Literatura científica selecionada sobre o tema "'fitness' clonal"

Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.

Flowering plants possess an unrivaled diversity of mechanisms for achieving sexual and asexual reproduction, often simultaneously. The commonest type of asexual reproduction is clonal growth (vegetative propagation) in which parental genotypes (genets) produce vegetative modules (ramets) that are capable of independent growth, reproduction, and often dispersal. Clonal growth leads to an expansion in the size of genets and increased fitness because large floral displays increase fertility and opportunities for outcrossing. Moreover, the clonal dispersal of vegetative propagules can assist “mate finding,” particularly in aquatic plants. However, there are ecological circumstances in which functional antagonism between sexual and asexual reproductive modes can negatively affect the fitness of clonal plants. Populations of heterostylous and dioecious species have a small number of mating groups (two or three), which should occur at equal frequency in equilibrium populations. Extensive clonal growth and vegetative dispersal can disrupt the functioning of these sexual polymorphisms, resulting in biased morph ratios and populations with a single mating group, with consequences for fertility and mating. In populations in which clonal propagation predominates, mutations reducing fertility may lead to sexual dysfunction and even the loss of sex. Recent evidence suggests that somatic mutations can play a significant role in influencing fitness in clonal plants and may also help explain the occurrence of genetic diversity in sterile clonal populations. Highly polymorphic genetic markers offer outstanding opportunities for gaining novel insights into functional interactions between sexual and clonal reproduction in flowering plants.

Colorful clones in the blood Stem cells in regenerating tissues such as the blood can acquire mutations that enable a growth advantage, increasing the chance of developing cancer. It is unclear how such diverse mutations promote clonal fitness. Avagyan et al . generated a platform in zebrafish to label clones with unique hues while inducing mutations in genes implicated in human blood disorders. Mutations in some genes caused clones to expand over time, resulting in clonal dominance. Progenitors in the dominant clone expressed anti-inflammatory factors to resist the inflammatory environment produced by their own mature progeny, leading to a self-perpetuating cycle promoting clonal fitness. Targeting these resistance pathways may be used to abate clonal hematopoiesis and prevent its associated pathology. —BAP

Abstract Summary Intra-tumor heterogeneity is one of the major factors influencing cancer progression and treatment outcome. However, evolutionary dynamics of cancer clone populations remain poorly understood. Quantification of clonal selection and inference of fitness landscapes of tumors is a key step to understanding evolutionary mechanisms driving cancer. These problems could be addressed using single-cell sequencing (scSeq), which provides an unprecedented insight into intra-tumor heterogeneity allowing to study and quantify selective advantages of individual clones. Here, we present Single Cell Inference of FItness Landscape (SCIFIL), a computational tool for inference of fitness landscapes of heterogeneous cancer clone populations from scSeq data. SCIFIL allows to estimate maximum likelihood fitnesses of clone variants, measure their selective advantages and order of appearance by fitting an evolutionary model into the tumor phylogeny. We demonstrate the accuracy our approach, and show how it could be applied to experimental tumor data to study clonal selection and infer evolutionary history. SCIFIL can be used to provide new insight into the evolutionary dynamics of cancer. Availability and implementation Its source code is available at https://github.com/compbel/SCIFIL.

Genome instability of cancer cells translates into increased entropy and lower information processing capacity, leading to metabolic reprograming toward higher energy states, presumed to be aligned with a cancer growth imperative. Dubbed as the cell adaptive fitness, the proposition postulates that the coupling between cell signaling and metabolism constrains cancer evolutionary dynamics along trajectories privileged by the maintenance of metabolic sufficiency for survival. In particular, the conjecture postulates that clonal expansion becomes restricted when genetic alterations induce a sufficiently high level of disorder, that is, high entropy, in the regulatory signaling network, abrogating as a result the ability of cancer cells to successfully replicate, leading to a stage of clonal stagnation. The proposition is analyzed in the context of an in-silico model of tumor evolutionary dynamics to illustrate how cell-inherent adaptive fitness may predictably constrain clonal evolution of tumors, which would have significant implications for the design of adaptive cancer therapies.

