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Evolutionary relationships of Aurora kinases: implications for model organism studies and the development of anti-cancer drugs.

BACKGROUND: As key regulators of mitotic chromosome segregation, the Aurora family of serine/threonine kinases play an important role in cell division. Abnormalities in Aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the ATP-binding domain of these kinases. From an evolutionary perspective, the species distribution of the Aurora kinase family is complex. Mammals uniquely have three Aurora kinases, Aurora-A, Aurora-B, and Aurora-C, while for other metazoans, including the frog, fruitfly and nematode, only Aurora-A and Aurora-B kinases are known. The fungi have a single Aurora-like homolog. Based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of Aurora kinases. However, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. Here, we present comprehensive evolutionary analyses of the Aurora kinase family. RESULTS: Phylogenetic trees suggest that all three vertebrate Auroras evolved from a single urochordate ancestor. Specifically, Aurora-A is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar Aurora-B and Aurora-C evolved more recently in mammals from a duplication of an ancestral Aurora-B/C gene found in cold-blooded vertebrates. All so-called Aurora-A and Aurora-B kinases of non-chordates are ancestral to the clade of chordate Auroras and, therefore, are not strictly orthologous to vertebrate counterparts. Comparisons of human Aurora-B and Aurora-C sequences to the resolved 3D structure of human Aurora-A lends further support to the evolutionary scenario that vertebrate Aurora-B and Aurora-C are closely related paralogs. Of the 26 residues lining the ATP-binding active site, only three were variant and all were specific to Aurora-A. CONCLUSIONS: In this study, we found that invertebrate Aurora-A and Aurora-B kinases are highly divergent protein families from their chordate counterparts. Furthermore, while the Aurora-A family is ubiquitous among all vertebrates, the Aurora-B and Aurora-C families in humans arose from a gene duplication event in mammals. These findings show the importance of understanding evolutionary relationships in the interpretation and transference of knowledge from studies of model organism systems to human cellular biology. In addition, given the important role of Aurora kinases in cancer, evolutionary analysis and comparisons of ATP-binding domains suggest a rationale for designing dual action anti-tumor drugs that inhibit both Aurora-B and Aurora-C kinases.

Amino Acid Sequence↗

Stable evolutionary signal in a yeast protein interaction network.

BACKGROUND: The recently emerged protein interaction network paradigm can provide novel and important insights into the innerworkings of a cell. Yet, the heavy burden of both false positive and false negative protein-protein interaction data casts doubt on the broader usefulness of these interaction sets. Approaches focusing on one-protein-at-a-time have been powerfully employed to demonstrate the high degree of conservation of proteins participating in numerous interactions; here, we expand his 'node' focused paradigm to investigate the relative persistence of 'link' based evolutionary signals in a protein interaction network of S. cerevisiae and point out the value of this relatively untapped source of information. RESULTS: The trend for highly connected proteins to be preferably conserved in evolution is stable, even in the context of tremendous noise in the underlying protein interactions as well as in the assignment of orthology among five higher eukaryotes. We find that local clustering around interactions correlates with preferred evolutionary conservation of the participating proteins; furthermore the correlation between high local clustering and evolutionary conservation is accompanied by a stable elevated degree of coexpression of the interacting proteins. We use this conserved interaction data, combined with P. falciparum/Yeast orthologs, as proof-of-principle that high-order network topology can be used comparatively to deduce local network structure in non-model organisms. CONCLUSION: High local clustering is a criterion for the reliability of an interaction and coincides with preferred evolutionary conservation and significant coexpression. These strong and stable correlations indicate that evolutionary units go beyond a single protein to include the interactions among them. In particular, the stability of these signals in the face of extreme noise suggests that empirical protein interaction data can be integrated with orthologous clustering around these protein interactions to reliably infer local network structures in non-model organisms.

Evolution, Molecular↗

Interpreting cancer genetics through a two-step "evolutionary cascade hypothesis": bridging neutral and selective perspectives.

