Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress‐induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress‐induced mutation that are being revealed experimentally in laboratory settings provide (...) compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double‐strand‐break‐dependent stress‐induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti‐evolvability therapeutics for infectious disease and cancer. (shrink)

The function of meiotic recombination has remained controversial, despite recent inroads into mechanisms. Ideas concerning a possible role of recombination in the elimination or efficient incorporation of mutations have been backed by theoretical studies but have lacked empirical support. Recent investigations into the basis for local variations in recombination frequency in yeast have uncovered a strong association between recombination initiation sites and transcriptional regulatory sequences. Other recent studies indicate a strong correlation between transcription and mutation rates in yeast genes. Taken (...) together, these data imply that distributions of recombination and mutation frequencies may be strongly correlated. This suggests that recombination may be targeted to genomic sites of high mutation frequency; such a ‘mutation‐tracking’ function would clearly aid in the shuffling of mutations to break up unfavorable and create favorable allelic combinations. Moreover, recent insights into the mechanism of gene conversion in yeast reveal a very strong inherent bias in favor of alleles on the non‐initiating homolog. Combined with mutation tracking, these findings suggest a novel and general mechanism by which allelic gene conversion may act to eliminate mutations. (shrink)

We hypothesize that heritable epigenetic changes can affect rates of fitness increase as well as patterns of genotypic and phenotypic change during adaptation. In particular, we suggest that when natural selection acts on pure epigenetic variation in addition to genetic variation, populations adapt faster, and adaptive phenotypes can arise before any genetic changes. This may make it difficult to reconcile the timing of adaptive events detected using conventional population genetics tools based on DNA sequence data with environmental drivers of adaptation, (...) such as changes in climate. Epigenetic modifications are frequently associated with somatic cell differentiation, but recently epigenetic changes have been found that can be transmitted over many generations. Here, we show how the interplay of these heritable epigenetic changes with genetic changes can affect adaptive evolution, and how epigenetic changes affect the signature of selection in the genetic record. (shrink)

Genomic imprinting is an epigenetic mechanism resulting in the preferential expression of the maternal or paternal alleles of a specific subset of genes in the mammalian genome. A key but relatively unexplored question is how imprints are established in the germline. New observations(1) on two classical imprinting disorders, the Prader‐Willi (PWS) and Angleman (AS) syndromes, offer the first genetic insight into this process. Molecular analysis of imprinting mutations that interfere with the appropriate establishment of the maternal and paternal epigenotypes (...) has led to the identification of imprinted transcripts that could be involved in switching imprints in the germlines. (shrink)

One central tenet of the Modern Evolutionary Synthesis , and the consensus view among biologists until now, is that all genetic mutations occur by “chance” or at “random” with respect to adaptation. However, the discovery of some molecular mechanisms enhancing mutation rate in response to environmental conditions has given rise to discussions among biologists, historians and philosophers of biology about the “chance” vs “directed” character of mutations . In fact, some argue that mutations due to a particular kind of (...) class='Hi'>mutator mechanisms challenge the Modern Synthesis because they are produced when and where needed by the organisms concerned. This paper provides a defense of the Modern Synthesis’ consensus view about the chance nature of all genetic mutations by reacting to Jablonka and Lamb’s analysis of genetic mutations and the explicit Lamarckian flavor of their arguments. I argue that biologists can continue to talk about chance mutations according to what I call and define as the notion of “evolutionary chance,” which I claim is the Modern Synthesis’ consensus view and a reformulation of Darwin’s most influential idea of “chance” variation. Advances in molecular genetics are therefore significant but not revolutionary with respect to the Modern Synthesis’ paradigm. (shrink)

Presenilin‐1 (PS1) is thought to regulate cell differentiation and survival by modulating the Notch signaling pathway. Mutations in PS1 have been shown to cause early‐onset inherited forms of Alzheimer's disease (AD) by a gain‐of‐function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid β‐peptide. The present article considers a second pathogenic mode of action of PS1 mutations, a defect in cellular calcium signaling characterized by overfilling of endoplasmic reticulum (...) (ER) calcium stores and altered capacitive calcium entry; this abnormality may impair synaptic plasticity and sensitize neurons to apoptosis and excitotoxicity. The calcium signaling defect has also been documented in lymphocytes, suggesting a contribution of immune dysfunction to the pathogenesis of AD. A better understanding of the calcium signaling defect resulting from PS1 mutations may lead to the development of novel preventative and therapeutic strategies for disorders of the nervous and immune systems. BioEssays 23:733–744, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Information about the structure, function and regulation of the maize Suppressormutator (Spm) transposable element has emerged from the genetic and molecular characterization of both deletion mutations and an unconventional type of reversible genetic change (epimutation). The element is subject to an epigenetic mechanism that can either stably inactivate it or specify one of a variety of heritable programs of differential element expression in development. The essay explores the relationship between the Spm element's epigenetic developmental programming mechanism and the (...) determinative events central to plant development and differentiation. (shrink)