It is widely accepted that favorable fitness in commensal colonization is one of the prime facilitators of clonal dissemination in bacteria. The question arises as to what kind of fitness advantage may be wielded by uropathogenic strains of the two predominant fluoroquinolone- and multidrug-resistant clonal groups of E. coli—ST131-H30 and ST1193, which has permitted their unprecedented pandemic-like global expansion in the last few decades. The colonization-associated genes’ content, carriage of low-cost plasmids, and integrons with weak promoters could certainly contribute to the fitness of the pandemic groups, although those genetic factors are common among other clonal groups as well. Also, ST131-H30 and ST1193 strains harbor fluoroquinolone-resistance conferring mutations targeting serine residues in DNA gyrase (GyrA-S83) and topoisomerase IV (ParC-S80) that, in those clonal backgrounds, might result in a commensal fitness benefit, i.e., beyond the antibiotic resistance per se. This fitness gain might have contributed not only to the widespread dissemination of these major clones in the healthcare setting but also to their long-term colonization of healthy individuals and, thus, circulation in the community, even in a low or no fluoroquinolone use environment. This evolutionary shift affecting commensal E. coli, initiated by mutations co-favorable in both antibiotics-treated patients and healthy individuals warrants more in-depth studies to monitor further changes in the epidemiological situation and develop effective measures to reduce the antibiotic resistance spread.

Populations facing novel environments are expected to evolve through the accumulation of adaptive substitutions. The dynamics of adaptation depend on the fitness landscape and possibly on the genetic background on which new mutations arise. Here, we model the dynamics of adaptive evolution at the phenotypic and genotypic levels, focusing on a Fisherian landscape characterized by a single peak. We find that Fisher's geometrical model of adaptation, extended to allow for small random environmental variations, is able to explain several features made recently in experimentally evolved populations. Consistent with data on populations evolving under controlled conditions, the model predicts that mean population fitness increases rapidly when populations face novel environments and then achieves a dynamic plateau, the rate of molecular evolution is remarkably constant over long periods of evolution, mutators are expected to invade and patterns of epistasis vary along the adaptive walk. Negative epistasis is expected in the initial steps of adaptation but not at later steps, a prediction that remains to be tested. Furthermore, populations are expected to exhibit high levels of phenotypic diversity at all times during their evolution. This implies that populations are possibly able to adapt rapidly to novel abiotic environments.

The work presented here investigates two basic properties of mutation rates in the unicellular chlorophyte Chlamydomonas reinhardtii. The first chapter is devoted to an investigation of the mutational heritability $ rm (V sb{M})$ of fitness in asexually propagated populations. This is the rate at which novel variation for fitness accumulates in a population. In two trials, values of $ rm V sb{M}$ = 4.5 and $4.7 times 10 sp{-3}$ of the environmental variance $ rm (V sb{E})$ were obtained. These values were at least an order of magnitude greater than estimates from other organisms of $ rm V sb{M}/V sb{E}$ for fitness or for quasineutral variation. The possibility that this was due to disruptive selection for types specialized for different parts of the culturing environment was investigated, and rejected. Other possible explanations, and future avenues for research, are discussed.<br>The second chapter extends the investigation from normal culturing conditions into stressful ones. Specifically, it considers the hypothesis that C. reinhardtii might increase its mutation rate as a general response to environmental stress. Stressed lines were found to display reduced mean fitness and an increased variance of fitness after being returned to normal culturing conditions. This was interpreted as evidence for increased mutation rates in treated lines relative to controls. Possible mechanisms underlying this phenomenon are discussed, along with suggestions for further research.