BACKGROUND: DNA mutations are the fundamental engines of cancer, driving its initiation and progression. The forces that fuel malignancy are also the architects of evolution, shaping life through genetic variations. Mutations, in fact, can emerge naturally from endogenous processes, such as oxidative DNA damage or errors in replication, as well as induced by external factors, including cosmic radiation and chemical carcinogens. MAIN BODY: A key question in cancer research is whether tumor evolution is primarily governed by selective bottlenecks, neutral evolution, or dynamic genetic plasticity. In this work, we examine cancer as a disease driven by evolutionary processes rooted in fundamental biological requirements, including sustained proliferation and nutrient utilization. We hypothesize that the accumulation of mutations activates an evolutionary switch, enabling tumor cells to acquire an enhanced capacity for survival, adaptation, and growth at rates far exceeding typical evolutionary timescales. We propose the "evolutionary cascade hypothesis," a unifying framework that integrates these models into a coherent sequence. At its core lies the failure of DNA repair mechanisms, representing a critical transition in cancer progression. This shift marks the transition from an initial non-Darwinian, neutral phase to a Darwinian, more deterministic phase. CONCLUSIONS: As predictive models of tumor evolution advance through genomic big data and artificial intelligence-driven analysis, the future of cancer treatment may extend beyond targeting individual mutations to disrupting the underlying evolutionary mechanisms that sustain malignancy. This paradigm shift could redefine therapeutic strategies and ultimately improve patient outcomes.

Humans↗

Distinct evolutionary trajectories of subgenomic centromeres in polyploid wheat.

BACKGROUND: Centromeres are crucial for precise chromosome segregation and maintaining genome stability during cell division. However, their evolutionary dynamics, particularly in polyploid organisms with complex genomic architectures, remain largely enigmatic. Allopolyploid wheat, with its well-defined hierarchical ploidy series and recent polyploidization history, serves as an excellent model to explore centromere evolution. RESULTS: In this study, we perform a systematic comparative analysis of centromeres in common wheat and its corresponding ancestral species, utilizing the latest comprehensive reference genome assembly available. Our findings reveal that wheat centromeres predominantly consist of five types of centromeric-specific retrotransposon elements (CRWs), with CRW1 and CRW2 being the most prevalent. We identify distinct evolutionary trajectories in the functional centromeres of each subgenome, characterized by variations in copy number, insertion age, and CRW composition. By utilizing CENH3-ChIP data across various ploidy levels, we uncover a series of CRW invasion events that have shaped the evolution of AA subgenome centromeres. Conversely, the evolutionary process of the DD subgenome centromeres involves their expansion from diploid to hexaploid wheat, facilitating adaptation to a larger genomic context. Integration of complete einkorn centromere assemblies and Aegilops tauschii pan-genomes further revealed subgenome-specific centromere evolutionary trajectories. By inclusion of synthetic hexaploid from S2-S3 generations, alongside 2x/6 × natural accessions, we demonstrate that DD subgenome centromere expansion represents a gradual evolutionary process rather than an immediate response to polyploidization. CONCLUSIONS: Our study provides a comprehensive landscape of centromere adaptation, evolution, and maturation, along with insights into how retrotransposon invasions drive centromere evolution in polyploid wheat.

Centromere↗

[Evolutionary saltations and evolution].

The term saltation is a composite notion covering different categories of supposed saltational evolutionary changes. One can distinguish interspecies, macroevolutionary and morphofunctional saltations corresponding to saltational arising of a new species, of general Bauplans of new macrotaxons, and of large-scale morphofunctional alterations (irrelevant to any taxonomic aspects). Current data confirm the possibility of interspecies and mophofunctional saltations as relatively rare modes of evolutionary changes. Morphofunctional saltations result in the arising of macromorphoses that can sometimes stimulate the beginning of macroevolutionary typogenesis. Saltationism extremely exaggerates the evolutionary role of saltations, considering these to be the main factor of speciation and macroevolution. However, saltations are only peculiar and relatively rare form of hereditary variability representing elementary evolutionary material. Natural selection is the principal evolutionary mechanism that produces new adaptations and integrates different systems of the organism in the process of typogenesis. The arising of general Bauplans of new macrotax by means of macroevolutionary saltations seems to be improbable.

Animals↗

Chance as an explanatory factor in evolutionary biology.