The recently developed CRISPR-Cas9 gene editing technology is transforming basic biomedical research, but it also may have therapeutic applications. This essay examines how the technology works, its possible applications in somatic and germline cell therapy, and the use of gene drives to control disease vectors like mosquito-borne illnesses. While potentially valuable, all of these applications present ethical problems, including the specific risks of unintentional mutations; pre-existing concerns over the relationship between biomedical technology, power, and procreation; and CRISPR’s unintended consequences for (...) the environment. (shrink)

A widely accepted tenet of evolutionary biology is that spontaneous mutations occur randomly with regard to their fitness effect. However, since the mutation rate varies along a genome and this variation can be subject to selection, organisms might evolve lower mutation rates at loci where mutations are most deleterious or increased rates where mutations are most needed. In fact, mechanisms of targeted hypermutation are known in organisms ranging from bacteria to humans. Here we review the main forces driving the evolution (...) of local mutation rates and identify the main limiting factors. Both targeted hyper‐ and hypomutation can evolve, although the former is restricted to loci under very frequent positive selection and the latter is severely limited by genetic drift. Nevertheless, we show how an association of repair with transcription or chromatin‐associated proteins could overcome the drift limit and lead to non‐random hypomutation along the genome in most organisms.Editor's suggested further reading in BioEssays Stress‐induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine Abstract. (shrink)

Biological mimicry is regarded by many as a textbook illustration of Darwin’s idea of evolution by random mutation followed by differential selection of reproductively fit specimens, resulting in gradual phenotypic change in a population. In this paper, I argue that some cases of so-called mimicry are probably merely look-a-likes and do not gain an advantage due to their similarity in appearance to something else. In cases where a similar appearance does provide a benefit, I argue that it is possible that (...) these forms of mimicry were created in a single generation. An interpretive response to an appearance as a sign can make a new structure perform drastically differently in an environment. In such cases, Darwin’s natural selection mechanism only helps to explain gradual the spread of these new forms, not the creation of them. I argue that biosemiosis should be regarded as a much more powerful mechanism for affecting evolutionary trajectories than the gradualist view allows. I focus on two cases of butterfly mimicry: the Viceroy (Nymphalidae: Limenitis archippus) and Monarch (Nymphalidae: Danaus plexippus) butterflies, supposed Müllerian mimics, and deadleaf mimic butterflies (Kallima). (shrink)

De Vries' mutation theory has not stood the test of time. The supposed mutations of Oenothera were in reality complex recombination phenomena, ultimately explicable in Mendelian terms, while instances of large-scale mutations were found wanting in other species. By 1915 the mutation theory had begun to lose its grip on the biological community; by de Vries' death in 1935 it was almost completely abandoned. Yet, as we have seen, during the first decade of the present century it achieved an enormous (...) popularity. As this paper has tried to suggest, one of the principal reasons for this was that de Vries' theory served as a banner around which a whole crowd of disaffected Darwinians or anti-Darwinians could rally. However, not all of those who favored de Vries did so for quite the same reasons. Underlying the multitude of views ran several common threads: a dissatisfaction with current Darwinian theory born out of misunderstanding natural selection, a general misunderstanding of the nature of species, and a prejudice against speculative, nontestable theories in biology.Supporters of de Vries were not the only opponents of Darwinism, nor was the mutation theory the only alternative to natural selection. In the early twentieth century a number of theories had been proposed to explain away the problems which Darwin had left unsolved. There was the idea of orthogenesis, championed by the American paleontologists Cope, Osborn and others; organic selection (or orthoplasy) was championed by M. M. Baldwin and C. Lloyd Morgan; there were the concepts of convergent evolution proposed by Hermann Friedmann, the theory of physiological selection by John George Romanes, and the concepts of reproductive divergence by H. M. Vernon. Virtually none of these men either accepted or were strong supporters of the de Vriesian theory, for each had his own particular ‘ism” to advocate as the major factor in evolution. The existence of a large number of such theories, each purporting to be the explanation, was characteristic of evolutionary theory at the turn of the century. It is to a large extent the emphasis on such fragmentary concepts that retarded development of the comprehensive theory of evolution which emerged in the 1920's and 1930's. For the historian, however, a study of these alternative theories is instructive in trying to understand the inherent difficulties which Dawwinian theory posed to biologists at the time. De Vries' mutation theory serves historically as a mirror to reflect the critical mood of a generation hostile to the theory of natural selection.It has often been claimed that it was impossible to understand the mechanism of natural selection until it could be placed in genetic and mathematical terms. It is certainly true that great strides have been made in population genetics and the treatment of evolutionary concepts with mathematical tools in the last forty years. But the very people who developed the genetical and mathematical approach to evolution were already convinced of the essential correctness of Darwinian theory before they started. Advances in an understanding of Mendelian heredity aided greatly in solving one important issue for evolutionists: the origin of variations. And the rigor with which selection acted could best be studied by observing changes in gene frequencies (calculated mathematically) over a number of generations. But as this paper has shown, two of the basic problems which biologists faced in evaluating Darwinian theory at the turn of the century-the nature of species, and the criteria of what constituted an acceptable explanation in biological science-could not be answered directly by mathematics. What mathematical and genetical theory did do was to help convince the skeptics of the validity of the Darwinian proposition.The change in explanatory criteria which many hailed as de Vries' most important contribution to evolutionary theory seems to have been part of a general emergence of twentieth-century biology from the domination of theorizers in the nineteenth. It also marked the emergence of America from the domination of biological, and particularly evolutionary, influence of Europeans. The change occurred in three areas: in the kinds of questions asked: testable versus non-testable; in the kind of data sought: quantitative versus qualitative; and in the kinds of theories proposed: analytical and reductive—the attempt to see complex processes in terms of simpler components-as opposed to synthetic and speculative. Although ultimately wrong in his idea, de Vries and his theories rode high on the wave of “experimentalism” which was the harbinger of a new era in evolutionary theory. (shrink)

