Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice.

Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.

Structural Basis of Egg Coat-Sperm Recognition at Fertilization.

Recognition between sperm and the egg surface marks the beginning of life in all sexually reproducing organisms. This fundamental biological event depends on the species-specific interaction between rapidly evolving counterpart molecules on the gametes. We report biochemical, crystallographic, and mutational studies of domain repeats 1-3 of invertebrate egg coat protein VERL and their interaction with cognate sperm protein lysin. VERL repeats fold like the functionally essential N-terminal repeat of mammalian sperm receptor ZP2, whose structure is also described here. Whereas sequence-divergent repeat 1 does not bind lysin, repeat 3 binds it non-species specifically via a high-affinity, largely hydrophobic interface. Due to its intermediate binding affinity, repeat 2 selectively interacts with lysin from the same species. Exposure of a highly positively charged surface of VERL-bound lysin suggests that complex formation both disrupts the organization of egg coat filaments and triggers their electrostatic repulsion, thereby opening a hole for sperm penetration and fusion.

Origin and evolution of microvilli.

BACKGROUND INFORMATION: Microvilli are finger-like, straight, and stable cellular protrusions that are filled with F-actin and present a stereotypical length. They are present in a broad range of cell types across the animal tree of life and mediate several fundamental functions, including nutrient absorption, photosensation, and mechanosensation. Therefore, understanding the origin and evolution of microvilli is key to reconstructing the evolution of animal cellular form and function. Here, we review the current state of knowledge on microvilli evolution and perform a bioinformatic survey of the conservation of genes encoding microvillar proteins in animals and their unicellular relatives. RESULTS: We first present a detailed description of mammalian microvilli based on two well-studied examples, the brush border microvilli of enterocytes and the stereocilia of hair cells. We also survey the broader diversity of microvilli and discuss similarities and differences between microvilli and filopodia. Based on our bioinformatic survey coupled with carefully reconstructed molecular phylogenies, we reconstitute the order of evolutionary appearance of microvillar proteins. We document the stepwise evolutionary assembly of the "molecular microvillar toolkit" with notable bursts of innovation at two key nodes: the last common filozoan ancestor (correlated with the evolution of microvilli distinct from filopodia) and the last common choanozoan ancestor (correlated with the emergence of inter-microvillar adhesions). CONCLUSION AND SIGNIFICANCE: We conclude with a scenario for the evolution of microvilli from filopodia-like ancestral structures in unicellular precursors of animals.

Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein.

BACKGROUND: Pontocerebellar hypoplasia (PCH) may present with supratentorial phenotypes and is often accompanied by microcephaly. Damaging mutations in the X-linked gene CASK produce self-limiting microcephaly with PCH in females but are often lethal in males. CASK deficiency leads to early degeneration of cerebellar granule cells but its role in other regions of the brain remains uncertain. METHOD: We generated a conditional Cask knockout mice and deleted Cask ubiquitously after birth at different times. We examined the clinical features in several subjects with damaging mutations clustered in the central part of the CASK protein. We have performed phylogenetic analysis and RT-PCR to assess the splicing pattern within the same protein region and performed in silico structural analysis to examine the effect of splicing on the CASK's structure. RESULT: We demonstrate that deletion of murine Cask after adulthood does not affect survival but leads to cerebellar degeneration and ataxia over time. Intriguingly, damaging hemizygous CASK mutations in boys who display microcephaly and cerebral dysfunction but without PCH are known. These mutations are present in two vertebrate-specific CASK exons. These exons are subject to alternative splicing both in forebrain and hindbrain. Inclusion of these exons differentially affects the molecular structure and hence possibly the function/s of the CASK C-terminus. CONCLUSION: Loss of CASK function disproportionately affects the cerebellum. Clinical data, however, suggest that CASK may have additional vertebrate-specific function/s that play a role in the mammalian forebrain. Thus, CASK has an ancient function shared between invertebrates and vertebrates as well as novel vertebrate-specific function/s.

Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.

BACKGROUND: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse. METHODS: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes. RESULTS: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01). CONCLUSION: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.

Quasi-Equilibrium States and Phase Transitions in Biological Evolution.