Le syndrome de Shwachman Diamond (SDS) est une ribosomopathie génétique rare entraînant une altération de la synthèse protéique associée à de nombreux symptômes, notamment une insuffisance médullaire et une neutropénie pouvant évoluer vers un syndrome de myélodysplasie ou une leucémie myéloïde aiguë. Les mutations bialléliques du gène SBDS sont responsables de plus de 90 % des cas de SDS et nous avons récemment identifié des mutations bialléliques EFL1 comme une nouvelle cause génétique de SDS. SBDS et EFL1 évincent le facteur elF6 de la sous-unité ribosomale pré60S, permettant à cette dernière d'interagir avec la sous-unité 40S pour former le ribosome mature 80S. L'acquisition naturelle d'événements génétiques somatiques au fil du temps participe au développement des maladies liées à l'âge et au développement des cancers. Cependant, dans les maladies mendéliennes, ces événements peuvent, dans de rares cas, contrer l'effet délétère de la mutation germinale et conférer un avantage sélectif aux cellules somatiquement modifiées, un phénomène appelé sauvetage génétique somatique (SGR). Nous avons récemment montré que plusieurs événements génétiques somatiques affectantl'expression ou la fonction d'elF6 sont fréquemment détectés dans les clones sanguins de patients atteints de SDS mais pas chez les individus sains, suggérant un mécanisme de SGR. Alors que la plupart de ces mutations somatiques induisent une déstabilisation de elF6 ou une haploinsuffisance d'EIF6, une mutation récurrente (N106S) n'affecte pas l'expression/stabilité d'elF6 mais réduit sa capacité à interagir avec la sous-unité 60S. Afin d'étudier plus en détail les conséquences fonctionnelles de l'haploinsuffisance de EIF6 et de la mutation N106S dans un contexte de SDS, j'ai introduit via CRISPR/Cas9 ces mutations dans des lignées fibroblastiques immortalisées de patients SDS et de contrôle. Ces modèles cellulaires originaux ont permis de déterminer l'impact de la mutation N106S sur la la localisation et la fonction d'elF6 mais aussi de préciser les effets de ces mutations sur plusieurs aspects du « fitness » cellulaire, notamment la biogenèse des ribosomes, le taux de traduction et la prolifération cellulaire. Dans l'ensemble, le développement de ce modèle a aidé à caractériser comment la mutation N106S et l'haploinsuffisance somatique de elF6 confèrent un avantage sélectif dans les cellules déficientes en SBDS ou EFL1<br>Shwachman Diamond syndrome (SDS) is a rare genetic ribosomopathy leading to impaired protein synthesis, which causes numerous symptoms including bone marrow failure and neutropenia that can evolve to myelodysplasia syndrome or acute myeloid leukaemia. Biallelic mutations in the SBDS gene are responsible of above 90% of the SDS cases and we recently identified biallelic EFL1 mutations as a novel cause of SDS. SBDS together with EFL1 remove the anti-association factor elF6 from the pre60S ribosomal subunit, allowing its interaction with the 40S subunit to form the mature ribosome 80S. Natural acquisition of somatic genetic events over time participâtes to age-related diseases and cancer development. However, in Mendelian diseases these events can, in rare case, counteract the deleterious effect of the germline mutation and provide a sélective advantage to the somatically modified cells, a phenomenon dubbed Somatic Genetic Rescue (SGR). We recently showed that several somatic genetic events affecting the expression or function of elF6 are frequently detected in blood clones from SDS patients but not in healthy individuals, suggesting a mechanism of SGR. While most of these somatic mutations induce elF6 destabilization or EIF6 haploinsufficiency, one récurrent mutation (N106S) did not affect the expression of elF6 but rather impact its ability to interact with the 60S subunit. In order to further investigate the functional conséquences of ElF6 haploinsufficiency and N106S mutation in a context of SDS, I introduced via CRISPR/Cas9 these mutations in immortalized fibroblastic cell line from SDS patients and control. These original cellular models hâve made it possible to détermine the impact of the N106S mutation on the localisation and function of elF6 and also to clarify the effects of these mutations on several aspects of cellular fitness, in particular ribosome biogenesis, translation rate and cell prolifération. Overall, the development of these cellular models has helped to characterise how the somatic N106S mutation and elF6 haploinsufficiency confer a sélective advantage in cells déficient in SBDS or EFL1