There is growing evidence that mutations can arise in non‐dividing cells (both bacterial and mammalian) in the absence of chromosomal replication. The processes that are involved are still largely unknown but may include two separate mechanisms. In the first, DNA lesions resulting from the action of endogenous mutagens may give rise to RNA transcripts with miscoded bases. If these confer the ability to initiate DNA replication, the DNA lesions may have an opportunity to miscode during replication and thus could give (...) rise to apparently ‘adaptive’ mutations. A second mechanism is suggested by recent work in starved bacteria, showing that there is much more turnover of chromosomal DNA than has been previously thought. This could permit polymerase errors to lead to mutations in non‐dividing cells. Such cryptic DNA synthesis, which may essentially replace existing DNA rather than duplicating it, could, in principle, act as an additional source of variability on which selection may act, initially in the absence of cell division. In mammals such processes would undoubtedly have implications for germ cell mutagenesis and carcinogenesis. (shrink)

Ageing is a complex phenomenon which remains a major challenge to modern biology. Although the evolutionary biology of ageing is well understood, the mechanisms that limit lifespan are unknown. The isolation and analysis of single‐gene mutations which extend lifespan (Age mutations) is likely to reveal processes which influence ageing. Caenorhabditis elegans is the only metazoan in which Age mutations have been identified. The Age mutations not only prolong life, but also confer a complex array of other phenotypes. Some of these (...) phenotypes provide clues to the evolutionary origins of these genes while others allude to mechanisms of lifespan‐extension. Many of the Age genes interact and share a second common phenotype, that of stress resistance. Rather than invertebrate ageing being determined by a ‘clock mechanism’, a picture is emerging of ageing as a non‐adaptive process determined, in part, by resistance to intrinsic stress mediated by stress‐response genes. (shrink)

Receptor oligomerization plays a key role in maintaining genome stability and restricting protein mutagenesis. When properly folded, protein monomers assemble as oligomeric receptors and interact with environmental ligands. In a gene-centered view, the ligand specificity expressed by these receptors is assumed to be causally predetermined by the cell genome. However, this mechanism does not fully explain how differentiated cells have come to express specific receptor repertoires and which combinatorial codes have been explored to activate their associated signaling pathways. It (...) is our contention that the plasma membrane acts as the locus where several contextual cues may be integrated. As such it allows the semiotic selection of those receptor configurations that provide cells with the minimum essential requirements for agency. The occurrence of protein misfolding makes it impossible for receptor monomers to assemble along the membrane and to sustain meaningful relationships with environmental ligands. How could a cell lineage deal with these loss-of-function mutations during evolution and restrain gene redundancy accordingly? In this paper, we will be arguing that the easiest way for bacteria clones to accomplish this goal is by getting rid of cells expressing mutated receptor proteins. The mechanism sustaining this cell selection is also occurring in many somatic tissues and its function is currently believed to counteract in vivo protein mutagenesis. Our discussion will be mainly focused on the significance and semiotic nature of the interplay between membrane receptors and the epigenetic control of gene expression, as mediated by the control of mismatched repairing and protein folding mechanisms. (shrink)

The evolution of sex in eukaryotes represents a paradox, given the “twofold” fitness cost it incurs. We hypothesize that the mutational dynamics of the mitochondrial genome would have favored the evolution of sexual reproduction. Mitochondrial DNA (mtDNA) exhibits a high‐mutation rate across most eukaryote taxa, and several lines of evidence suggest that this high rate is an ancestral character. This seems inexplicable given that mtDNA‐encoded genes underlie the expression of life's most salient functions, including energy conversion. We propose that negative (...) metabolic effects linked to mitochondrial mutation accumulation would have invoked selection for sexual recombination between divergent host nuclear genomes in early eukaryote lineages. This would provide a mechanism by which recombinant host genotypes could be rapidly shuffled and screened for the presence of compensatory modifiers that offset mtDNA‐induced harm. Under this hypothesis, recombination provides the genetic variation necessary for compensatory nuclear coadaptation to keep pace with mitochondrial mutation accumulation. (shrink)