We developed a macroscopic description of the evolutionary dynamics by following the temporal dynamics of the total Shannon entropy of sequences, denoted by S, and the average Hamming distance between them, denoted by H. We argue that a biological system can persist in the so-called quasi-equilibrium state for an extended period, characterized by strong correlations between S and H, before undergoing a phase transition to another quasi-equilibrium state. To demonstrate the results, we conducted a statistical analysis of SARS-CoV-2 data from the United Kingdom during the period between March 2020 and December 2023. From a purely theoretical perspective, this allowed us to systematically study various types of phase transitions described by a discontinuous change in the thermodynamic parameters. From a more-practical point of view, the analysis can be used, for example, as an early warning system for pandemics.

Adaptive increases in respiratory capacity and O2 affinity of subsarcolemmal mitochondria from skeletal muscle of high-altitude deer mice.

Aerobic energy demands have led to the evolution of complex mitochondrial reticula in highly oxidative muscles, but the extent to which metabolic challenges can be met with adaptive changes in physiology of specific mitochondrial fractions remains unresolved. We examined mitochondrial mechanisms supporting adaptive increases in aerobic performance in deer mice (Peromyscus maniculatus) adapted to the hypoxic environment at high altitude. High-altitude and low-altitude mice were born and raised in captivity, and exposed as adults to normoxia or hypobaric hypoxia (12 kPa O2 for 6-8 weeks). Subsarcolemmal and intermyofibrillar mitochondria were isolated from the gastrocnemius, and a comprehensive substrate titration protocol was used to examine mitochondrial physiology and O2  kinetics by high-resolution respirometry and fluorometry. High-altitude mice had greater yield, respiratory capacity for oxidative phosphorylation, and O2 affinity (lower P50 ) of subsarcolemmal mitochondria compared to low-altitude mice across environments, but there were no species difference in these traits in intermyofibrillar mitochondria. High-altitude mice also had greater capacities of complex II relative to complexes I + II and higher succinate dehydrogenase activities in both mitochondrial fractions. Exposure to chronic hypoxia reduced reactive oxygen species (ROS) emission in high-altitude mice but not in low-altitude mice. Our findings suggest that functional changes in subsarcolemmal mitochondria contribute to improving aerobic performance in hypoxia in high-altitude deer mice. Therefore, physiological variation in specific mitochondrial fractions can help overcome the metabolic challenges of life at high altitude.

Guerrilla eugenics: gene drives in heritable human genome editing.

CRISPR-Cas9 genome editing can and has altered human genomes, bringing bioethical debates about this capability to the forefront of philosophical and policy considerations. Here, I consider the underexplored implications of CRISPR-Cas9 gene drives for heritable human genome editing. Modification gene drives applied to heritable human genome editing would introduce a novel form of involuntary eugenic practice that I term guerrilla eugenics. Once introduced into a genome, stealth genetic editing by a gene drive genetic element would occur each subsequent generation irrespective of whether reproductive partners consent to it and irrespective of whether the genetic change confers any benefit. By overriding the ability to 'opt in' to genome editing, gene drives compromise the autonomy of carrier individuals and their reproductive partners to choose to use or avoid genome editing and impose additional burdens on those who hope to 'opt out' of further genome editing. High incidence of an initially rare gene drive in small human communities could occur within 200 years, with evolutionary fixation globally in a timeframe that is thousands of times sooner than achievable by non-drive germline editing. Following any introduction of heritable gene drives into human genomes, practices intended for surveillance or reversal also create fundamental ethical problems. Current policy guidelines do not comment explicitly on gene drives in humans. These considerations motivate an explicit moratorium as being warranted on gene drive development in heritable human genome editing.

The Evolution of the Human Hand From an Anthropologic Perspective.

Coupled with the developing brain and freed from ambulatory responsibilities, the human hand has experienced osteologic and myologic changes throughout evolutionary time that have permitted manipulative capacities of social, functional, and cultural importance in modern-day human life. Hand cupping, precision gripping, and power gripping are at the root of these evolutionary developments. It is in appreciation of the evolutionary trajectory that we can truly understand how 'form is function.' The structure of the human hand is distinct in many ways from that of even our closest relatives in the primate order (ie, chimpanzees). We present some of the key anatomic changes and evolutionary anatomic remnants of the human hand. The human hand is truly an amazing organ-the product of millions of years of selective changes.

Octavio Ocampo, Mexican painter: a metamorphic look at the discourse between the local and the global.