Extraintestinal pathogenic E. coli (ExPEC) is the major aetiological agent of urinary tract infections (UTIs) in humans. The emergence of the CTX-M producing E. coli ST131 clone represents a major challenge to public health worldwide because of its ability to cause a wide range of difficult-to-treat infections in the healthcare and community settings. The key aim of this study was to characterise the traits that give E. coli ST131 a competitive fitness advantage over other potential ExPEC clones. Comparative phenotypic characterisation of a collection of ExPEC strains showed that there was no difference between ST131 and non-ST131 strains in terms of their growth rates in different culture media, their capacity to associate with, invade and form intracellular bacterial communities within T24 human bladder epithelial cells and their ability to persist within U937 human macrophages. Afterwards, this study tested and compared the metabolic activity of a collection of ST131 and non-ST131 strains using two different testing methodologies: API strips and phenotypic microarray (PM) technology. Our API data showed that ST131 strains had a lower metabolic activity for 5 substrates. Further testing of the metabolic activity of E. coli using phenotypic microarray demonstrated the absence of a specific metabolic profile for ST131 strains suggesting that ST131 is not a metabolically distinct lineage of ExPEC and thus altered metabolism might not contribute to the fitness of this clone. The gene content of a group of E. coli including ST131 and non-ST131 strains was investigated to identify the presence of other loci that are uniquely associated with ST131 H30Rx clade, which involves ST131 isolates belonging to the fimH30 lineage and associated with fluoroquinolones resistance and CTX-M-15 production. Our data identified the presence of 150 loci unique to ST131 H30Rx strains, and the most striking finding at a genomic level was the identification of the secondary flagellar locus Flag 2 as a region uniquely associated with ST131 H30Rx strains. The ability of a collection of ST131 and non-ST131 strains to resist human serum was tested and compared. Our data showed that all ST131 and ST73 strains were associated with high serum resistance phenotype, and this might suggest serum resistance as an important factor in driving the current success of this ST131 as a major cause of bloodstream infections worldwide. Given many reports showing that polysaccharide capsules might be a major factor allowing E. coli to resist the human serum, and based on many studies demonstrating the genetic and biochemical diversity in the capsule region of ST131 strains, the capsule region of a collection of ExPEC belonging to ST131 H30Rx clade and non-ST131 was tested in more detail at a genomic and biochemical level. Our capsule genetics data showed a surprising level of diversity within the capsule locus of the H30Rx clade with a phylogenetic distribution highly suggestive of frequent recombination at the locus. Subsequent analysis demonstrated that this recombination had no obvious detectable effect on virulence-associated phenotypes in-vitro. Given the level of diversity observed at the capsule locus of ST131 H30Rx strains, it is tempting to speculate that there is significant selective pressure occurring at this site during the life cycle of the H30Rx clade, and that frequent recombination allows the clade to subvert that pressure and might provide a fitness advantage to ST131. This study provided detailed insights into the phenotypic, metabolic and genetic traits of ST131 and highlighted the factors that might drive its success.

Los virus producen graves pérdidas económicas en la agricultura. Esta problemática es muy dinámica ya que cada año aparecen nuevas virosis y es frecuente los fenómenos de emergencia con una rápida expansión de los virus. El control de las enfermedades víricas resulta poco eficaz en muchos casos porque la población viral es capaz de evolucionar y superar dichas estrategias. Por ello es clave entender la dinámica de las poblaciones y los factores implicados en la evolución de los virus con respecto a distintos aspectos de su biología del ciclo viral: replicación, movimiento dentro de la planta, respuesta a los mecanismos de defensa de la planta, transmisión a otras plantas, etc. El objetivo de esta tesis ha sido el estudio de los factores implicados en la evolución de dos virus que difieren en su variabilidad genética y gama de huéspedes: i) el Virus 1 del marchitamiento del haba (Broad bean wilt virus 1, BBWV-1), del género Fabavirus; y ii) el Virus del mosaico del tabaco (Tobacco mosaic virus, TMV) del género Tobamovirus. Primero se han desarrollado una serie de herramientas metodológicas que han permitido la detección rápida de BBWV-1 mediante hibridación molecular de improntas, la detección y cuantificación de BBWV-1 y TMV y su diferenciación de otras virosis del mismo género mediante RT-PCR cuantitativa a tiempo real. Se ha llevado a cabo la construcción de clones de cDNA del genoma completo de BBWV-1 para obtener transcritos infecciosos que puedan ser usados para estudiar la biología molecular, evolución y epidemiología. Una vez desarrollado esta metodología se ha usado para evaluar la eficacia biológica de BBWV-1 en el huésped y el efecto de algunos factores: concentración del inóculo, estado de desarrollo de la planta, tipo de huésped, aplicación de un activador de la defensa de la planta, y la infección con otro virus. Así mismo se han estudiado los factores relacionados con la eficacia biológica del virus durante su transmisión por pulgones: título viral<br>Ferriol Safont, I. (2012). FACTORS INVOLVED IN THE EVOLUTION OF BROAD BEAN WILT VIRUS 1 AND TOBACCO MOSAIC VIRUS [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/16000<br>Palancia