Darwinian evolutionary biology has often been criticized for appealing to the notion of 'chance' in its explanations. According to some critics, such appeals exhibit the explanatory poverty of evolutionary theory. In response, defenders of Darwinism sometimes downplay the importance of 'chance' in evolution. I believe that both of these approaches are mistaken. The main thesis of this paper is that the term 'chance' encompasses a number of distinct concepts, and that at least some of these concepts serve essential explanatory functions in evolutionary biology. This claim is defended by way of an historical survey of the major concepts of 'chance' in the history of evolutionary biology, especially the concepts used by Jean Baptiste Lamarck, Charles Darwin, and Sewall Wright. An examination of their biologies shows how the concepts of 'chance' used cohere with their major scientific objectives and methods. These concepts survive and continue to function as important explanatory factors in contemporary evolutionary biology. Examples of such usage are given, and the explanatory status of 'chance' assessed.

Adaptation, Biological↗

Polygenic and monogenic adaptation drive evolutionary rescue at different magnitudes of environmental change.

Understanding the genetic basis of rapid adaptation is key to predicting species' evolutionary responses to environmental change. However, it is still debatable whether many small-effect mutations or a few large-effect mutations underlie rapid adaptation, and how this knowledge can predict population survival or extinction. To address this question, we performed a series of ecologically grounded forward-in-time genetic simulations to study rapid adaptation and extinction with increasing magnitudes of environmental change. These simulations were seeded with genomic variation of the plant Arabidopsis thaliana to have a realistic genomic structure, with one (monogenic) to 1,000 (polygenic) variants with varying heritabilities contributing to an environmental adaptive trait. Our results revealed two distinct scenarios of rapid adaptation and population rescue. Under small-to-moderate environmental shifts, high polygenic traits increased evolutionary rescue probability. Under extreme environmental shifts, high polygenic traits lead predictably to extinction, yet monogenic traits sometimes produce one-off winning adaptive genotypes. We interpret our rapid evolutionary rescue findings in terms of the fundamental theorem of natural selection, where trait polygenicity shapes the distribution of genetic variance in fitness across replicates and, in turn, the probability of population survival, with polygenic architectures producing more stable and predictable fitness variance and monogenic architectures generating highly skewed and variable outcomes. These results highlight the insights genomics gives us into the (un)predictability of species' evolutionary responses to global change, with management implications for assisted adaptation and conservation.

Arabidopsis↗

Utilizing evolutionary conservation to detect deleterious mutations and improve genomic prediction in cassava.

INTRODUCTION: Cassava (Manihot esculenta) is an annual root crop which provides the major source of calories for over half a billion people around the world. Since its domestication ~10,000 years ago, cassava has been largely clonally propagated through stem cuttings. Minimal sexual recombination has led to an accumulation of deleterious mutations made evident by heavy inbreeding depression. METHODS: To locate and characterize these deleterious mutations, and to measure selection pressure across the cassava genome, we aligned 52 related Euphorbiaceae and other related species representing millions of years of evolution. With single base-pair resolution of genetic conservation, we used protein structure models, amino acid impact, and evolutionary conservation across the Euphorbiaceae to estimate evolutionary constraint. With known deleterious mutations, we aimed to improve genomic evaluations of plant performance through genomic prediction. We first tested this hypothesis through simulation utilizing multi-kernel GBLUP to predict simulated phenotypes across separate populations of cassava. RESULTS: Simulations showed a sizable increase of prediction accuracy when incorporating functional variants in the model when the trait was determined by<100 quantitative trait loci (QTL). Utilizing deleterious mutations and functional weights informed through evolutionary conservation, we saw improvements in genomic prediction accuracy that were dependent on trait and prediction. CONCLUSION: We showed the potential for using evolutionary information to track functional variation across the genome, in order to improve whole genome trait prediction. We anticipate that continued work to improve genotype accuracy and deleterious mutation assessment will lead to improved genomic assessments of cassava clones.

cassava (Manihot esculenta)↗

Evolutionary process and the ecology of human immune function.

