Significant Selection Gradients Research Articles

Abstract B002: Modeling evolutionary therapy for GI malignancies

Abstract Despite development of personalized treatments GI cancer like pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain dismal outcomes. While some patients are potentially curable with surgery and chemotherapy, most unresectable cases are invariably lethal. To advance patient care, we rely on clinical trials to test new therapeutic approaches. Here, we assume that the highest dose of a drug that does not cause severe toxicities is optimal for cancer treatment. However, this treatment strategy, in many cases, may be more harmful for the patient. Adopting principles from the field of evolutionary biology and pest management could offer more effective strategies that can be used for patients with metastatic PDAC and CRC. Resistance mechanisms are assumed to come with an energy cost, making the organism/cell less fit than others in the population. When high doses of treatment are applied, it results in a significant selection gradient by eliminating sensitive populations, freeing resources and facilitating resistant population growth. Such evolutionary dynamics and interactions within the tumor microenvironment can be modeled and exploited, in the form of adaptive strategies, for treatment of CRC and PDAC. It is our central hypothesis that integration of evolutionary dynamics and into PDAC and CRC treatment will delay emergence of resistance, enhance quality of life, and improve clinical outcomes. Our preliminary observations in co-cultured drug sensitive and resistant cell containing spheroids show that a higher proportion of drug sensitive cells inhibits the proliferation of drug resistant cells over time, in the presence of chemotherapeutic agents 5-FU and Oxaliplatin. We also demonstrate a role for the MLL family of histone methyltransferases in the epigenetic regulation of genes involved in chemoresistance. RNA-seq data has shown differential gene expression in metabolic genes regulated by histone methyltransferase KMT2A, KM2TB and KMT2D knockout (KO) cells including Gstt1, CYP26B1 and PYGL. In addition to this, KMT2A, KM2TB and KMT2D KOs show differential sensitivity to chemotherapeutic agents Gemcitabine, SN-38, 5-FU and Oxaliplatin. Further, analysis of KMT2A, KM2TB and KMT2D KO cells will provide mechanistic insight of the epigenetic regulation of metabolic patterns in drug resistant cells. This strategy would provide an approach for reducing exposure to toxic drugs, improving patient quality of life and renewing hope for prolonged control of metastatic PDAC and CRC. This proposal represents a bedside-to-bench-to-bedside project; identifying a shortcoming in how we currently treat PDAC and CRC patients, developing solutions in the lab and ultimately translating such strategies to benefit patients. Citation Format: Glancis Luzeena Raja Arul, Ezequiel Tolosa, Ryan M. Carr, Martin E. Fernandez-Zapico. Modeling evolutionary therapy for GI malignancies [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B002.

How does contemporary selection shape oak phenotypes?

Most existing forests are subjected to natural and human‐mediated selection pressures, which have increased due to climate change and the increasing needs of human societies for wood, fibre and fuel resources. It remains largely unknown how these pressures trigger evolutionary changes. We address this issue here for temperate European oaks (Quercus petraea and Q. robur), which grow in mixed stands, under even‐aged management regimes. We screened numerous functional traits for univariate selection gradients and for expected and observed genetic changes over two successive generations. In both species, growth, leaf morphology and physiology, and defence‐related traits displayed significant selection gradients and predicted shifts, whereas phenology, water metabolism, structure and resilience‐related traits did not. However, the direction of the selection response and the potential for adaptive evolution differed between the two species. Quercus petraea had a much larger phenotypic and genetic variance of fitness than Q. robur. This difference raises concerns about the adaptive response of Q. robur to contemporary selection pressures. Our investigations suggest that Q. robur will probably decline steadily, particularly in mixed stands with Q. petraea, consistent with the contrasting demographic dynamics of the two species.

Fitness consequences of fish circadian behavioural variation in exploited marine environments.

The selective properties of fishing that influence behavioural traits have recently gained interest. Recent acoustic tracking experiments have revealed between-individual differences in the circadian behavioural traits of marine free-living fish; these differences are consistent across time and ecological contexts and generate different chronotypes. Here, we hypothesised that the directional selection resulting from fishing influences the wild circadian behavioural variation and affects differently to individuals in the same population differing in certain traits such as awakening time or rest onset time. We developed a spatially explicit social-ecological individual-based model (IBM) to test this hypothesis. The parametrisation of our IBM was fully based on empirical data; which represent a fishery formed by patchily distributed diurnal resident fish that are exploited by a fleet of mobile boats (mostly bottom fisheries). We ran our IBM with and without the observed circadian behavioural variation and estimated selection gradients as a quantitative measure of trait change. Our simulations revealed significant and strong selection gradients against early-riser chronotypes when compared with other behavioural and life-history traits. Significant selection gradients were consistent across a wide range of fishing effort scenarios. Our theoretical findings enhance our understanding of the selective properties of fishing by bridging the gaps among three traditionally separated fields: fisheries science, behavioural ecology and chronobiology. We derive some general predictions from our theoretical findings and outline a list of empirical research needs that are required to further understand the causes and consequences of circadian behavioural variation in marine fish.