Art and science is an area of research that has strengthened recently, mainly due to the impact of interdisciplinary work. At the same time, approaches between the humanities and the sciences have succeeded in re-signifying traditional views towards critical positions such as postcolonialism, especially in the colonially so-called "Global South". In this paper, we want to review the case of the work of the Mexican artist Octavio Ocampo through works that present the case of biological and cultural evolution. From this, we want to reflect on the public perception of science in Mexico, the tensions between social and natural sciences, and the urgent need to strengthen the postcolonial discourse in scientific practice.

Recent gene duplications dominate evolutionary dynamics of adaptor protein complex subunits in embryophytes.

Adaptor protein complexes and the related complexes COPI and TSET function in packaging vesicles for transport among endomembrane compartments in eukaryotic cells. Differences in the complement of these complexes in lineages such as yeast and mammals as well as apicomplexan and kinetoplastid parasites via loss or duplication of subunits appears to reflect specialization in their respective trafficking systems. The model plant Arabidopsis thaliana possesses multiple paralogues for adaptor protein complex subunits, raising questions as to the timing and extent of these duplications in embryophytes (land plants). However, adaptor protein complex evolution in embryophytes is unexplored. Therefore, we analyzed genomes of diverse embryophytes and closely related green algae using extensive homology searches and phylogenetic analysis of 35 complex subunit proteins. The results reveal numerous paralogues, the vast majority of which, approximately 97%, arose from recent duplication events. This suggests that specialization of these protein complexes may occur frequently but independently in embryophytes.

The Indeterminacy Bottleneck: Implications for Habitable Worlds.

It is often assumed that the transition between chemical evolution and biological evolution undergoes a smooth process; that once life has arisen, it will automatically 'flood' a solar system body. However, there is no a priori reason to assume that a link between them is a given. The fact that both chemical evolution and biological evolution meet in a single point can be critical. Thus, one may ask: can a world's environment be favourable for chemical evolution but not for biological evolution, or vice versa? This is an important question worth exploration because certain worlds in the solar system in the past seemed to possess the possibility of chemical evolution, while several worlds in the present seem to exhibit such a possibility. Have such solar system bodies thus been, or are, 'flooded' by life? Did they possess the opportunity for biological evolution? The answer depends on the very nature of certain conditions under which evolution occurs, which may indicate that a link between chemical evolution and biological evolution is not automatically realised on a habitable solar system body. Thus, these conditions imply that in the emergence and distribution of cellular life, there exists an indeterminacy bottleneck at which chemical evolution and biological evolution meet through a single cell, whose descendants goes 'information explosive', 'entropy implosive' and 'habitat expansive', which determine whether life moves on to new environments. The consequence is that a world's environment can indeed be favourable for biological evolution, but not for chemical evolution. Thus, even if chemical evolution leads to the emergence of a microbial organism in a world, then it is not a given that such a first life form will be subjected to distribution to other environments; and not a given that its existence will continue in the environment it originated in. Thus, the bottleneck may be one of the decisive factors in the differences between habitable and inhabited worlds.

The evolution of high-fidelity social learning.

A defining feature of human culture is that knowledge and technology continually improve over time. Such cumulative cultural evolution (CCE) probably depends far more heavily on how reliably information is preserved than on how efficiently it is refined. Therefore, one possible reason that CCE appears diminished or absent in other species is that it requires accurate but specialized forms of social learning at which humans are uniquely adept. Here, we develop a Bayesian model to contrast the evolution of high-fidelity social learning, which supports CCE, against low-fidelity social learning, which does not. We find that high-fidelity transmission evolves when (1) social and (2) individual learning are inexpensive, (3) traits are complex, (4) individual learning is abundant, (5) adaptive problems are difficult and (6) behaviour is flexible. Low-fidelity transmission differs in many respects. It not only evolves when (2) individual learning is costly and (4) infrequent but also proves more robust when (3) traits are simple and (5) adaptive problems are easy. If conditions favouring the evolution of high-fidelity transmission are stricter (3 and 5) or harder to meet (2 and 4), this could explain why social learning is common, but CCE is rare.

Extremophiles: a special or general case in the search for extra-terrestrial life?