Le dysfonctionnement, la défectuosité et les erreurs sont des phénomènes qui peuvent aider à mieux comprendre les entités affectées par ces incidents. L’analyse approfondie du fonctionnement et du dysfonctionnement facilite en particulier la découverte, l’explication et la modélisation théorique des structures, fonctions et mécanismes propres à un système. Dans certains cas, les dysfonctionnements sont le seul moyen d’accéder aux processus internes d’un certain système. Le présent essai analyse les méthodes de diverses disciplines tenant compte de dysfonctionnements tels que les mutations, (...) les illusions optiques, les erreurs d’action ou les lapsus linguistiques et identifie les motifs communs aux stratégies de recherche basées sur le dysfonctionnement. Ces stratégies contribuent à la décomposition de systèmes, à la reconstruction de séquences d’événements, à la localisation de sous-systèmes, ainsi qu’au développement et au test d’hypothèses mécanistes. (shrink)

Abstract“Selfish” gene theories have offered invaluable insight into eukaryotic genome evolution, but they can also be misleading. The “selfish mitochondrion” hypothesis, developed in the 90s explained uniparental organelle inheritance as a mechanism of conflict resolution, improving cooperation between genetically distinct compartments of the cell. But modern population genetic models provided a more general explanation for uniparental inheritance based on mutational variance redistribution, modulating the efficiency of both purifying and adaptive selection. Nevertheless, as reviewed here, “selfish” conflict theories still dominate (...) the literature. While these hypotheses are rich in metaphor and highly intuitive, selective focus on only one type of mitochondrial mutation limits the generality of our understanding and hinders progress in mito‐nuclear evolution theory. Recognizing that uniparental inheritance may have evolved—and is maintained across the eukaryotic tree of life—because of its influence on mutational variance and improved selection will only increase the generality of our evolutionary reasoning, retaining “selfish” conflict explanations as a special case of a much broader theory. (shrink)

The highly structured mechanisms of cancers, their tendency to occur as a response to environmental stress, and the existence of oncogenes, suggest that neoplasticity may represent more than a biological disfunction. It is proposed that cancer exists as a phylogenetic mechanism serving to promote hyperevolution, albeit at the expense of the ontogeny, that is similar to a process recently discovered in bacterial mutations. Cell-surface-associated nucleic acid in tumorigenic cells and sperm cell vectorization of foreign DNA indicate the existence of (...) essential mechanisms necessary to the occurrence of cancer mediated hyperevolution. An analysis of the proposed mechanism indicates that for mutagenesis of chemical cytology, stress induced neoplasticity confers an evolutionary advantage of more than two orders of magnitude. (shrink)

Le dysfonctionnement, la défectuosité et les erreurs sont des phénomènes qui peuvent aider à mieux comprendre les entités affectées par ces incidents. L’analyse approfondie du fonctionnement et du dysfonctionnement facilite en particulier la découverte, l’explication et la modélisation théorique des structures, fonctions et mécanismes propres à un système. Dans certains cas, les dysfonctionnements sont le seul moyen d’accéder aux processus internes d’un certain système. Le présent essai analyse les méthodes de diverses disciplines tenant compte de dysfonctionnements tels que les mutations, (...) les illusions optiques, les erreurs d’action ou les lapsus linguistiques et identifie les motifs communs aux stratégies de recherche basées sur le dysfonctionnement. Ces stratégies contribuent à la décomposition de systèmes, à la reconstruction de séquences d’événements, à la localisation de sous-systèmes, ainsi qu’au développement et au test d’hypothèses mécanistes. (shrink)

The existing numerous adaptive variants of differential evolution have been improved the search ability of classic DE to certain extent. Nevertheless, those variants of DE do not obtain the promising performance in solving black box problems with unknown features, which is mainly because the adaptive rules of those variants are designed according to their designers’ cognition on the problem features. To enhance the optimization ability of DE in optimizing black box problems with unknown features, a differential evolution with autonomous selection (...) of mutation strategies and control parameters is proposed in this paper, inspired by autonomous decision-making mechanism of reinforcement learning. In ASDE, a historical experience archive with population features is utilized to preserve accumulated historical experience of the combination of mutation strategies and control parameters. Furthermore, the accumulated historical experience can be autonomously mapped into rules repository, and the individuals can choose the combination of mutation strategies and control parameters according to those rules. Additionally, an updating and utilization mechanism of the historical experience is designed to assure that the historical experience can be effectively accumulated and utilized efficiently. Compared with some state-of-the-art intelligence algorithms on 15 functions of CEC2015, 28 functions of CEC2017, and parameter extraction problems of the photovoltaic model, ASDE has the advantages of solution accuracy, convergence speed, and robustness in solving black box problems with unknown features. (shrink)

