Biological lessons for strategic resistance management.

Biological resistance to pesticides, vaccines, antibiotics, and chemotherapies creates huge costs to society, including extensive morbidity and mortality. We simultaneously face costly resistance to social changes, such as those required to resolve human-wildlife conflicts and conserve biodiversity and the biosphere. Viewing resistance as a force that impedes change from one state to another, we suggest that an analysis of biological resistance can provide unique and potentially testable insights into understanding resistance to social changes. We review key insights from managing biological resistance and develop a framework that identifies seven strategies to overcome resistance. We apply this framework to consider how it might be used to understand social resistance and generate potentially novel hypotheses that may be useful to both enhance the development of strategies to manage resistance and modulate change in socio-ecological systems.

The effect of participation in accountable care organization on electronic health information exchange practices in U.S. hospitals.

BACKGROUND: Accountable care organizations (ACOs) are a recent incentive program that are designed to address inefficiencies in the U.S. health care sector. To meet their design objectives, ACO participants must engage in greater electronic health information exchange (HIE) practices both internally and externally with care participants, such as patients and other providers. PURPOSE: The aim of this study was to examine the relationship between hospital participation in ACOs and electronic HIE practices with different participants of care and how these practices vary differentially across market types. APPROACH: Grounding our work in the reward-motivational view of organizational action, we proposed hypotheses that linked hospital participation in ACOs to three dimensions of HIE practices (intraorganizational, interorganizational, and provider-patient HIE practices). We tested our hypotheses by analyzing a sample of 1,926 hospitals. RESULTS: Hospital participation in ACOs is associated with greater intraorganizational and provider-patient HIE practices, but not interorganizational HIE practices. We also found that whereas the relationship between ACO participation and intra- and interorganizational HIE practices remains unchanged irrespective of the degree of competition in the health care market, the relationship between ACO participation and provider-patient HIE practices holds true only for hospitals operating in noncompetitive markets. PRACTICE IMPLICATIONS: Our results showed that hospitals participating in ACOs vary in their HIE practices, and attributes of the local market in which ACO participants operate in contribute to this variation. These insights should provide guidance to researchers, policymakers, and hospital administrators who aim to improve the effectiveness of ACOs.

Molecular Biology and Evolution of Cancer: From Discovery to Action.

Cancer progression is an evolutionary process. During this process, evolving cancer cell populations encounter restrictive ecological niches within the body, such as the primary tumor, circulatory system, and diverse metastatic sites. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform cancer biology in new and meaningful ways. We also highlight current challenges to applying these concepts, and propose ways in which incorporating these concepts could identify new therapeutic modes and vulnerabilities in cancer.

A New Mechanism for Mendelian Dominance in Regulatory Genetic Pathways: Competitive Binding by Transcription Factors.

We report a new mechanism for allelic dominance in regulatory genetic interactions that we call binding dominance. We investigated a biophysical model of gene regulation, where the fractional occupancy of a transcription factor (TF) on the cis-regulated promoter site it binds to is determined by binding energy (-ΔG) and TF dosage. Transcription and gene expression proceed when the TF is bound to the promoter. In diploids, individuals may be heterozygous at the cis-site, at the TF's coding region, or at the TF's own promoter, which determines allele-specific dosage. We find that when the TF's coding region is heterozygous, TF alleles compete for occupancy at the cis-sites and the tighter-binding TF is dominant in proportion to the difference in binding strength. When the TF's own promoter is heterozygous, the TF produced at the higher dosage is also dominant. Cis-site heterozygotes have additive expression and therefore codominant phenotypes. Binding dominance propagates to affect the expression of downstream loci and it is sensitive in both magnitude and direction to genetic background, but its detectability often attenuates. While binding dominance is inevitable at the molecular level, it is difficult to detect in the phenotype under some biophysical conditions, more so when TF dosage is high and allele-specific binding affinities are similar. A body of empirical research on the biophysics of TF binding demonstrates the plausibility of this mechanism of dominance, but studies of gene expression under competitive binding in heterozygotes in a diversity of genetic backgrounds are needed.