Since time immemorial life has been viewed as fragile, yet over the past few decades it has been found that many extreme environments are inhabited by organisms known as extremophiles. Knowledge of their emergence, adaptability, and limitations seems to provide a guideline for the search of extra-terrestrial life, since some extremophiles presumably can survive in extreme environments such as Mars, Europa, and Enceladus. Due to physico-chemical constraints, the first life necessarily came into existence at the lower limit of its conceivable complexity. Thus, the first life could not have been an extremophile; furthermore, since biological evolution occurs over time, then the dual knowledge regarding what specific extremophiles are capable of, and to the analogue environment on extreme worlds, will not be sufficient as a search criterion. This is because, even though an extremophile can live in an extreme environment here-and-now, its ancestor however could not live in that very same environment in the past, which means that no contemporary extremophiles exist in that environment. Furthermore, a theoretical framework should be able to predict whether extremophiles can be considered a special or general case in the galaxy. Thus, a question is raised: does Earth's continuous habitability represent an extreme or average value for planets? Thus, dependent on whether it is difficult or easy for worlds to maintain the habitability, the search for extra-terrestrial life with a focus on extremophiles will either represent a search for dying worlds, or a search for special life on living worlds, focusing too narrowly on extreme values.

Varieties Of Evolved Forms Of Consciousness, Including Mathematical Consciousness.

I shall introduce a complex, apparently unique, cross-disciplinary approach to understanding consciousness, especially ancient forms of mathematical consciousness, based on joint work with Jackie Chappell (Birmingham Biosciences) on the Meta-Configured Genome (MCG) theory. All known forms of consciousness (apart from recent very simple AI forms) are products of biological evolution, in some cases augmented by products of social, or technological evolution. Forms of consciousness differ between organisms with different sensory mechanisms, needs and abilities; and in complex animals can vary across different stages of development before and after birth or hatching or pupation, and before or after sexual and other kinds of maturity (or senility). Those forms can differ across individuals with different natural talents and environments, some with and some without fully functional sense organs or motor control functions (in humans: hearing, sight, touch, taste, smell, proprioception and other senses), along with mechanisms supporting meta-cognitive functions such as recollection, expectation, foreboding, error correction, and so forth, and varying forms of conscious control differing partly because of physical differences, such as conjoined twins sharing body parts. Forms of consciousness can also differ across individuals in different cultures with different shared theories, and social practices (e.g., art-forms, musical traditions, religions, etc.). There are many unanswered questions about such varieties of consciousness in products of biological evolution. Most of the details are completely ignored by most philosophers and scientists who focus only on a small subset of types of human consciousness-resulting in shallow theories. Immanuel Kant was deeper than most, though his insights, especially insights into mathematical consciousness tend to be ignored by recent philosophers and scientists, for bad reasons. This paper, partly inspired by Turing's 1952 paper on chemistry-based morphogenesis, supporting William James' observation that all known forms of consciousness must have been products of biological evolution in combination with other influences, attempts to provide (still tentative and incomplete) foundations for a proper study of the variety of biological and non-biological forms of consciousness, including the types of mathematical consciousness identified by Kant in 1781.

Reducing Patient Loneliness With Artificial Agents: Design Insights From Evolutionary Neuropsychiatry.

Loneliness is a growing public health issue that substantially increases the risk of morbidity and mortality. Artificial agents, such as robots, embodied conversational agents, and chatbots, present an innovation in care delivery and have been shown to reduce patient loneliness by providing social support. However, similar to doctor and patient relationships, the quality of a patient's relationship with an artificial agent can impact support effectiveness as well as care engagement. Incorporating mammalian attachment-building behavior in neural network processing as part of an agent's capabilities may improve relationship quality and engagement between patients and artificial agents. We encourage developers of artificial agents intended to relieve patient loneliness to incorporate design insights from evolutionary neuropsychiatry.

Yersinia pestis Survival and Replication in Potential Ameba Reservoir.

Plague ecology is characterized by sporadic epizootics, then periods of dormancy. Building evidence suggests environmentally ubiquitous amebae act as feral macrophages and hosts to many intracellular pathogens. We conducted environmental genetic surveys and laboratory co-culture infection experiments to assess whether plague bacteria were resistant to digestion by 5 environmental ameba species. First, we demonstrated that Yersinia pestis is resistant or transiently resistant to various ameba species. Second, we showed that Y. pestis survives and replicates intracellularly within Dictyostelium discoideum amebae for ˃48 hours postinfection, whereas control bacteria were destroyed in <1 hour. Finally, we found that Y. pestis resides within ameba structures synonymous with those found in infected human macrophages, for which Y. pestis is a competent pathogen. Evidence supporting amebae as potential plague reservoirs stresses the importance of recognizing pathogen-harboring amebae as threats to public health, agriculture, conservation, and biodefense.