Les populations ouest européennes de Phytophthora infestans, l’oomycète responsable du mildiou chez la pomme de terre, sont caractérisées par une structure clonale et un remplacement rapide des lignées dominantes. Cette thèse visait à identifier les déterminants écologiques, phénotypiques et évolutifs du caractère invasif de ces lignées clonales. Pour cela, les dynamiques génotypiques et phénotypiques de populations ont été analysées sur deux échelles de temps, l’une sur près d’une décennie et l’autre via un suivi longitudinal sur deux épidémies consécutives. Ces suivis étaient complétés par l’étude des réponses adaptatives au sein de ces populations liées aux principaux traits d’histoire de vie du parasite. Ces résultats tendent à rejeter l’hypothèse, souvent avancée, que la capacité invasive est liée à une plus grande agressivité des nouvelles lignées par rapport aux anciennes. De plus, le suivi sur deux ans a révélé un scénario complexe, avec la présence de deux lignées clonales domalors que les isolats 6_A1 produisent un grand nombre de petits sporanges, ceux des 13_A2 sont moins nombreux mais de plus grande taille. La coexistence au sein d’une même population de ces stratégies pourrait être due au trade-off entre nombre et taille des sporanges que nous avons également mis en évidence. Enfin, différentes réponses à la température entre ces lignées clonales ont été observées, ainsi que des patrons d’adaptation locale au sein de populations géographiquement éloignées. Ces travaux soulignent que différents facteurs d'adaptation peuvent impacter les mêmes traits biologiqu<br>West European populations of Phytophthora infestans, the oomycete causing late blight in potato, are characterized by a clonal structure and rapid replacement of dominant lineages. This work thus aimed to identify the ecological, phenotypic and evolutionary determinants of the invasive character of these clonal lineages. To this end, the phenotypic and genotypic population dynamics were analysed over two time scales, one over nearly a decade and a shorter one consisting in a longitudinal tracking over two consecutive epidemics. This monitoring was supplemented by the analysis of adaptive responses within these populations with respect to the main life-history traits of the parasite. These results tend to reject the hypothesis, often advanced, that the invasive ability is linked to a higher aggressiveness of the new clonal lineages compared to the previous ones. Moreover, the short-term study revealed complex scenario, involving the presence of two main clonal lineages (6_A1 and 13_A2)while 6_A1 isolates produced many, small sporangia, those of 13_A2 isolates are fewer but bigger. The coexistence within a single population of these strategies could result from the trade-off between the spore size and spore number, that we also demonstrated. Finally, differential responses between clones to temperature were observed, as well as clear local adaptation patterns among geographically distant populations. This work highlight that different adaptive factors can impact the same biological traits of P. infestans and that it is crucial to think about the consequences of these concom

