Context-dependent selection as the keystone in the somatic evolution of cancer.

Somatic evolution of cancer involves a series of mutations, and attendant changes, in one or more clones of cells. A "bad luck" type model assumes chance accumulation of mutations. The clonal expansion model assumes, on the other hand, that any mutation leading to partial loss of regulation of cell proliferation will give a selective advantage to the mutant. However, a number of experiments show that an intermediate pre-cancer mutant has only a conditional selective advantage. Given that tissue microenvironmental conditions differ across individuals, this selective advantage to a mutant could be widely distributed over the population. We evaluate three models, namely "bad luck", context-independent, and context-dependent selection, in a comparative framework, on their ability to predict patterns in total incidence, age-specific incidence, stem cell number-incidence relationship and other known phenomena associated with cancers. Results show that among the factors considered in the model, context dependence is necessary and sufficient to explain observed epidemiological patterns, and that cancer evolution is largely selection-limited, rather than mutation-limited. A wide range of physiological, genetic and behavioural factors influence the tissue micro-environment, and could therefore be the source of this context dependence in somatic evolution of cancer. The identification and targeting of these micro-environmental factors that influence the dynamics of selection offer new possibilities for cancer prevention.

Isolation and structure elucidation of halymeniaol, a new antimalarial sterol derivative from the red alga Halymenia floresii.

A new mono-hydroxy acetylated sterol derivative: 12ß-hydroxy-3ß, 15α, 16ß-triacetoxy-cholest-5-en-7-one (halymeniaol) (1), and cholesterol (2) were isolated from the marine red alga Halymenia floresii. The structure of the compound 1 (halymeniaol) was established from its spectral data, derived from HRMS/MS and 2D NMR. Compound 1 exhibited growth inhibitory activity against chloroquine-resistant Plasmodium falciparum 3D7 strain with an IC50 of 3.0 µM.

Protein aggregation in E. coli : short term and long term effects of nutrient density.

During exponential growth some cells of E. coli undergo senescence mediated by asymmetric segregation of damaged components, particularly protein aggregates. We showed previously that functional cell division asymmetry in E. coli was responsive to the nutritional environment. Short term exposure as well as long term selection in low calorie environments led to greater cell division symmetry and decreased frequency of senescent cells as compared to high calorie environments. We show here that long term selection in low nutrient environment decreased protein aggregation as revealed by fluorescence microscopy and proportion of insoluble proteins. Across selection lines protein aggregation was correlated significantly positively with the RNA content, presumably indicating metabolic rate. This suggests that the effects of caloric restriction on cell division symmetry and aging in E. coli may work via altered protein handling mechanisms. The demonstrable effects of long term selection on protein aggregation suggest that protein aggregation is an evolvable phenomenon rather than being a passive inevitable process. The aggregated proteins progressively disappeared on facing starvation indicating degradation and recycling demonstrating that protein aggregation is a reversible process in E. coli.

Evolution of aging and death: what insights bacteria can provide.

Several unresolved issues, paradoxes, and information voids characterize the field of evolution of aging. The recent discovery of aging-like phenomenon in Escherichia coli, marked by asymmetric segregation of damaged components, particularly protein aggregates, has created a number of new possibilities that remain underexplored. Bacterial systems can potentially throw light on issues such as: whether evolution of aging and evolution of death are different phenomena; whether aging is inevitable for life or is an evolved strategy; whether there could be selection for aging or aging is a pleiotropic effect of some other selection; what are the possible mechanisms of antagonistic pleiotropy, if any; and whether there are mechanisms of aging that are conserved throughout the hierarchy of life. Bacterial aging itself is underexplored and least understood as of now, but even scratching the surface appears to reveal things that may compel us to revise some of the classical concepts about evolution of aging. This warrants more focused and innovative inquiry into aging-like processes in bacteria.

Blackmailing: the keystone in the human mating system.