Clusters of incompatible genotypes evolve with limited dispersal.

Theoretical and empirical studies have shown heterogeneous selection to be the primary driver for the evolution of reproductively isolated genotypes in the absence of geographic barriers. Here, we ask whether limited dispersal alone can lead to the evolution of reproductively isolated genotypes despite the absence of any geographic barriers or heterogeneous selection. We use a spatially-explicit, individual-based, landscape genetics program to explore the influences of dispersal strategies on reproductive isolation. We simulated genetic structure in a continuously distributed population and across various dispersal strategies (ranging from short- to long-range individual movement), as well as potential mate partners in entire population (ranging from 20 to 5000 individuals). We show that short-range dispersal strategies lead to the evolution of clusters of reproductively isolated genotypes despite the absence of any geographic barriers or heterogeneous selection. Clusters of genotypes that are reproductively isolated from other clusters can persist when migration distances are restricted such that the number of mating partners is below about 350 individuals. We discuss how our findings may be applicable to particular speciation scenarios, as well as the need to investigate the influences of heterogeneous gene flow and spatial selection gradients on the emergence of reproductively isolating genotypes.

Hybrid incompatibility despite pleiotropic constraint in a sequence-based bioenergetic model of transcription factor binding.

Hybrid incompatibility can result from gene misregulation produced by divergence in trans-acting regulatory factors and their cis-regulatory targets. However, change in trans-acting factors may be constrained by pleiotropy, which would in turn limit the evolution of incompatibility. We employed a mechanistically explicit bioenergetic model of gene expression wherein parameter combinations (number of transcription factor molecules, energetic properties of binding to the regulatory site, and genomic background size) determine the shape of the genotype-phenotype (G-P) map, and interacting allelic variants of mutable cis and trans sites determine the phenotype along that map. Misregulation occurs when the phenotype differs from its optimal value. We simulated a pleiotropic regulatory pathway involving a positively selected and a conserved trait regulated by a shared transcription factor (TF), with two populations evolving in parallel. Pleiotropic constraints shifted evolution in the positively selected trait to its cis-regulatory locus. We nevertheless found that the TF genotypes often evolved, accompanied by compensatory evolution in the conserved trait, and both traits contributed to hybrid misregulation. Compensatory evolution resulted in "developmental system drift," whereby the regulatory basis of the conserved phenotype changed although the phenotype itself did not. Pleiotropic constraints became stronger and in some cases prohibitive when the bioenergetic properties of the molecular interaction produced a G-P map that was too steep. Likewise, compensatory evolution slowed and hybrid misregulation was not evident when the G-P map was too shallow. A broad pleiotropic "sweet spot" nevertheless existed where evolutionary constraints were moderate to weak, permitting substantial hybrid misregulation in both traits. None of these pleiotropic constraints manifested when the TF contained nonrecombining domains independently regulating the respective traits.

Hybrid incompatibility arises in a sequence-based bioenergetic model of transcription factor binding.