Le clade C de Escherichia coli ST131, pathogène extra-intestinal (ExPEC) multirésistant aux antibiotiques, a émergé dans le monde entier au début des années 2000. La compréhension de son essor fait partie des enjeux majeurs de santé publique. Pour participer à cette compréhension, nous avons pris en considération l’histoire phylogénique de ST131 et axé nos recherches sur la comparaison du clade C avec son progéniteur, le clade B, qui est lui composé de souches globalement sensibles aux antibiotiques. L’histoire phylogénétique du clone ST131 décrit la diversification du clade B ancestral en différents sous-clades B (de B1 à B5), B5 donnant naissance au clade C, qui lui-même s’est diversifié en deux sous-clades, C1 et C2. Nous avons souhaité connaitre l’évolution de ces différents sous-clades en termes de fréquence relative au sein de tous les ExPEC. Pour cela, nous avons analysé les génomes de ST131 identifiés au sein de E. coli bactériémiques systématiquement collectés en Angleterre entre 2001 et 2012. Cette analyse a montré que, durant la période étudiée, (i) ST131 faisait partie des quelques clones dominants, avec en son sein une dominance des souches de clade C, en particulier celles de sous-clade C2 et (ii) les souches de clade B persistaient de manière stable, en particulier celles de sous-clades B4 et B5, malgré une fréquence relative globale plus faible que celle du clade C. Par ailleurs, nous avons constitué une collection de 39 souches ST131 qui se sont avérées représentatives de la diversité des clades et sous-clades B et C, à l’exception d’une souche B4 (nommée Hybride), porteuse de l’allèle fimH30, normalement spécifique du clade C. Grâce à cette collection, nous avons exploré la croissance et la formation de biofilm précoce (après 2, 3 et 5 h d’incubation) des souches de clade B et C. Toutes les souches possédaient des capacités de croissance égales, alors qu’elles différaient quant à la formation de biofilm : biofilm plus fréquemment observé en 2 h chez le clade B que chez le clade C. Puis, deux souches représentatives du clade B et du clade C, nommées Ancêtre et Émergente, respectivement, ainsi que Hybride ont été soumises à des compétitions deux à deux in vitro et in vivo (dans divers modèles murins). En dépit de l’absence de différences de fitness in vitro entre ces trois souches, Émergente s’est montrée chez la souris moins bonne colonisatrice des tractus intestinaux et/ou urinaires et moins virulente dans le modèle de septicémie que Ancêtre et Hybride. Faisant référence au gène fimB non fonctionnel chez toutes les souches de clade C, gène codant un des régulateurs de la synthèse des fimbriae de type 1 qui participent à la formation du biofilm et à l’adhésion bactérienne, nous l’avons délété chez Ancêtre et Hybride. Bien que la délétion du gène fimB abolissait in vitro la formation du biofilm précoce observée chez les souches parentales, aucun effet n’a été observé lors de la mise en compétition des mutants avec leurs souches parentales, in vitro comme in vivo ; mutant et souche parentale se comportaient de manière équivalente au regard de la colonisation intestinale et de la virulence chez la souris.Au total, ces travaux suggèrent qu’une perte de virulence globale, processus connu pour améliorer le niveau de transmission bactérien, est survenue chez le clade C de ST131 en plus de son acquisition d’une multirésistance aux antibiotiques, deux évolutions susceptibles de lui assurer un meilleur fitness, notamment dans les environnements sous pression antibiotique<br>The clade C of Escherichia coli ST131, an extra-intestinal pathogen (ExPEC) multidrug-resistant, emerged worldwide in the early 2000s. Understanding its expansion is one of the major public health challenges. To contribute to this understanding, we took into consideration the phylogenesis of ST131 and focused our research on comparing the clade C with its progenitor, the clade B, which is composed of strains globally sensitive to antibiotics.The phylogenesis of the clone ST131 describes the diversification of the ancestral clade B into different B subclades (from B1 to B5), B5 giving rise to clade C, which itself has diversified into two subclades, C1 and C2. We wanted to learn about the evolution of these different subclades in terms of relative frequency within all ExPECs. For this purpose, we analyzed the ST131 genomes identified within bacteriemic E. coli systematically collected in England between 2001 and 2012. This analysis showed that, during the studied period, (i) ST131 was one of the few dominant clones, with a dominance of clade C strains, particularly those of subclade C2 and (ii) clade B strains persisted in a stable manner, particularly those of subclades B4 and B5, despite an overall relative frequency lower than that of clade C. Besides, we have compiled a collection of 39 ST131 strains that have been found to be representative of the diversity of B and C clades and subclades, with the exception of one B4 strain (called Hybrid), which carries the fimH30 allele, normally specific to the clade C. Through this collection, we have explored the growth and formation of early biofilm (after 2, 3 and 5 hours of incubation) of clade B and C strains. All strains had equal growth capacities, while they differed in biofilm formation: biofilm was more frequently observed in 2 h in clade B strains than in clade C strains. Then, two representative strains of clades B and C, called Ancestor and Emergent, respectively, as well as Hybrid, were subjected to competitions two by two in vitro and in vivo (in various mouse models). Despite the absence of in vitro fitness differences between these three strains, Emergent was found to be less effective in colonizing the intestinal and/or urinary tract in mice and less virulent in the sepsis model than Ancestor and Hybrid. Referring to the non-functional fimB gene in all strains of clade C, a gene encoding one of the regulators of type 1 fimbriae synthesis involved in biofilm formation and bacterial adhesion, we have deleted it in Ancestor and Hybrid. Although the deletion of the fimB gene abolished in vitro the formation of early biofilm observed in parental strains, no effect was observed when mutants were put in competition with their parental strains, in vitro and in vivo; mutant and parental strain also behaved equally with regard to intestinal colonization and virulence in mice. In total, this work suggests that a global loss of virulence, a process known to improve the level of bacterial transmission, has occurred in ST131 clade C in addition to its acquisition of a multidrug resistance, two evolutions likely to ensure better fitness, especially in environments under antibiotic pressure

As Hamilton observed, the stability of cooperation within clonal groups of cells is no mystery, since the cells’ inclusive fitness interests are aligned. However, the process of social group transformation, by means of which a social group of cells is transformed into a multicellular individual with a division of labour among multiple cell types, remains mysterious. In both multicellular organisms and eusocial insects, group size and the number of specialized types are closely linked. As Bourke has argued, positive feedback is likely to be crucial in explaining the relationship between size and complexity, and a social perspective on the organism helps us understand this feedback loop. This chapter proposes an expanded feedback loop in which the relationship between group size and specialization is mediated by the degree of redundancy (which may be either passive or active) in task structures.

