that are involved in the evolutionary constraint on the number of cervical vertebral numbers in mammals. Factors involved are due to internal selection and involve susceptibility to cancer, stillbirths and neuronal problems. It is intriguing how similar genetic networks can lead to fundamentally different animals. Clearly the same genes are used for different purposes. It is therefore important to try to find these differences. The search, for homology between organisms, and the enthusiasm about similarities that come with it, at times impedes the discovery of such differences. I have searched the literature for differences within vertebrates in the functioning and expression patterns of Hox genes during the development of the vertebral axis. The ensuing implications for homology of structures and genes are discussed. The vertebral column is a promising model system for the evaluation of the relationship between homologous Hox genes and homologous structures because of the large conservation of Hox gene expression patterns along the anterior axis. However, extensive remodelling of the vertebrate column indicates that important changes in the genetic basis must have taken place. A survey of the literature indicates that the correlation between Hox gene expression areas and vertebral regions is not such that one can predict the borders between vertebral regions on the basis of Hox gene expression patterns. The involvement of Hox genes in the development of identity of vertebrae is complex and the problems regarding the value of gene expression patterns for the determination of anatomical homology are discussed.

Animals↗
PubMedDate not supplied

A reassessment of sexual dimorphism in human senescence: theory, evidence, and causation.

Age-specific mortality rates of men are higher than those of women, and men have shorter average life spans than women. This has been interpreted as evidence of sexual dimorphism in rates of senescence. However, because mortality can be caused by numerous factors in addition to senescence, higher mortality rates do not necessarily indicate more rapid senescence. In this paper, we (1) emphasize the necessity of decoupling mortality and senescence when considering sexual dimorphism in senescence, (2) present a theoretical framework for the hypothesis that selection affects senescence in human males and females differently due to different life history characteristics, (3) consider phenotypic evidence from the literature that human males show a later onset of senescence than human females, despite exhibiting higher mortality rates, and (4) discuss the potential roles of mutation accumulation and antagonistic pleiotropy in the evolution of sexual dimorphism in senescence.

Aging↗
PubMed1985

Facioscapulohumeral dystrophy with cochlear hearing loss and tortuosity of retinal vessels.

We report on a mother and her three children with facioscapulohumeral dystrophy (FSHD), sensorineural hearing loss, and marked tortuosity of the retinal vessels. Initially the children presented with speech difficulties and hearing deficit. Hearing loss ranged from mild to severe. An audiologic evaluation, including brain stem auditory evoked responses in all patients, indicated a cochlear origin of hearing loss and intact pathways from the cochlea to the temporal lobe. The association of FSHD with hearing loss and tortuosity of the retinal vessels suggests previously unrecognized pleiotropy of FSHD (McKusick 15890) or a "new" type of FSHD.

Adolescent↗