Postzygotic isolation between incipient species results from the accumulation of incompatibilities that arise as a consequence of genetic divergence. When phenotypes are determined by regulatory interactions, hybrid incompatibility can evolve even as a consequence of parallel adaptation in parental populations because interacting genes can produce the same phenotype through incompatible allelic combinations. We explore the evolutionary conditions that promote and constrain hybrid incompatibility in regulatory networks using a bioenergetic model (combining thermodynamics and kinetics) of transcriptional regulation, considering the bioenergetic basis of molecular interactions between transcription factors (TFs) and their binding sites. The bioenergetic parameters consider the free energy of formation of the bond between the TF and its binding site and the availability of TFs in the intracellular environment. Together these determine fractional occupancy of the TF on the promoter site, the degree of subsequent gene expression and in diploids, and the degree of dominance among allelic interactions. This results in a sigmoid genotype-phenotype map and fitness landscape, with the details of the shape determining the degree of bioenergetic evolutionary constraint on hybrid incompatibility. Using individual-based simulations, we subjected two allopatric populations to parallel directional or stabilizing selection. Misregulation of hybrid gene expression occurred under either type of selection, although it evolved faster under directional selection. Under directional selection, the extent of hybrid incompatibility increased with the slope of the genotype-phenotype map near the derived parental expression level. Under stabilizing selection, hybrid incompatibility arose from compensatory mutations and was greater when the bioenergetic properties of the interaction caused the space of nearly neutral genotypes around the stable expression level to be wide. F2's showed higher hybrid incompatibility than F1's to the extent that the bioenergetic properties favored dominant regulatory interactions. The present model is a mechanistically explicit case of the Bateson-Dobzhansky-Muller model, connecting environmental selective pressure to hybrid incompatibility through the molecular mechanism of regulatory divergence. The bioenergetic parameters that determine expression represent measurable properties of transcriptional regulation, providing a predictive framework for empirical studies of how phenotypic evolution results in epistatic incompatibility at the molecular level in hybrids.

Evo-devo beyond morphology: from genes to resource use.

How does genetic innovation translate into ecological innovation? Although evo-devo has successfully linked genes to morphology, the next stage is elucidating how genes predict resource use. This can be attained by broadening the focus of evo-devo from [genes→morphology], to [genes→morphology→functional ecology]. We suggest that the fields of evo-devo, functional morphology, and evolutionary ecology should be united under a common framework based on three predictions. The first is that morphological disparity should scale positively with functional complexity among different radiations. The second is that functional complexity should correlate negatively with the predictability of evolutionary divergence within lineages, and the third is that functional complexity should define the genetic architecture of adaptive radiations. These predictions could enable a broader understanding of how genetic variation is translated into variation in resource use.

The genetics of sex chromosomes: evolution and implications for hybrid incompatibility.

Heteromorphic sex chromosomes, where one sex has two different types of sex chromosomes, face very different evolutionary consequences than do autosomes. Two important features of sex chromosomes arise from being present in only one copy in one of the sexes: dosage compensation and the meiotic silencing of sex chromosomes. Other differences arise because sex chromosomes spend unequal amounts of time in each sex. Thus, the impact of evolutionary processes (mutation, selection, genetic drift, and meiotic drive) differs substantially between each sex chromosome, and between the sex chromosomes and the autosomes. Sex chromosomes also play a disproportionate role in Haldane's rule and other important patterns related to hybrid incompatibility, and thus speciation. We review the consequences of sex chromosomes on hybrid incompatibility. A theme running through this review is that epigenetic processes, notably those related to chromatin, may be more important to the evolution of sex chromosomes and the evolution of hybrid incompatibility than previously recognized.

The population genetics of X-autosome synthetic lethals and steriles.

Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation-selection balance conditions for X-autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X-autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane's rule.

Niche explosion.

The following syndrome of features occurs in several groups of phytophagous insects: (1) wingless females, (2) dispersal by larvae, (3) woody hosts, (4) extreme polyphagy, (5) high abundance, resulting in status as economic pests, (6) invasiveness, and (7) obligate parthenogenesis in some populations. If extreme polyphagy is defined as feeding on 20 or more families of hostplants, this syndrome is found convergently in several species of bagworm moths, tussock moths, root weevils, and 5 families of scale insects. We hypothesize that extreme polyphagy in these taxa results from "niche explosion", a positive feedback loop connecting large population size to broad host range. The niche explosion has a demographic component (sometimes called the "amplification effect" in studies of pathogens) as well as a population-genetic component, due mainly to the increased effectiveness of natural selection in larger populations. The frequent origins of parthenogenesis in extreme polyphages are, in our interpretation, a consequence of this increased effectiveness of natural selection and consequent reduced importance of sexuality. The niche explosion hypothesis makes detailed predictions about the comparative genomics and population genetics of extreme polyphages and related specialists. It has a number of potentially important implications, including an explanation for the lack of observed trade-offs between generalists and specialists, a re-interpretation of the ecological correlates of parthenogenesis, and a general expectation that Malthusian population explosions may be amplified by Darwinian effects.

