Gene expression regulates metabolite homeostasis during the Crabtree effect: Implications for the adaptation and evolution of Metabolism.

A key issue in both molecular and evolutionary biology has been to define the roles of genes and phenotypes in the adaptation of organisms to environmental changes. The dominant view has been that an organism's metabolic adaptations are driven by gene expression and that gene mutations, independent of the starting phenotype, are responsible for the evolution of new metabolic phenotypes. We propose an alternate hypothesis, in which the phenotype and genotype together determine metabolic adaptation both in the lifetime of the organism and in the evolutionary selection of adaptive metabolic traits. We tested this hypothesis by flux-balance and metabolic-control analysis of the relative roles of the starting phenotype and gene expression in regulating the metabolic adaptations during the Crabtree effect in yeast, when they are switched from a low- to high-glucose environment. Critical for successful short-term adaptation was the ability of the glycogen/trehalose shunt to balance the glycolytic pathway. The role of later gene expression of new isoforms of glycolytic enzymes, rather than flux control, was to provide additional homeostatic mechanisms allowing an increase in the amount and efficiency of adenosine triphosphate and product formation while maintaining glycolytic balance. We further showed that homeostatic mechanisms, by allowing increased phenotypic plasticity, could have played an important role in guiding the evolution of the Crabtree effect. Although our findings are specific to Crabtree yeast, they are likely to be broadly found because of the well-recognized similarities in glucose metabolism across kingdoms and phyla from yeast to humans.

Frontiers in Molecular Evolutionary Medicine.

This paper surveys some of the important insights that molecular evolution has contributed to evolutionary medicine; they include phage therapy, cancer biology, helminth manipulation of the host immune system, quality control of gametes, and pathogen outbreaks. Molecular evolution has helped to revolutionize our understanding of cancer, of autoimmune disease, and of the origin, spread, and pathogenesis of emerging diseases, where it has suggested new therapies, illuminated mechanisms, and revealed historical processes: all have practical therapeutic implications. While much has been accomplished, much remains to be done.

Association of Long-Term Risk of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils in Childhood.

Importance: Surgical removal of adenoids and tonsils to treat obstructed breathing or recurrent middle-ear infections remain common pediatric procedures; however, little is known about their long-term health consequences despite the fact that these lymphatic organs play important roles in the development and function of the immune system. Objective: To estimate long-term disease risks associated with adenoidectomy, tonsillectomy, and adenotonsillectomy in childhood. Design, Setting, and Participants: A population-based cohort study of up to 1 189 061 children born in Denmark between 1979 and 1999 and evaluated in linked national registers up to 2009, covering at least the first 10 and up to 30 years of their life, was carried out. Participants in the case and control groups were selected such that their health did not differ significantly prior to surgery. Exposures: Participants were classified as exposed if adenoids or tonsils were removed within the first 9 years of life. Main Outcomes and Measures: The incidence of disease (defined by International Classification of Diseases, Eighth Revision [ICD-8] and Tenth Revision [ICD-10] diagnoses) up to age 30 years was examined using stratified Cox proportional hazard regressions that adjusted for 18 covariates, including parental disease history, pregnancy complications, birth weight, Apgar score, sex, socioeconomic markers, and region of Denmark born. Results: A total of up to 1 189 061 children were included in this study (48% female); 17 460 underwent adenoidectomy, 11 830 tonsillectomy, and 31 377 adenotonsillectomy; 1 157 684 were in the control group. Adenoidectomy and tonsillectomy were associated with a 2- to 3-fold increase in diseases of the upper respiratory tract (relative risk [RR], 1.99; 95% CI, 1.51-2.63 and RR, 2.72; 95% CI, 1.54-4.80; respectively). Smaller increases in risks for infectious and allergic diseases were also found: adenotonsillectomy was associated with a 17% increased risk of infectious diseases (RR, 1.17; 95% CI, 1.10-1.25) corresponding to an absolute risk increase of 2.14% because these diseases are relatively common (12%) in the population. In contrast, the long-term risks for conditions that these surgeries aim to treat often did not differ significantly and were sometimes lower or higher. Conclusions and Relevance: In this study of almost 1.2 million children, of whom 17 460 had adenoidectomy, 11 830 tonsillectomy, and 31 377 adenotonsillectomy, surgeries were associated with increased long-term risks of respiratory, infectious, and allergic diseases. Although rigorous controls for confounding were used where such data were available, it is possible these effects could not be fully accounted for. Our results suggest it is important to consider long-term risks when making decisions to perform tonsillectomy or adenoidectomy.

Evolutionary public health: introducing the concept.