The conventional approach to developing disease‐modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic driver (...) of age‐of‐onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals. (shrink)

Diploid germ cells produce haploid gametes through meiosis, a unique type of cell division. Independent reassortment of parental chromosomes and their recombination leads to ample genetic variability among the gametes. Importantly, new mutations also occur during meiosis, at frequencies much higher than during the mitotic cell cycles. These meiotic mutations are associated with genetic recombination and depend on double‐strand breaks (DSBs) that initiate crossing over. Indeed, sequence variation among related strains is greater around recombination hotspots than elsewhere in the genome, (...) presumably resulting from recombination‐associated mutations. Significantly, enhanced mutagenicity in meiosis may lead to faster divergence during evolution, as germ‐line mutations are the ones that are transmitted to the progeny and thus have an evolutionary impact. The molecular basis for mutagenicity in meiosis may be related to the repair of meiotic DSBs by polymerases, or to the exposure of single‐strand DNA to mutagenic agents during its repair. (shrink)

The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with (...) KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. (shrink)

In order to solve the shortcomings of particle swarm optimization in solving multiobjective optimization problems, an improved multiobjective particle swarm optimization algorithm is proposed. In this study, the competitive strategy was introduced into the construction process of Pareto external archives to speed up the search process of nondominated solutions, thereby increasing the speed of the establishment of Pareto external archives. In addition, the descending order of crowding distance method is used to limit the size of external archives and dynamically adjust (...) particle parameters; in order to solve the problem of insufficient population diversity in the later stage of algorithm iteration, time-varying Gaussian mutation strategy is used to mutate the particles in external archives to improve diversity. The simulation experiment results show that the improved algorithm has better convergence and stability than the other compared algorithms. (shrink)

Trinucleotide repeat expansions are now a well‐established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar musclar atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome breakage (...) can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG‐rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3′ untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed. (shrink)

The Origin of Human Nature offers an original and fertile way to integrate spiritual and scientific views of human evolution. It offers a new and refreshing alternative to the way we think about our origins - random mutation (mechanistic neo-Darwinism), Genesis (God did it all personally), and Intelligent Design (God personally does what we can't otherwise account for). The result is an invigorating perspective on how our best qualities - our capacity for love, our appreciation of beauty, our altruistic capability, (...) our creativity and our intelligence - have come into being and evolved. By showing evolution as a creative and intelligent process with its own inherent logic, The Origin of Human Nature resolves the dilemma of how to have both truth and ethics at the same time. Instead of starting in an imagined remote and uncertain past and moving to the present, this book starts at the certain and immediate present and works back. That consciousness, creativity, and intelligence exist is certain. The question is, how can these have evolved? Dr. Albert Low has made a study of human nature throughout his life. In writing this book, he draws on his prolonged meditations on creativity and the human condition, his years of providing psychological and spiritual counseling, and a wide-ranging knowledge of Western psychology, philosophy, and science. He takes issue with Richard Dawkins' published texts, and provides a point-by-point rebuttal of the neo-Darwinist argument. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and inversions (...) of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

Mutations in enhancer‐associated chromatin‐modifying components and genomic alterations in non‐coding regions of the genome occur frequently in cancer, and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin‐modifying factors might affect enhancer activity of disease‐relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions, or deletions but also larger genomic rearrangements such as duplications, deletions, translocations, and inversions (...) of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer‐regulated and disease‐relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues. (shrink)

A mechanism for the generation of the morphological left‐right asymmetry in higher organisms is proposed, based on the idea that chirality at the molecular level is the primordial source for macroscopic asymmetry. This mechanism accounts for a variety of experimental results on artificial production of situs inversus and fits well with mutations in mice causing visceral transposition.

Adaptive phenotypic plasticity allows organisms to cope with environmental variability, and yet, despite its adaptive significance, phenotypic plasticity is neither ubiquitous nor infinite. In this review, we merge developmental and population genetic perspectives to explore costs and limits on the evolution of plasticity. Specifically, we focus on the role of modularity in developmental genetic networks as a mechanism underlying phenotypic plasticity, and apply to it lessons learned from population genetic theory on the interplay between relaxed selection and mutation accumulation. (...) We argue that the environmental specificity of gene expression and the associated reduction in pleiotropic constraints drive a fundamental tradeoff between the range of plasticity that can be accommodated and mutation accumulation in alternative developmental networks. This tradeoff has broad implications for understanding the origin and maintenance of plasticity and may contribute to a better understanding of the role of plasticity in the origin, diversification, and loss of phenotypic diversity. (shrink)