Hybrid incompatibility genes: remnants of a genomic battlefield?

Hybrid incompatibility (including sterility, lethality, and less extreme negative effects) interests evolutionary biologists because of its role in speciation as a reproductive isolating barrier. It also has unusual genetic properties, being mainly due to interactions between at least two genes. Recent studies have identified some of the interacting genes that underlie hybrid incompatibility. These genes represent a wide array of functions, including those involved in oxidative respiration, nuclear trafficking, DNA-binding, and plant defense. Accumulating evidence suggests genomic conflict frequently drives the divergence causing incompatibilities in hybrids. The evidence bearing on this genomic conflict hypothesis is assessed and ways to test it conclusively are suggested.

Relaxed selection in the wild.

Natural populations often experience the weakening or removal of a source of selection that had been important in the maintenance of one or more traits. Here we refer to these situations as 'relaxed selection,' and review recent studies that explore the effects of such changes on traits in their ecological contexts. In a few systems, such as the loss of armor in stickleback, the genetic, developmental and ecological bases of trait evolution are being discovered. These results yield insights into whether and how fast a trait is reduced or lost under relaxed selection. We provide a prospectus and a framework for understanding relaxed selection and trait loss in natural populations. We also examine its implications for applied issues, such as antibiotic resistance and the success of invasive species.

Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift.

Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.

Speciation despite gene flow when developmental pathways evolve.

Evolutionary biologists assume that species formation requires a drastic reduction in gene exchange between populations, but the rate sufficient to prevent speciation is unknown. To study speciation, we use a new class of population genetic models that incorporate simple developmental genetic rules, likely present in all organisms, to construct the phenotype. When we allow replicate populations to evolve in parallel to a new, shared optimal phenotype, often their hybrids acquire poorly regulated phenotypes: Dobzhansky-Muller incompatibilities arise and postzygotic reproductive isolation evolves. Here we show that, although gene exchange does inhibit this process, it is the proportion of migrants exchanged (m) rather than the number of migrants (Nm) that is critical, and rates as high as 16 individuals exchanged per generation still permit the evolution of postzygotic isolation. Stronger directional selection counters the inhibitory effect of gene flow, increasing the speciation probability. We see similar results when populations in a standard two-locus, two-allele Dobzhansky-Muller model are subject to simultaneous directional selection and gene flow. However, in developmental pathway models with more than two loci, gene flow is more able to impede speciation. Genetic incompatibilities arise as frequent by-products of adaptive evolution of traits determined by regulatory pathways, something that does not occur when phenotypes are modeled using the standard, additive genetic framework. Development therefore not only constrains the microevolutionary process, it also facilitates the interactions among genes and gene products that make speciation more likely-even in the face of strong gene flow.

Hidden evolution: progress and limitations in detecting multifarious natural selection.

From illustrative examples of research on the best-studied group of species to date, Drosophila melanogaster and its closest relatives, we argue that selection is multifarious, but often hidden. Selective fixation of new, highly advantageous alleles is the most parsimonious explanation for a typical pattern of molecular variation observed in genomic regions characterized by very low recombination: drastically reduced DNA sequence variation within species and typical levels of sequence divergence among species. At the same time, the identity of the gene (or genes) influenced by selection is not just difficult to discern; it may be impossible. Studies of the genetic basis of reproductive isolation demonstrate that, although the D. melanogaster complex species appear virtually identical, dozens of currently unidentified genes contribute to hybrid sterility. We argue that these findings are best explained by selectively-driven functional divergence and demonstrate the multifarious nature of selection. Although multifarious selection certainly occurs, the exact characters responsible for differences in survival and reproductive success are unknown. We do not see these inherent limits as a cause for despair or a problem for evolutionary biology. Instead, we hope to raise awareness of these complexities of evolution by highlighting both the progress and the limitations of characterizing multifarious natural selection.