BACKGROUND: The human mating system is characterized by bi-parental care and faithful monogamy is highly valued in most cultures. Marriage has evolved as a social institution and punishment for extra pair mating (EPM) or adultery is common. However, similar to other species with bi-parental care, both males and females frequently indulge in EPM in secrecy since it confers certain gender specific genetic benefits. Stability of faithful monogamy is therefore a conundrum. We model human mating system using game theory framework to study the effects of factors that can stabilize or destabilize faithful committed monogamy. RESULTS: Although mate guarding can partly protect the genetic interests, we show that it does not ensure monogamy. Social policing enabled by gossiping is another line of defense against adultery unique to humans. However, social policing has a small but positive cost to an individual and therefore is prone to free riding. We suggest that since exposure of adultery can invite severe punishment, the policing individuals can blackmail opportunistically whenever the circumstances permit. If the maximum probabilistic benefit of blackmailing is greater than the cost of policing, policing becomes a non-altruistic act and stabilizes in the society. We show that this dynamics leads to the coexistence of different strategies in oscillations, with obligate monogamy maintained at a high level. Deletion of blackmailing benefit from the model leads to the complete disappearance of obligate monogamy. CONCLUSIONS: Obligate monogamy can be maintained in the population in spite of the advantages of EPM. Blackmailing, which makes policing a non-altruistic act, is crucial for the maintenance of faithful monogamy. Although biparental care, EPM, mate guarding and punishment are shared by many species, gossiping and blackmailing make the human mating system unique.

Phenotypic plasticity and effects of selection on cell division symmetry in Escherichia coli.

Aging has been demonstrated in unicellular organisms and is presumably due to asymmetric distribution of damaged proteins and other components during cell division. Whether the asymmetry-induced aging is inevitable or an adaptive and adaptable response is debated. Although asymmetric division leads to aging and death of some cells, it increases the effective growth rate of the population as shown by theoretical and empirical studies. Mathematical models predict on the other hand, that if the cells divide symmetrically, cellular aging may be delayed or absent, growth rate will be reduced but growth yield will increase at optimum repair rates. Therefore in nutritionally dilute (oligotrophic) environments, where growth yield may be more critical for survival, symmetric division may get selected. These predictions have not been empirically tested so far. We report here that Escherichia coli grown in oligotrophic environments had greater morphological and functional symmetry in cell division. Both phenotypic plasticity and genetic selection appeared to shape cell division time asymmetry but plasticity was lost on prolonged selection. Lineages selected on high nutrient concentration showed greater frequency of presumably old or dead cells. Further, there was a negative correlation between cell division time asymmetry and growth yield but there was no significant correlation between asymmetry and growth rate. The results suggest that cellular aging driven by asymmetric division may not be hardwired but shows substantial plasticity as well as evolvability in response to the nutritional environment.

Sociobiological control of plasmid copy number in bacteria.

All genes critical for plasmid replication regulation are located on the plasmid rather than on the host chromosome. It is possible therefore that there can be copy-up "cheater" mutants. In spite of this possibility, low copy number plasmids appear to exist stably in host populations. We examined this paradox using a multilevel selection model. Simulations showed that, a slightly higher copy number mutant could out-compete the wild type. Consequently, another mutant with still higher copy number could invade the first invader. However, the realized benefit of increasing intra-host fitness was saturating whereas that of inter-host fitness was exponential. As a result, above a threshold, intra-host selection was overcompensated by inter-host selection and the low copy number wild type plasmid could back invade a very high copy number plasmid. This led to a rock-paper-scissor (RPS) like situation that allowed the coexistence of plasmids with varied copy numbers. Furthermore, another type of cheater that had lost the genes required for conjugation but could hitchhike on a conjugal plasmid, could further reduce the advantage of copy-up mutants. These sociobiological interactions may compliment molecular mechanisms of replication regulation in stabilizing the copy numbers.

Metabolic syndrome: aggression control mechanisms gone out of control.