Evolutionary principles inform central design features of human immune defenses and provide key insights into this complicated host defense system. This article explores the selection pressures and adaptive responses that have elaborated the immune system over the course of evolution and discusses their implications for understanding contemporary immune development and function. Special attention is given to the challenges posed by diverse, rapidly evolving pathogens and the mammalian response to these challenges. The process of lymphocyte diversity generation and subsequent clonal selection is quintessentially Darwinian: pathogens provide selection pressure that drives differential replication of host immune cell lines, resulting in changes in genetic frequencies within an individual's population of lymphocytes. The immune system also incorporates nongenetic transgenerational processes in the transfer of antibodies from mother to offspring through the placenta and breast milk. The consequences of these observations for human development, health, and the ecology of immune function are considered throughout the life cycle. Specifically, evolutionary processes provide insight into autoimmunity, thymic function, lymphocyte development, infectious disease risk, and lactation. While much work in evolutionary medicine focuses on the discordance between evolved biology and rapidly changing cultural environments, with respect to the immune system, evolutionary processes may be most revealing when applied within individuals. Am. J. Hum. Biol. 11:705-717, 1999. Copyright 1999 Wiley-Liss, Inc.

Journal Article↗

Introduction: evolutionary theory and the search for a unified theory of fertility.

Demography and evolutionary biology share common origins but have divergent emphasis on the role of theory in understanding population phenomena. A unified theory of fertility would be beneficial in explaining variation in demographic characteristics across geographic and temporal gulfs and in integrating disparate perspectives. The six papers in this thematic collection represent a nascent but vital field: human evolutionary demography. These papers examine the ways in which evolutionary theory can inform, strengthen, and focus research on topics of long-standing interest to demographers by explicitly modeling the relationship of socioecological variables to life history traits. The papers demonstrate that an understanding of human life history evolution and the use of evolutionary theory as an organizing framework can lead to a productive reassessment of five areas, which are of long-standing concern to demographers, and which conventional demographic approaches have had limited success in understanding. These are conflicts of interest between parents and children and between men and women, the allocation of resources to competing and/or alternative forms of investment in reproduction and parenting, resource flow within the household, demographic transitions and particularly the fertility transition associated with economic development, and variation in life history characteristics such as fertility and mortality across populations. Future research integrating models of trait-environment correlation with models of individual information processing and decision-making will help identify areas of focus, revitalize current models, and play a leading role in the development of a unified theory of fertility applicable across societies and times.

Birth Rate↗

Darwinian fitness, evolutionary entropy and directionality theory.

Two recent articles provide computational and empirical validation of the following analytical fact: the outcome of competition between an invading genotype and that of a resident population is determined by the rate at which the population returns to its original size after a random perturbation. This phenomenon can be quantitatively described in terms of the demographic parameter termed "evolutionary entropy", a measure of the variability in the age at which individuals produce offspring and die. The two articles also validate certain predictions of directionality theory, an evolutionary model that integrates demography and ecology with population genetics. In particular, directionality theory predicts that in populations that spend the greater part of their life cycle in the stationary growth phase, evolution will result in an increase in entropy. These species will be described by a late age of sexual maturity, small progeny sets and a broad reproductive time-span. In populations that undergo large fluctuations in size, however, the evolutionary outcome will be different. When the average size is large, evolution will result in a decrease in entropy-these populations will be described by early age of sexual maturity, large numbers of offspring and narrow reproductive span but when the average size is small, the evolutionary outcome will be random and non-directional.

Age Factors↗

Erotomanic stalking in evolutionary perspective.

Erotomania, the delusion of being loved by another person, comprises marked sex differences concerning prevalence rates and behavior. Whereas traditional psychiatry has considered erotomania to be almost entirely restricted to women, recent studies have revealed that criminal offenses associated with the condition occur much more frequently in men. The main hypothesis of this article is that these findings may be explained in terms of evolutionary theory. Erotomania, accordingly, may be viewed as a pathological variant of a specific sexual strategy that evolved under selection pressures of the human environment of evolutionary adaptedness. The overt behavior is related to the pursuit of long-term mating, its potentially beneficial effect on inclusive fitness of the individual, and disparate strategies of the sexes to ensure sexual fidelity of the potential partner. Therefore, the evolutionary approach provides a plausible explanation as to why forensically relevant erotomania prevails in men. The pathological process of delusional misinterpretation of perceived signals from the social environment itself may result from poor reality testing due to a failure of social meta-cognition. The evolutionary perspective may provide additional insights into the nature of sex-specific behaviors and may improve our understanding of forensically relevant behaviors.