Mutational robustness facilitates evolutionary innovations. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation is thus a special case of a general mechanism linking innovation to robustness. The potential power of this mechanism to promote evolutionary innovations on large time scales is illustrated here with several examples. These include the role of gene duplications in the vertebrate radiation, flowering plant evolution and (...) heart development, which encompass some of the most striking innovations in the evolution of life. BioEssays 30:367–373, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

This article describes how empirical discoveries in the 1930s–1950s regarding population variation for chromosomal inversions affected Theodosius Dobzhansky and Richard Goldschmidt. A significant fraction of the empirical work I discuss was done by Dobzhansky and his coworkers; Goldschmidt was an astute interpreter, with strong and unusual commitments. I argue that both belong to a mechanistic tradition in genetics, concerned with the effects of chromosomal organization and systems on the inheritance patterns of species. Their different trajectories illustrate how scientists’ commitments affect (...) how they interpret new evidence and adjust to it. Dobzhansky was moved to revised views about selection, while Goldschmidt moved his attention to different genetic phenomena. However different, there are significant connections between the two that enrich our understanding of their views. I focus on two: the role of developmental considerations in Dobzhansky’s thought and the role of neutrality and drift in Goldschmidt’s evolutionary account. Dobzhansky’s struggle with chromosomal variation is not solely about competing schools of thought within the selectionist camp, as insightfully articulated by John Beatty, but also a story of competition between selectionist thinking and developmental perspectives. In contraposition, Goldschmidt emphasized the role of low penetrance mutations that spread neutrally and pointed out that drift could result from developmental canalization. This account adds to the dominant story about Goldschmidt’s resistance to the splitting of development from genetics, as told by Garland Allen and Michael Dietrich. The story I tell illustrates how developmental thinking and genetic thinking conflicted and influenced researchers with different convictions about the significance of chromosomal organization. (shrink)

Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro‐environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity of mechanistic target of rapamycin complex 2 (...) (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies. (shrink)

The mutations that cause many forms of inherited retinal degenerations have been identified, yet the mechanisms by which these mutations lead to death of photoreceptor cells of the retina are not completely understood. Investigations of the pathways from mutation to retinal degeneration have focused on spontaneous and engineered animal models of disease. Based on the studies performed to date, four major categories of degeneration mechanism can be identified. These include disruption of photoreceptor outer segment morphogenesis, metabolic overload, dysfunction of (...) retinal pigment epithelial cells, and chronic activation of phototransduction. Future investigations will likely identify additional mechanisms of photoreceptor damage. This review will summarize what has been learned from studying animal models of non-syndromic inherited retinal degenerations. BioEssays 23:605–618, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Mutations in the daf-2 and age-1 genes cause constitutive dauer larva formation and double adult life span in C. elegans. Their effect on life span has excited considerable interest and their effect on dauer formation has facilitated rapid progress in their genetic and molecular analysis. Two recent papers12,13 report that daf-2 encodes a member of the insulin-receptor family and that age-1 encodes a PI3 kinase subunit, a second-messenger producing enzyme known to act downstream of the mammalian insulin receptor. These findings (...) provide the first mechanistic insight into the well-established link between metabolism and aging. BioEssays 20:113–115, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Phylogenetically controlled studies across multiple species correct for taxonomic confounds in physiological performance traits. Therefore, they are preferred over comparisons of two or few closely‐related species. Funding bodies, referees and journal editors nowadays often even reject to consider detailed comparisons of two or few closely related species. Here, we plea for a less dogmatic stance on such comparisons, because phylogenetic studies come with their own limitations similar in magnitude as those of two‐species comparisons. Two‐species comparisons are particularly relevant and instructive (...) for understanding physiological pathways and de novo mutations in three contexts: in a purely mechanistic context, when differences in the regulation of a trait are the focus of investigation, when a physiological trait lacks a direct connection to fitness, and when physiological measures cannot easily be standardized among laboratories. In conclusion, phylogenetic comparative and two‐species studies have different strengths and weaknesses and combining these complementary approaches will help integrating biology. (shrink)

Graphical AbstractTo mechanistically understand the dynamics of complex ecosystems, Yize Chen et al. employ symbolic regression (SR), a machine learning method that automatically reverse-engineers both model structure and parameters from temporal data. SR randomly assembles candidate models, computes the model fitness, and employs mutation and crossover to build better ones. The Pareto front reflects the trade-off between complexity and fitness of candidate models. More details can be found in article number 1900069 by Yize Chen et al.