An upcoming hypothesis about the evolutionary origins of metabolic syndrome is that of a 'soldier' to 'diplomat' transition in behaviour and the accompanying metabolic adaptations. Theoretical as well as empirical studies have shown that similar to the soldier and diplomat dichotomy, physically aggressive and non-aggressive strategists coexist in animal societies with negative frequency dependent selection. Although dominant individuals have a higher reproductive success obtained through means such as greater access to females, subordinate individuals have alternative means such as sneak-mating for gaining a substantial reproductive success. The alternative behavioural strategies are associated with different neurophysiologic and metabolic states. Subordinate individuals typically have low testosterone, high plasma cholesterol and glucocorticoids and elevated serotonin signalling whereas dominant ones are characterized by high testosterone, low brain serotonin and lower plasma cholesterol. Food and sex are the main natural causes of aggression. However, since aggression increases the risk of injury, aggression control is equally crucial. Therefore chronic satiety in the form of fat should induce aggression control. It is not surprising that the satiety hormone serotonin has a major role in aggression control. Further chronically elevated serotonin signalling in the hypothalamus induces peripheral insulin resistance. Meta-analysis shows that most of the anti-aggression signal molecules are pro-obesity and pro-insulin-resistance. Physical aggression is known to increase secretion of epidermal growth factor (EGF) in anticipation of injuries and EGF is important in pancreatic beta cell regeneration too. In anticipation of injuries aggression related hormones also facilitate angiogenesis and angiogenesis dysfunction is the root cause of a number of co-morbidities of insulin resistance syndrome. Reduced injury proneness typical of 'diplomat' life style would also reorient the immune system resulting into delayed wound healing on the one hand and increased systemic inflammation on the other. Diabetes is negatively associated with physically aggressive behaviour. We hypothesize that suppression of physical aggression is the major behavioural cue for the development of metabolic syndrome. Preliminary trials of behavioural intervention indicate that games and exercises involving physical aggression reduce systemic inflammation and improve glycemic control.

The co-optimization of floral display and nectar reward.

In most insect-pollinated flowers, pollinators cannot detect the presence of nectar without entering the flower. Therefore, flowers may cheat by not producing nectar and may still get pollinated. Earlier studies supported this 'cheater flower' hypothesis and suggested that the cost saving by cheater flowers could be the most predominant selective force in the evolution of nectarless flowers. Previous models as well as empirical studies have addressed the problem of optimizing the proportion of nectarless and nectarful flowers. However, there has been no attempt to optimize the investment in nectar production along with that in floral display. One of the key questions that arises is whether the floral display will evolve to be an honest indicator of nectar reward. We use a mathematical model to cooptimize the investments in nectar and floral display in order to achieve maximum reproductive success. The model assumes that pollinators rely on a relative rather than an absolute judgement of reward. A conspicuous floral display attracts naive pollinators on the one hand and enhances pollinator learning on the other. We show that under these assumptions, plant-pollinator co-evolution leads to honest signalling, i.e. a positive correlation between display and reward.

Obesity as a perceived social signal.

Fat accumulation has been classically considered as a means of energy storage. Obese people are theorized as metabolically 'thrifty', saving energy during times of food abundance. However, recent research has highlighted many neuro-behavioral and social aspects of obesity, with a suggestion that obesity, abdominal obesity in particular, may have evolved as a social signal. We tested here whether body proportions, and abdominal obesity in particular, are perceived as signals revealing personality traits. Faceless drawings of three male body forms namely lean, muscular and feminine, each with and without abdominal obesity were shown in a randomized order to a group of 222 respondents. A list of 30 different adjectives or short descriptions of personality traits was given to each respondent and they were asked to allocate the most appropriate figure to each of them independently. The traits included those directly related to physique, those related to nature, attitude and moral character and also those related to social status. For 29 out of the 30 adjectives people consistently attributed specific body forms. Based on common choices, the 30 traits could be clustered into distinct 'personalities' which were strongly associated with particular body forms. A centrally obese figure was perceived as "lethargic, greedy, political, money-minded, selfish and rich". The results show that body proportions are perceived to reflect personality traits and this raises the possibility that in addition to energy storage, social selection may have played some role in shaping the biology of obesity.

Evolutionary origins of insulin resistance: a behavioral switch hypothesis.