Delusions↗

Incorporating pathologists' criteria of malignancy into the evolutionary model for cancer development.

A wide variety of alterations in cell and tissue structure still form the basis for cancer diagnosis by pathologists. Cancer development is recognized to be an evolutionary process [Foulds, 1954; Cairns, 1975; Nowell, 1976; Sager, 1982; Tomlinson et al., 1996; Cahill et al., 1999; Tomlinson and Bodmer, 1999], but the phenotypic changes diagnostic of cancer (pathologists' "criteria of malignancy") have not been integrated into the existing evolutionary framework. Since phenotypic changes bear an important relationship to the genetic and physiologic changes underlying Darwinian evolution, we propose that diagnostic structural alterations also bear an important and predictable relation to both the cancer genes and the functional alterations active at any particular step in the development of a cancer. Cancer genes are predicted to mediate the acquisition of cellular-level diagnostic criteria and the diagnostic cellular-level structural changes should reflect in a useful manner the altered cell physiology required for the cell to achieve increased "cellular fitness" at any particular step of colonal evolution. Tissue-level criteria of malignancy should relate less directly to specific cancer genes, but tissue-level criteria should still provide essential insight into the interplay of the altered cellular fitness with the constraints imposed by the cells' microenvironment. The evolutionary framework allows tissue-level criteria of malignancy to be expressed in terms of viable hypotheses for the mechanism of clonal expansion at any particular step in cancer development. This approach to conveying the tissue-level criteria of malignancy complements pattern recognition approaches to diagnosis, and establishes common ground between pathology and cell biology. When viewed from this perspective, the functions of cancer genes appear quite different from those predicted by the "Gatekeeper, Caretaker" or "Hallmarks of Cancer" models. Finally, a full evolutionary framework incorporating the criteria of malignancy restores congruity between the histogenetic classification and the emerging molecular classification of cancer.

Cell Transformation, Neoplastic↗

The corpus callosum as an evolutionary innovation.

The corpus callosum (CC) is the major interhemispheric fibre bundle in the eutherian brain and has been described as a true evolutionary innovation. This paper reviews the current literature with regard to functional, developmental and genetic concepts that may help elucidate the evolutionary origin of this structure. It has been suggested that the CC arose in the eutherian brain as a more direct and, therefore, more effective system for the interhemispheric integration of topographically organized sensory cortices than the anterior commissure (AC) and hippocampal commissure (HC) already present in nonplacental mammals. It can also be argued, however, that the ability of the CC to integrate the newly evolving motor cortices of placental mammals may have played a role in the evolutionary fixation of this structure. Investigations into the developmental mechanism involved in the formation of the CC and their underlying patterns of gene expression make it possible to formulate a tentative hypothesis about the evolutionary origin of this commissure. This paper suggests that changes in the developmental patterns of the expression of certain regulatory genes may have allowed a first group of callosal pioneering axons to cross the cortical midline. These pioneering fibres may have used the axons of the HC to find their way across the midline. Additional callosal fibres may then have fasciculated with these pioneers. Once the CC had formed in this way, more complex systems of axonal guidance may have evolved over time, thus enabling a gradual increase in the size and complexity of the CC.

Animals↗

Evolutionary identification of a subtype specific functional site in the ligand binding domain of steroid receptors.

Nuclear receptors are ubiquitous eukaryotic ligand-activated transcription factors that modulate gene expression through varied interactions. However, the highly conserved functional sites known today seem insufficient to explain receptor specific recruitment of different coactivator and corepressor proteins and regulation of transcription. To search for new receptor-subtype specific functional sites, we applied difference evolutionary trace (difference ET) analysis to the ligand binding domain of steroid receptors, a subgroup of the nuclear receptor (NR) family. This computational approach identified a new functional site located on a surface opposite to currently known protein-protein interaction sites and distinct from the ligand binding pocket. Strikingly, the literature shows that in vivo variations at residues in the new site are linked to androgen resistance and leukemia, and our own targeted mutations to this site lower but do not eradicate transcriptional activation by estrogen receptor alpha (ERalpha), with reduced ligand binding affinity and SRC-1 interaction. Thus, these data demonstrate that this evolutionary important surface can function as an allosteric site that modulates some but not all receptor binding interactions. Evolutionary analysis further shows that this allosteric regulatory site is shared among all NRs from groups 2 (HNF4-like) and 4 (NGFIB-like), suggesting a role among many nuclear receptors. Its concave structure, hydrophobic composition, and residue variability among nuclear receptors further suggest that it would be amenable for specific drug design. This highlights the power of evolutionary information for the identification of new functional sites even in a protein family as well studied as NRs.