While its mechanism and biological significance are unknown, the utility of a short mitochondrial DNA sequence as a “barcode” providing accurate species identification has revolutionized the classification of organisms. Since highest accuracy was achieved with recently diverged species, hopes were raised that barcodes would throw light on the speciation process. Indeed, a failure of a maternally donated, rapidly mutating, mitochondrial genome to coadapt its gene products with those of a paternally donated nuclear genome could result in developmental failure, thus (...) creating a post-zygotic barrier leading to reproductive isolation and sympatric branching into independent species. However, the barcode itself encodes a highly conserved, species-invariant, protein, and the discriminatory power resides in the non-amino acid specific bases of synonymous codons. It is here shown how the latter could register changes in the oligonucleotide frequencies of nuclear DNA that, when they fail to match in pairing meiotic chromosomes, could reproductively isolate the parents so launching a primary divergence into two species. It is proposed that, while not itself contributing to speciation, the barcode sequence provides an index of the nuclear DNA oligonucleotide frequencies that drive speciation. (shrink)

Within a physicalist-mechanistic worldview, in which we cannot be more than intelligent, self-reproducing biomachines or biobots, fundamentals of a new approach to the science of human self-explanation are outlined. Some a priori logical necessities, or determinants, of any biobot’s control system design are recognized. Evolution had to satisfy them, but neuroscience and cognitive science so far do not clearly see these basics. It is concluded that the old part of the brain still contains the genetically fixed drives, responses, and the (...) physiological control. Here is the seat of an ancient somatic self that is not intelligent but is still the active center of our life. The neocortex has evolved to serve the somatic self with intelligence by individually building a virtual model of the external material and social world. This model is used by the somatic self to “pre-play” intended actions and responses to see whether they would satisfy its needs. This schema of global brain function provides the neurological foundation for the ego-id dichotomy in analytic psychology, as well as some critique of it. Following the groundbreaking experiments by Benjamin Libet and John-Dylan Haynes et al. , consciousness is taken as a “theater” that presents what the neural networks already have worked out, and freedom of the will is limited. The explosive growth of culture and civilization began when neocortical power exceeded a certain threshold. This can be taken as a quasi-mutation that projected us into a supra-biological space of existence that is new to natural history. It is not clear whether this event will lead to a positive future for humanity or to doom. Functional religion is seen as a neurosystemic attempt to bring back the earlier natural state. Thus, it can be valuable when cleared of mythological ballast. (shrink)

Christopher Boorse’s biostatistical theory of medical disorder claims that biological part-dysfunction (i.e., failure of an internal mechanism to perform its biological function), a factual criterion, is both necessary and sufficient for disorder. Jerome Wakefield’s harmful dysfunction analysis of medical disorder agrees that part-dysfunction is necessary but rejects the sufficiency claim, maintaining that disorder also requires that the part-dysfunction causes harm to the individual, a value criterion. In this paper, I present two considerations against the sufficiency claim. First, I analyze (...) Boorse’s central argument for the sufficiency claim, the “pathologist argument,” which takes pathologists’ intuitions about pathology as determinative of medical disorder and conclude that it begs the question and fails to support the sufficiency claim. Second, I present four counterexamples from the medical literature in which salient part-dysfunctions are considered nondisorders, including healthy disease carriers, HIV-positive status, benign mutations, and situs inversus totalis, thus falsifying the sufficiency claim and supporting the harm criterion. (shrink)

The drive to describe cultural history as an evolutionary process has two sources. One from within social theory is part of the impetus to convert social studies into "social sciences" providing them with the status accorded to the natural sciences. The other comes from within biology and biological anthropology in the belief that the theory of evolution must be universal in its application to all functions of all living organisms. The social scientific theory of cultural evolution is pre-Darwinian, employing a (...) developmental model of unfolding characterized by intrinsic directionality, by definable stages that succeed each other and by some criterion of progress. It is arbitrary in its definitions of progress and has had the political problem that a diachronic claim of cultural progress implies a synchronic differential valuation of present-day cultures. The biological scheme creates an isomorphism between the Darwinian mechanism of evolution and cultural history, postulating rules of cultural "mutation", cultural inheritance and some mechanism of natural selection among cultural alternatives. It uses simplistic ad hoc notions of individual acculturation and of the differential survival and reproduction of cultural elements. It is unclear what useful work is done by substituting the metaphor of evolution for history. (shrink)

The mammalian placenta exhibits elevated expression of endogenous retroviruses (ERVs), but the evolutionary significance of this feature remains unclear. I propose that ERV‐mediated regulatory evolution was, and continues to be, an important mechanism underlying the evolution of placental development. Many recent studies have focused on the co‐option of ERV‐derived genes for specific functional adaptations in the placenta. However, the co‐option of ERV‐derived regulatory elements could potentially lead to the incorporation of entire gene regulatory networks, which, I argue, would facilitate (...) relatively rapid developmental evolution of the placenta. I suggest a model in which an ancient retroviral infection led to the establishment of the ancestral placental developmental gene network through the co‐option of ERV‐derived regulatory elements. Consequently, placental development would require elevated tolerance to ERV activity. This in turn would expose a continuous stream of novel ERV mutations that may have catalyzed the developmental diversification of the mammalian placenta. (shrink)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the biogenesis (...) of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