Fluctuating selection across years and phenotypic variation in food-deceptive orchids.

Nectarless flowers that deceive pollinators offer an opportunity to study asymmetric plant-insect interactions. Orchids are a widely used model for studying these interactions because they encompass several thousand species adopting deceptive pollination systems. High levels of intra-specific phenotypic variation have been reported in deceptive orchids, suggesting a reduced consistency of pollinator-mediated selection on their floral traits. Nevertheless, several studies report on widespread directional selection mediated by pollinators even in these deceptive orchids. In this study we test the hypothesis that the observed selection can fluctuate across years in strength and direction thus likely contributing to the phenotypic variability of this orchid group. We performed a three-year study estimating selection differentials and selection gradients for nine phenotypic traits involved in insect attraction in two Mediterranean orchid species, namely Orchis mascula and O. pauciflora, both relying on a well-described food-deceptive pollination strategy. We found weak directional selection and marginally significant selection gradients in the two investigated species with significant intra-specific differences in selection differentials across years. Our data do not link this variation with a specific environmental cause, but our results suggest that pollinator-mediated selection in food-deceptive orchids can change in strength and in direction over time. In perennial plants, such as orchids, different selection differentials in the same populations in different flowering seasons can contribute to the maintenance of phenotypic variation often reported in deceptive orchids.

Epigenetic variation creates potential for evolution of plant phenotypic plasticity

Heritable variation in plant phenotypes, and thus potential for evolutionary change, can in principle not only be caused by variation in DNA sequence, but also by underlying epigenetic variation. However, the potential scope of such phenotypic effects and their evolutionary significance are largely unexplored. Here, we conducted a glasshouse experiment in which we tested the response of a large number of epigenetic recombinant inbred lines (epiRILs) of Arabidopsis thaliana--lines that are nearly isogenic but highly variable at the level of DNA methylation--to drought and increased nutrient conditions. We found significant heritable variation among epiRILs both in the means of several ecologically important plant traits and in their plasticities to drought and nutrients. Significant selection gradients, that is, fitness correlations, of several mean traits and plasticities suggest that selection could act on this epigenetically based phenotypic variation. Our study provides evidence that variation in DNA methylation can cause substantial heritable variation of ecologically important plant traits, including root allocation, drought tolerance and nutrient plasticity, and that rapid evolution based on epigenetic variation alone should thus be possible.

Resistance and tolerance to herbivory in Solidago altissima (Asteraceae): Genetic variability, costs, and selection for multiple traits

Quantifying the genetic variability, fitness costs, and selection gradients associated with plant defense traits is necessary to understand their evolution and continued persistence in populations. Few studies have simultaneously examined the costs, benefits, and genetic variability in multiple traits related to plant resistance and tolerance to herbivory. • Using 103 Solidago altissima (Asteraceae) genets from two populations previously studied in situ, we conducted a common garden experiment to assess genetic variability, costs, selection gradients, and correlations among resistance, tolerance, and various resistance and tolerance traits (i.e., lateral branching, relative growth rate, leaf addition and senescence rate, specific leaf area, and leaf toughness). • We report evidence for significant genetic variability in resistance and various tolerance-related traits but low broad-sense heritability (H(2) < 0.14) for all traits. For all traits examined, no correlation existed between trait levels of parent ramets (measured in their field of origin) and daughter ramets (measured in the common garden), suggesting plasticity in goldenrod traits. We found a strong cost of resistance and selection gradient against high resistance. Conversely, we found no evidence of costs but did find significant selection gradients favoring increased tolerance and many tolerance trait levels. • Our study suggests that herbivores impose selection favoring increased tolerance and reduced resistance in goldenrods. In this environment, we expect that over time, resistant genets will decrease in frequency. Despite strong selection pressures, the evolution of tolerance in this environment may be constrained by the low broad-sense heritability in tolerance traits.