Allosteric Site↗

An evolutionary trace method defines binding surfaces common to protein families.

X-ray or NMR structures of proteins are often derived without their ligands, and even when the structure of a full complex is available, the area of contact that is functionally and energetically significant may be a specialized subset of the geometric interface deduced from the spatial proximity between ligands. Thus, even after a structure is solved, it remains a major theoretical and experimental goal to localize protein functional interfaces and understand the role of their constituent residues. The evolutionary trace method is a systematic, transparent and novel predictive technique that identifies active sites and functional interfaces in proteins with known structure. It is based on the extraction of functionally important residues from sequence conservation patterns in homologous proteins, and on their mapping onto the protein surface to generate clusters identifying functional interfaces. The SH2 and SH3 modular signaling domains and the DNA binding domain of the nuclear hormone receptors provide tests for the accuracy and validity of our method. In each case, the evolutionary trace delineates the functional epitope and identifies residues critical to binding specificity. Based on mutational evolutionary analysis and on the structural homology of protein families, this simple and versatile approach should help focus site-directed mutagenesis studies of structure-function relationships in macromolecules, as well as studies of specificity in molecular recognition. More generally, it provides an evolutionary perspective for judging the functional or structural role of each residue in protein structure.

Amino Acid Sequence↗

George Price's contributions to evolutionary genetics.

George Price studied evolutionary genetics for approximately seven years between 1967 and 1974. During that brief period Price made three lasting contributions to evolutionary theory; these were: (i) the Price Equation, a profound insight into the nature of selection and the basis for the modern theories of kin and group selection; (ii) the theory of games and animal behavior, based on the concept of the evolutionarily stable strategy; and (iii) the modern interpretation of Fisher's fundamental theorem of natural selection, Fisher's theorem being perhaps the most cited and least understood idea in the history of evolutionary genetics. This paper summarizes Price's contributions and briefly outlines why, toward the end of his painful intellectual journey, he chose to focus his deep humanistic feelings and sharp, analytical mind on abstract problems in evolutionary theory.

Animals↗

The evolutionary ecology of dominance-recessivity.

An "adaptive dynamics" modelling approach to the evolution of dominance-recessivity is presented. In this approach, fitness derives from an explicit ecological scenario, and both evolutionary attractivity and invasibility of resident populations are examined. The ecology consists of a within-individual part representing a locus with regulated activity and a between-individual part that is a two-patch soft selection model. Evolutionary freedom is allowed at a single locus. The evolutionary analysis considers directed random walks on trait space, generated by repeated invasions of mutants. The phenotype of an individual is determined by allelic parameters. Mutations can have two effects: they either affect the affinity of the promoter sequence for transcription factors, or they affect the gene product. The dominance interaction between alleles derives from their promoter affinities. Additive genetics is evolutionarily unstable when selection and evolution maintain two alleles in the population. In such a situation, dominance interactions can become stationary and close to additive genetics or they continue to evolve at a very slow pace towards dominance-recessivity. The probability that a specific dominance interaction will evolve depends on the relative mutation rate of promoter compared to gene product and the distribution of mutational effect sizes. Either allele in the dimorphism can become dominant, and dominance-recessivity is always most likely to evolve. Evolution then approaches a population state where every phenotype has maximum viability in one of the two patches. When the within-individual part is replaced by a housekeeping locus that codes for a metabolic enzyme, evolution favours a population of two alleles under the same conditions as for a regulated locus. In the case of a housekeeping gene, however, the evolutionary dynamical system approaches a population state where the heterozygote and only one homozygote phenotype are equivalent to the optimum phenotypes in the two patches.

Alleles↗