The emerging discipline of evolutionary medicine is breaking new ground in understanding why people become ill. However, the value of evolutionary analyses of human physiology and behaviour is only beginning to be recognised in the field of public health. Core principles come from life history theory, which analyses the allocation of finite amounts of energy between four competing functions-maintenance, growth, reproduction, and defence. A central tenet of evolutionary theory is that organisms are selected to allocate energy and time to maximise reproductive success, rather than health or longevity. Ecological interactions that influence mortality risk, nutrient availability, and pathogen burden shape energy allocation strategies throughout the life course, thereby affecting diverse health outcomes. Public health interventions could improve their own effectiveness by incorporating an evolutionary perspective. In particular, evolutionary approaches offer new opportunities to address the complex challenges of global health, in which populations are differentially exposed to the metabolic consequences of poverty, high fertility, infectious diseases, and rapid changes in nutrition and lifestyle. The effect of specific interventions is predicted to depend on broader factors shaping life expectancy. Among the important tools in this approach are mathematical models, which can explore probable benefits and limitations of interventions in silico, before their implementation in human populations.

Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy.

Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the rest of the human genome, with evidence that the relationship between CAD and lifetime reproductive success is antagonistic. This supports the presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel explanation for the maintenance and high prevalence of CAD in modern humans. Lastly, we found that positive selection more often targeted CAD gene regulatory variants using HapMap3 lymphoblastoid cell lines, which further highlights the unique biological significance of candidate adaptive loci underlying CAD. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD.

How elephants beat cancer.

Elephants have significantly reduced their risk of cancer by duplicating an important gene called TP53.

The importance of the timescale of the fitness metric for estimates of selection on phenotypic traits during a period of demographic change.

Although fitness is central to the evolutionary process, metrics vary by timescale. Different timescales may give rise to different estimates of selection, especially during demographic transitions caused by rapid environmental and socioeconomic change. In this study, we used a dataset of a human population in Finland from 1775 to 1950 to compare two fitness metrics and their estimates of selection pressures, before and during a demographic transition. Both metrics, lifetime reproductive success and an annual metric of individual performance, declined while selection on the ages at first and last reproduction remained nearly constant, favouring individuals with wider reproductive windows. The ability to partition the annual metric into contributions from reproduction and survival revealed the short-term effects of a famine and the reversal of selection pressure via the survival component of annual fitness. Although the metrics generally agreed, the annual metric detected the effects of environmental variation and demographic change occurring within a generation.

Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.

Opposite phenotypic and behavioural traits associated with copy number variation and disruptions to imprinted genes with parent-of-origin effects have led to the hypothesis that autism and schizophrenia share molecular risk factors and pathogenic mechanisms, but a direct phenotypic comparison of how their risks covary has not been attempted. Here, we use health registry data collected on Denmark's roughly 5 million residents between 1978 and 2009 to detect opposing risks of autism and schizophrenia depending on normal variation (mean ± 1 s.d.) in adjusted birth size, which we use as a proxy for diametric gene-dosage variation in utero. Above-average-sized babies (weight, 3691-4090 g; length, 52.8-54.3 cm) had significantly higher risk for autism spectrum (AS) and significantly lower risk for schizophrenia spectrum (SS) disorders. By contrast, below-average-sized babies (2891-3290 g; 49.7-51.2 cm) had significantly lower risk for AS and significantly higher risk for SS disorders. This is the first study directly comparing autism and schizophrenia risks in the same population, and provides the first large-scale empirical support for the hypothesis that diametric gene-dosage effects contribute to these disorders. Only the kinship theory of genomic imprinting predicts the opposing risk patterns that we discovered, suggesting that molecular research on mental disease risk would benefit from considering evolutionary theory.

The demographic transition influences variance in fitness and selection on height and BMI in rural Gambia.

Recent human history is marked by demographic transitions characterized by declines in mortality and fertility. By influencing the variance in those fitness components, demographic transitions can affect selection on other traits. Parallel to changes in selection triggered by demography per se, relationships between fitness and anthropometric traits are also expected to change due to modification of the environment. Here we explore for the first time these two main evolutionary consequences of demographic transitions using a unique data set containing survival, fertility, and anthropometric data for thousands of women in rural Gambia from 1956-2010. We show how the demographic transition influenced directional selection on height and body mass index (BMI). We observed a change in selection for both traits mediated by variation in fertility: selection initially favored short females with high BMI values but shifted across the demographic transition to favor tall females with low BMI values. We demonstrate that these differences resulted both from changes in fitness variance that shape the strength of selection and from shifts in selective pressures triggered by environmental changes. These results suggest that demographic and environmental trends encountered by current human populations worldwide are likely to modify, but not stop, natural selection in humans.

Genetic links between post-reproductive lifespan and family size in Framingham.