Fecundity selection on ornamental plumage colour differs between ages and sexes and varies over small spatial scales

Avian plumage colours are some of the most conspicuous sexual ornaments, and yet standardized selection gradients for plumage colour have rarely been quantified. We examined patterns of fecundity selection on plumage colour in blue tits (Cyanistes caeruleus L.). When not accounting for environmental heterogeneity, we detected relatively few cases of selection. We found significant disruptive selection on adult male crown colour and yearling female chest colour and marginally nonsignificant positive linear selection on adult female crown colour. We discovered no new significant selection gradients with canonical rotation of the matrix of nonlinear selection. Next, using a long-term data set, we identified territory-level environmental variables that predicted fecundity to determine whether these variables influenced patterns of plumage selection. The first of these variables, the density of oaks within 50 m of the nest, influenced selection gradients only for yearling males. The second variable, an inverse function of nesting density, interacted with a subset of plumage selection gradients for yearling males and adult females, although the strength and direction of selection did not vary predictably with population density across these analyses. Overall, fecundity selection on plumage colour in blue tits appeared rare and inconsistent among sexes and age classes.

Selection on domestication traits and quantitative trait loci in crop–wild sunflower hybrids

The strength and extent of gene flow from crops into wild populations depends, in part, on the fitness of the crop alleles, as well as that of alleles at linked loci. Interest in crop-wild gene flow has increased with the advent of transgenic plants, but nontransgenic crop-wild hybrids can provide case studies to understand the factors influencing introgression, provided that the genetic architecture and the fitness effects of loci are known. This study used recombinant inbred lines (RILs) generated from a cross between crop and wild sunflowers to assess selection on domestication traits and quantitative trait loci (QTL) in two contrasting environments, in Indiana and Nebraska, USA. Only a small fraction of plants (9%) produced seed in Nebraska, due to adverse weather conditions, while the majority of plants (79%) in Indiana reproduced. Phenotypic selection analysis found that a mixture of crop and wild traits were favoured in Indiana (i.e. had significant selection gradients), including larger leaves, increased floral longevity, larger disk diameter, reduced ray flower size and smaller achene (seed) mass. Selection favouring early flowering was detected in Nebraska. QTLs for fitness were found at the end of linkage groups six (LG6) and nine (LG9) in both field sites, each explaining 11-12% of the total variation. Crop alleles were favoured on LG9, but wild alleles were favoured on LG6. QTLs for numerous domestication traits overlapped with the fitness QTLs, including flowering date, achene mass, head number, and disk diameter. It remains to be seen if these QTL clusters are the product of multiple linked genes, or individual genes with pleiotropic effects. These results indicate that crop trait values and alleles may sometimes be favoured in a noncrop environment and across broad geographical regions.

ECOLOGICAL AND EVOLUTIONARY MECHANISMS FOR LOW SEED : OVULE RATIOS: NEED FOR A PLURALISTIC APPROACH?

Central to the ecology and evolution of a broad range of plants is understanding why they routinely have submaximal reproduction manifested as low seed : ovule and fruit : flower ratios. We know much less about the processes responsible for low seed : ovule ratios than we do for fruit : flower ratios. Current hypotheses for low seed : ovule ratios are largely drawn from those for fruit : flower ratios, including proximate (ecological) causes of pollen limitation, resource limitation, and pollen quality, as well as the ultimate (evolutionary) hypothesis of "bet hedging" on stochastic pollination. Yet, such mechanisms operating on fruit : flower ratios at the whole-plant level may not best explain low seed : ovule ratios at the individual-flower level. We tested each of these proximate and ultimate causes for low seed : ovule ratios using the specialized pollination mutualism between senita cacti (Pachycereus schottii) and senita moths (Upiga virescens). Seed : ovule ratios were consistently low (approximately 0.61). Such excess ovule production by senita likely has a strong genetic component given the significant differences among plants in ovule number and the consistency in ovule production by plants within and among flowering seasons. Excess ovule production and low seed : ovule ratios could not be explained by pollen limitation, resource limitation, pollen quality, or bet hedging. Nevertheless, phenotypic selection analyses did show significant selection gradients for increased ovule number, suggesting that other evolutionary processes may be responsible for excess ovule production and low seed : ovule ratios. In contrast, low fruit : flower ratios at the whole-plant level were explained by an apparent equilibrium between pollen and resource limitation. Thus, mechanisms responsible for low fruit : flower ratios at the whole-plant level are not necessarily in accord with those of low seed : ovule ratios at the individual-flower level. This suggests that we may need to adopt a more pluralistic approach to seed : ovule ratios and consider alternative hypotheses, including a greater array of proximate and ultimate causes. Initial results of this study suggest that floral allometry, selection on correlated floral traits, stigma clogging with pollen grains, and style clogging with pollen tubes may provide promising avenues for understanding low seed : ovule ratios.