Over recent years, evidence has been accumulating in favour of the free radical theory of aging, first proposed by Harman. Despite this, an understanding of the mechanism by which cells might succumb to the effects of free radicals has proved elusive. This paper proposes such a mechanism, based on a previously unexplored hypothesis for the proliferation of mutant mitochondrial DNA: that mitochondria with reduced respiratory function, due to a mutation or deletion affecting the respiratory chain, suffer less frequent (...) lysosomal degradation, because they inflict free radical damage more slowly on their own membranes. Once such a mutation occurs in a mitochondrion of a non‐dividing cell, therefore, mitochondria carrying it will rapidly populate that cell, thereby destroying the cell's respiratory capability. The accumulation of cells that have undergone this transition results in aging at the organismal level. The consistency of the hypothesis with known facts is discussed, and technically feasible tests are suggested, of both the proposed mechanism and its overall contribution to mammalian aging. (shrink)

Comparative biological morphology with the study of active reaction is contrasted with Genetics as the study of passive mutation. The students of Genetics investigate anatomical characters only, never anatomical constructions, which are capable of reorganisation when the biological-morphological equilibrium of the organism has been disturbed. The biological anatomy ofOpisthocomus cristatus andStringops habroptilus shows, that three successive disturbances in the bio-morphological equilibrium are reacted to purposively by anatomical re-construction. These reactions are no accidental mutations, but are anatomical reactions, related to, and (...) affecting, the organism as a whole. — In sharp contrast to anatomical reaction, resulting, during phylogeny, in a re-organisation, is the “technics” of individual development. The hereditary process is, like every physiological or embryological process, a fixed mechanism, which remains constant till an active reaction leads to re-construction and at the same time an appropriate change of the mechanisms. The re-moulding of species is no passive, “technical” process, but a creative act of the organisms themselves.A la science de l'hérédité, comme science de la mutation passive, on oppose la morphologie biologique comparé avec la doctrine de la réaction active. Les génétistes n'examinent en général que les symptômes anatomiques, jamais les constructions anatomiques capables d'être transformées, lorsque les organismes sont troublés dans leur équilibre bio-morphologique. L'anatomie biologique de l'Opisthocomus cristatus et duStringops habroptilus montre, qu'à des troubles trois fois répétés de léquilibre biomorphologique répondent, de façon significative, des transformations anatomiques. Ces réponses ne sont pas des transformations dues au hasard, mais des réactions anatomiques se rapportant à l'organisme entier. — A la réaction anatomique produisant une transformation au cours de la phylogénèse s'oppose nettement la technique du développement individuel. Le processus héréditaire constitute, comme tout processus physiologique et embryologique, un mécanisme déterminé, qui reste constant jusqu'à ce qu'une réaction active amène une transformation et change ainsi le mécanisme de façon appropriée. La transformation de l'espèce n'est pas un processus passif et technique, mais un acte créatif des organismes eux-mêmes. (shrink)

During the 1920s and 1930s, many biologists questioned the viability of Darwin’s theory as a mechanism of evolutionary change. In the early 1940s, and only after a number of alternatives were suggested, Darwinists succeeded to establish natural selection and gene mutation as the main evolutionary mechanisms. While that move, today known as the neo-Darwinian synthesis, is taken as signalling a triumph of evolutionary theory, certain critical problems in evolution—in particular the evolution of animal function—could not be addressed with this (...) approach. Here I demonstrate this through reconstruction of the evolutionary theory of Joseph Needham (1900–1995), who pioneered the biochemical study of evolution and development. In order to address such problems, Needham employed Herbert Spencer’s principles of emergence and Ernst Haeckel’s theory of recapitulation. While Needham did not reject Darwinian theory, Spencerian and Haeckelian frameworks happened to better fit his findings and their evolutionary relevance. He believed selectionist and genetic approaches to be important but far from sufficient for explaining how evolutionary transformations occur. (shrink)

Comparative biological morphology, incorporating the study of active reaction, is contrasted with genetics as the study of passive mutation. Geneticists investigate anatomical characters, never anatomical constructions, which are capable of reorganization when the biological-morphological equilibrium of the organism has been disturbed. The anatomy of Opisthocomus cristatus and Stringops habroptilus demonstrate that three successive disturbances in the bio-morphological equilibrium are reacted to purposively by anatomical reconstruction. These reactions are no accidental mutations, but are anatomical reactions, related to, and affecting, the organism (...) as a whole. In sharp contrast to such anatomical reaction, resulting, during phylogeny, in reorganization, are the “technics” [i.e., mechanistic bases] of individual development. The hereditary process is, like every physiological or embryological process, a fixed mechanism, which remains constant until an active reaction leads to reconstruction and at the same time an appropriate change of the mechanisms. The remolding of species is therefore no passive, “technical” process, but a creative act of the organisms themselves. [Original English abstract; not translated.]. (shrink)