BACKGROUND: Insulin resistance, which can lead to a number of diseases including type 2 diabetes and coronary heart disease, is believed to have evolved as an adaptation to periodic starvation. The "thrifty gene" and "thrifty phenotype" hypotheses constitute the dominant paradigm for over four decades. With an increasing understanding of the diverse effects of impairment of the insulin signaling pathway, the existing hypotheses are proving inadequate. PRESENTATION OF THE HYPOTHESIS: We propose a hypothesis that insulin resistance is a socio-ecological adaptation that mediates two phenotypic transitions, (i) a transition in reproductive strategy from "r" (large number of offspring with little investment in each) to "K" (smaller number of offspring with more investment in each) and (ii) a transition from "stronger to smarter" or "soldier to diplomat" i.e. from relatively more muscle dependent to brain dependent lifestyle. A common switch could have evolved for the two transitions since the appropriate environmental conditions for the two transitions are highly overlapping and interacting. TESTING THE HYPOTHESIS: Gestational insulin resistance diverts more energy through the placenta, resulting in increased investment per offspring. On the other hand, insulin resistance is associated with reduced ovulation. The insulin signaling pathway is also related to longevity. Insulin resistance diverts more nutrients to the brain as compared to muscle. Also, hyperinsulinemia has direct positive effects on cognitive functions of the brain. The hypothesis gets support from known patterns in human clinical data and recent research on the molecular interactions in the insulin signaling pathway. Further we state many predictions of the hypothesis that can be tested experimentally or epidemiologically. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis can bring about a significant change in the line of treatment as well as public health policies for the control of metabolic syndrome.

Sarcocystosis of chital-dhole: conditions for evolutionary stability of a predator parasite mutualism.

BACKGROUND: For parasites with a predator-prey life cycle, the completion of the life cycle often depends on consumption of parasitized prey by the predator. In the case of such parasite species the predator and the parasite have common interests and therefore a mutualistic relationship is possible. Some evidence of a predator-parasite mutualism was reported from spotted deer or chital (Axix axis) as a prey species, dhole or Indian wild-dog (Cuon alpinus) as the predator and a protozoan (Sarcocystis axicuonis) as the parasite. We examine here, with the help of a model, the ecological conditions necessary for the evolution and stability of such a mutualistic relationship. A two - level game theory model was designed in which the payoff of a parasite is decided not only by alternative parasite strategies but also by alternative host strategies and vice versa. Conditions for ESS were examined. RESULTS: A tolerant predator strategy and a low or moderately virulent parasite strategy which together constitute mutualism are stable only at a high frequency of recycling of parasite and a substantial prey - capture benefit to the predator. Unlike the preliminary expectation, parasite will not evolve towards reduced virulence, but reach an optimum moderate level of virulence. CONCLUSION: The available data on the behavioral ecology of dhole and chital suggest that they are likely to meet the stability criteria and therefore a predator-parasite mutualism can be stable in this system. The model also points out the gaps in the current data and could help directing further empirical work.

Nectarless flowers: ecological correlates and evolutionary stability.

In animal-pollinated flowers, the pollinators cannot detect the presence of nectar before entering flowers, and therefore flowers may cheat by not producing nectar. An earlier model suggested that a mixed strategy of producing nectarful and nectarless flowers would be evolutionarily stable. Here we compare nectarless flowers as a cheating strategy with three competing hypotheses namely "visit-more-flowers", "cross-pollination enhancement" and "better contact". We collected field data on 28 species of plants to test some of the differential predictions of the hypotheses. Nectarless flowers were detected in 24 out of 28 plant species. Correlations of percent nectarless flowers with floral and ecological variables support the cheater flower hypothesis. We further model the cost-benefits of cheating and show that an evolutionary stable ratio of nectarless to nectarful flowers can be reached. The equilibrium ratio is mainly decided by factors associated with pollinator density and pollinator learning.

Patterns in abundance and diversity of faecally dispersed parasites of tiger in Tadoba National Park, central India.

BACKGROUND: Importance of parasites in ecological and evolutionary interactions is being increasingly recognized. However, ecological data on parasites of important host species is still scanty. We analyze the patterns seen in the faecal parasites of tigers in the Tadoba National Park, India, and speculate on the factors and processes shaping the parasite community and the possible implications for tiger ecology. RESULTS: The prevalence and intensities were high and the parasite community was dominated by indirect life cycle parasites. Across all genera of parasites variance scaled with the square of the mean and there was a significant positive correlation between prevalence and abundance. There was no significant association between different types of parasites. CONCLUSIONS: The 70 samples analyzed formed 14 distinct clusters. If we assume each of the clusters to represent individual tigers that were sampled repeatedly and that resident tigers are more likely to be sampled repeatedly, the presumed transient tigers had significantly greater parasite loads than the presumed resident ones.