Selection on floral traits through male fertility in a natural plant population

Most studies on selection in plants estimate female fitness components and neglect male mating success, although the latter might also be fundamental to understand adaptive evolution. Information from molecular genetic markers can be used to assess determinants of male mating success through parentage analyses. We estimated paternal selection gradients on floral traits in a large natural population of the herb Mimulus guttatus using a paternity probability model and maximum likelihood methods. This analysis revealed more significant selection gradients than a previous analysis based on regression of estimated male fertilities on floral traits. There were differences between results of univariate and multivariate analyses most likely due to the underlying covariance structure of the traits. Multivariate analysis, which corrects for the covariance structure of the traits, indicated that male mating success declined with distance from and depended on the direction to the mother plants. Moreover, there was directional selection for plants with fewer open flowers which have smaller corollas, a smaller anther–stigma separation, more red dots on the corolla and a larger fluctuating asymmetry therein. For most of these traits, however, there was also stabilizing selection indicating that there are intermediate optima for these traits. The large number of significant selection gradients in this study shows that even in relatively large natural populations where not all males can be sampled, it is possible to detect significant paternal selection gradients, and that such studies can give us valuable information required to better understand adaptive plant evolution.

Selection on reproductive characters: floral morphology in Asclepias syriaca

Pollinia insertions and removals represent a convenient index of male and female fertilities in the Asclepiadaceae. This fact, in conjunction with regression analysis, allows estimation and comparison of gender-specific selection acting on floral characters in Asclepias syriaca. Univariate regression analysis indicates statistically significant selection on minute aspects of floral morphology through the male and especially female reproductive pathways. Analyses using multiple regression to correct for overall plant size do not qualitatively change the univariate results. The relatively large number of statistically significant selection gradients suggests active adaptation of floral morphological features to the pollinator fauna. Selection through female function differs significantly from selection on the same trait through male function for four traits, emphasizing an antagonism between genders in hermaphrodites. This antagonism and the absence of selection of the antagonistic traits through net fertility are consistent with an equilibrium quantitative genetic perspective, while greater opportunity for selection through female function is counter to expectations based on Bateman's principle of sexual selection.

Selection on reproductive characters: floral morphology in Asclepias syriaca

Pollinia insertions and removals represent a convenient index of male and female fertilities in the Asclepiadaceae. This fact, in conjunction with regression analysis, allows estimation and comparison of gender-specific selection acting on floral characters in Asclepias syriaca. Univariate regression analysis indicates statistically significant selection on minute aspects of floral morphology through the male and especially female reproductive pathways. Analyses using multiple regression to correct for overall plant size do not qualitatively change the univariate results. The relatively large number of statistically significant selection gradients suggests active adaptation of floral morphological features to the pollinator fauna. Selection through female function differs significantly from selection on the same trait through male function for four traits, emphasizing an antagonism between genders in hermaphrodites. This antagonism and the absence of selection of the antagonistic traits through net fertility are consistent with an equilibrium quantitative genetic perspective, while greater opportunity for selection through female function is counter to expectations based on Bateman's principle of sexual selection.

Spatial variation in selection in a plant-pollinator system in the wadis of Sinai, Egypt.

We studied an insect-plant pollination system in adjacent steep-sided wadis and a connecting plain in the mountains of southern Sinai (Egypt): this environment creates a strongly divided habitat, which may promote the local differentiation of sub-populations. We tested for spatial differences in phenotypic reproductive characters of the only plant flowering abundantly in early spring, Alkanna orientalis (Boraginaceae), and its major pollinator at that time of year, Anthophora pauperata (Apoidea, Anthophoridae). There were significant morphological differences between sub-populations of Alkanna, mainly between plants from the narrower wadis and those on the interconnecting plain. Flowers on the plain were larger, with wider corollas and more nectar standing crop; these plants retained more flowers on the inflorescence, but received many fewer visits to flowers. There was a significant selection gradient between flower size and maternal fitness (seed set) in the plain, but not elsewhere. Natural selection may have increased resources devoted to attracting insect visitors in response to fewer pollinating visits in the plain. Consistent with this explanation, by experimentally manipulating flower number per plant, we showed that within a wadi having more flowers on a plant secured more visits.