BACKGROUND AND OBJECTIVES: Is there a trade-off between children ever born (CEB) and post-reproductive lifespan in humans? Here, we report a comprehensive analysis of reproductive trade-offs in the Framingham Heart Study (FHS) dataset using phenotypic and genotypic correlations and a genome-wide association study (GWAS) to look for single-nucleotide polymorphisms (SNPs) that are related to the association between CEB and lifespan. METHODOLOGY: We calculated the phenotypic and genetic correlations of lifespan with CEB for men and women in the Framingham dataset, and then performed a GWAS to search for SNPs that might affect the relationship between post-reproductive lifespan and CEB. RESULTS: We found significant negative phenotypic correlations between CEB and lifespan in both women (rP = -0.133, P < 0.001) and men (rP = -0. 079, P = 0.036). The genetic correlation was large, highly significant and strongly negative in women (rG = -0.877, P = 0.009) in a model without covariates, but not in men (P = 0.777). The GWAS identified five SNPs associated with the relationship between CEB and post-reproductive lifespan in women; some are near genes that have been linked to cancer. None were identified in men. CONCLUSIONS AND IMPLICATIONS: We identified several SNPs for which the relationship between CEB and post-reproductive lifespan differs by genotype in women in the FHS who were born between 1889 and 1958. That result was not robust to changes in the sample. Further studies on larger samples are needed to validate the antagonistic pleiotropy of these genes.

Constraints on the coevolution of contemporary human males and females.

Because autosomal genes in sexually reproducing organisms spend on average half their time in each sex, and because the traits that they influence encounter different selection pressures in males and females, the evolutionary responses of one sex are constrained by processes occurring in the other sex. Although intralocus sexual conflict can restrict sexes from reaching their phenotypic optima, no direct evidence currently supports its operation in humans. Here, we show that the pattern of multivariate selection acting on human height, weight, blood pressure and glucose, total cholesterol, and age at first birth differs significantly between males and females, and that the angles between male and female linear (77.8 ± 20.5°) and nonlinear (99.1 ± 25.9°) selection gradients were closer to orthogonal than zero, confirming the presence of sexually antagonistic selection. We also found evidence for intralocus sexual conflict demonstrated by significant changes in the predicted male and female responses to selection of individual traits when cross-sex genetic covariances were included and a significant reduction in the angle between male- and female-predicted responses when cross-sex covariances were included (16.9 ± 15.7°), compared with when they were excluded (87.9 ± 31.6°). We conclude that intralocus sexual conflict constrains the joint evolutionary responses of the two sexes in a contemporary human population.

Evolutionary medicine: its scope, interest and potential.

This review is aimed at readers seeking an introductory overview, teaching courses and interested in visionary ideas. It first describes the range of topics covered by evolutionary medicine, which include human genetic variation, mismatches to modernity, reproductive medicine, degenerative disease, host-pathogen interactions and insights from comparisons with other species. It then discusses priorities for translational research, basic research and health management. Its conclusions are that evolutionary thinking should not displace other approaches to medical science, such as molecular medicine and cell and developmental biology, but that evolutionary insights can combine with and complement established approaches to reduce suffering and save lives. Because we are on the cusp of so much new research and innovative insights, it is hard to estimate how much impact evolutionary thinking will have on medicine, but it is already clear that its potential is enormous.

Evolution and medicine in undergraduate education: a prescription for all biology students.

The interface between evolutionary biology and the biomedical sciences promises to advance understanding of the origins of genetic and infectious diseases in humans, potentially leading to improved medical diagnostics, therapies, and public health practices. The biomedical sciences also provide unparalleled examples for evolutionary biologists to explore. However, gaps persist between evolution and medicine, for historical reasons and because they are often perceived as having disparate goals. Evolutionary biologists have a role in building a bridge between the disciplines by presenting evolutionary biology in the context of human health and medical practice to undergraduates, including premedical and preprofessional students. We suggest that students will find medical examples of evolution engaging. By making the connections between evolution and medicine clear at the undergraduate level, the stage is set for future health providers and biomedical scientists to work productively in this synthetic area. Here, we frame key evolutionary concepts in terms of human health, so that biomedical examples may be more easily incorporated into evolution courses or more specialized courses on evolutionary medicine. Our goal is to aid in building the scientific foundation in evolutionary biology for all students, and to encourage evolutionary biologists to join in the integration of evolution and medicine.

Measuring selection in contemporary human populations.

Are humans currently evolving? This question can be answered using data on lifetime reproductive success, multiple traits and genetic variation and covariation in those traits. Such data are available in existing long-term, multigeneration studies - both clinical and epidemiological - but they have not yet been widely used to address contemporary human evolution. Here we review methods to predict evolutionary change and attempts to measure selection and inheritance in humans. We also assemble examples of long-term studies in which additional measurements of evolution could be made. The evidence strongly suggests that we are evolving and that our nature is dynamic, not static.