Positive selection and functional divergence of farnesyl pyrophosphate synthase genes in plants.

BACKGROUND: Farnesyl pyrophosphate synthase (FPS) belongs to the short-chain prenyltransferase family, and it performs a conserved and essential role in the terpenoid biosynthesis pathway. However, its classification, evolutionary history, and the forces driving the evolution of FPS genes in plants remain poorly understood. RESULTS: Phylogeny and positive selection analysis was used to identify the evolutionary forces that led to the functional divergence of FPS in plants, and recombinant detection was undertaken using the Genetic Algorithm for Recombination Detection (GARD) method. The dataset included 68 FPS variation pattern sequences (2 gymnosperms, 10 monocotyledons, 54 dicotyledons, and 2 outgroups). This study revealed that the FPS gene was under positive selection in plants. No recombinant within the FPS gene was found. Therefore, it was inferred that the positive selection of FPS had not been influenced by a recombinant episode. The positively selected sites were mainly located in the catalytic center and functional areas, which indicated that the 98S and 234D were important positively selected sites for plant FPS in the terpenoid biosynthesis pathway. They were located in the FPS conserved domain of the catalytic site. We inferred that the diversification of FPS genes was associated with functional divergence and could be driven by positive selection. CONCLUSIONS: It was clear that protein sequence evolution via positive selection was able to drive adaptive diversification in plant FPS proteins. This study provides information on the classification and positive selection of plant FPS genes, and the results could be useful for further research on the regulation of triterpenoid biosynthesis.

Fluctuating effects of genetic and plastic changes in body mass on population dynamics in a large herbivore.

Recent studies suggest that evolutionary changes can occur on a contemporary time scale. Hence, evolution can influence ecology and vice-versa. To understand the importance of eco-evolutionary dynamics in population dynamics, we must quantify the relative contribution of ecological and evolutionary changes to population growth and other ecological processes. To date, however, most eco-evolutionary dynamics studies have not partitioned the relative contribution of plastic and evolutionary changes in traits on population, community, and ecosystem processes. Here, we quantify the effects of heritable and non-heritable changes in body mass distribution on survival, recruitment, and population growth in wild bighorn sheep (Ovis canadensis) and compare their importance to the effects of changes in age structure, population density, and weather. We applied a combination of a pedigree-based quantitative genetics model, statistical analyses of demography, and a new statistical decomposition technique, the Geber method, to a long-term data set of bighorn sheep on Ram Mountain (Canada), monitored individually from 1975 to 2012. We show three main results: (1) The relative importance of heritable change in mass, non-heritable change in mass, age structure, density, and climate on population growth rate changed substantially over time. (2) An increase in body mass was accompanied by an increase in population growth through higher survival and recruitment rate. (3) Over the entire study period, changes in the body mass distribution of ewes, mostly through non-heritable changes, affected population growth to a similar extent as changes in age structure or in density. The importance of evolutionary changes was small compared to that of other drivers of changes in population growth but increased with time as evolutionary changes accumulated. Evolutionary changes became increasingly important for population growth as the length of the study period considered increased. Our results highlight the complex ways in which ecological and evolutionary changes can affect population dynamics and illustrate the large potential effect of trait changes on population processes.

Phylogeographic Evidence for 2 Genetically Distinct Zoonotic Plasmodium knowlesi Parasites, Malaysia.

Infections of humans with the zoonotic simian malaria parasite Plasmodium knowlesi occur throughout Southeast Asia, although most cases have occurred in Malaysia, where P. knowlesi is now the dominant malaria species. This apparently skewed distribution prompted an investigation of the phylogeography of this parasite in 2 geographically separated regions of Malaysia, Peninsular Malaysia and Malaysian Borneo. We investigated samples collected from humans and macaques in these regions. Haplotype network analyses of sequences from 2 P. knowlesi genes, type A small subunit ribosomal 18S RNA and cytochrome c oxidase subunit I, showed 2 genetically distinct divergent clusters, 1 from each of the 2 regions of Malaysia. We propose that these parasites represent 2 distinct P. knowlesi types that independently became zoonotic. These types would have evolved after the sea-level rise at the end of the last ice age, which separated Malaysian Borneo from Peninsular Malaysia.