The innate and the adaptive immune system efficiently cooperate to protect us from infections. The ancient innate immune system, dating back to the first multicellular organisms, utilizes phagocytic cells, soluble antimicrobial peptides, and the complement system for an immediate line of defence against pathogens. Using a limited number of germline-encoded pattern recognition receptors including the Toll-like, RIG-1-like, and NOD-like receptors, the innate immune system recognizes so-called pathogen-associated molecular patterns (PAMPs). PAMPs are specific for groups of related microorganisms and represent highly conserved, mostly non-protein molecules essential for the pathogens' life cycles. Hence, escape mutants strongly reduce the pathogen's fitness. An important task of the innate immune system is to distinguish between harmless antigens and potentially dangerous pathogens. Ideally, innate immune cells should activate the adaptive immune cells only in the case of invading pathogens. The evolutionarily rather new adaptive immune system, which can be found in jawed fish and higher vertebrates, needs several days to mount an efficient response upon its first encounter with a certain pathogen. As soon as antigen-specific lymphocyte clones have been expanded, they powerfully fight the pathogen. Importantly, memory lymphocytes can often protect us from reinfections. During the development of T and B lymphocytes, many millions of different receptors are generated by somatic recombination and hypermutation of gene segments making up the antigen receptors. This process carries the inherent risk of autoimmunity, causing most inflammatory rheumatic diseases. In contrast, inadequate activation of the innate immune system, especially activation of the inflammasomes, may cause autoinflammatory syndromes.

Abstract Mutual aid cannot evolve unless it offers compensating direct benefits for an actor or indirect benefits for her relatives. This phrase is a gene’s eye version of Darwin’s statement that no adaptation can arise for the exclusive good of another species. Such thinking has inspired studies that explored how Hamilton’s rule can explain adaptation in symbiotic mutualisms. When studies tracked genetics, they converged on the conclusion that interspecific “altruism” is always driven by clonal or family altruism within the partner species, which confirmed Darwin’s insight and earlier conclusions that “altruism between species” is a misnomer. I review the dynamics of cooperation and conflict in symbioses where unicellular partners associate with a multicellular host either by voluntarily horizontal acquisition or in a coerced setting of vertical transmission. I then consider symmetry and redundancy of partnerships and their degree of genetic closure, showing that hosts either maintain societies of symbionts or have a lifetime non-redundant partnerships with a single symbiont. This suggests that the egalitarian MTE origin of LECA can be understood by the same non-redundant closure principle that I used in Chapter 4 to explain the recurrent MTEs towards organismal multicellularity and colonial superorganismality. This explanation includes the origin of meiotic sex and can likely be extended to the origin of the first prokaryote cell. In general, the arguments in this and the previous chapter imply the conjectures that (1) higher grades of organismality did not emerge, they were naturally selected adaptive syndromes (2) their ancestral properties had nothing to do with being relatively big or complex; and (3) non-redundant partnership was essential to suppress conflict over resource acquisition, while reproductive allocation conflicts appear to have been unimportant at MTE origins.

Abstract An alternative approach to that used in the last chapter is invasibility analysis, which consists of asking if a clone displaying an alternate life history can invade a resident population. While one could compare results for markedly different life histories, in general, invasibility analysis has been used to locate the optimal combinations of parameter values rather than qualitatively different life histories. As with the “Fisherian” optimality approach, sexual reproduction is ignored. Invasibility analysis is used extensively, and is most useful, when fitness is density-dependent and there is age-or stage-structuring in the model. The method can handle stable, cyclical, and chaotic population dynamics. In this section I first consider the general structure of age- and stage-structured models and then describe the two general approaches of invasibility analysis, namely pairwise-invasibility and multiple-invasibility analysis. For all that you ever wanted to know about matrix population models see Caswell (2002).

The innate and the adaptive immune system efficiently cooperate to protect us from infections. The ancient innate immune system, dating back to the first multicellular organisms, utilizes phagocytic cells, soluble antimicrobial peptides, and the complement system for an immediate line of defence against pathogens. Using a limited number of germline-encoded pattern recognition receptors including the Toll-like, RIG-1-like, and NOD-like receptors, the innate immune system recognizes so-called pathogen-associated molecular patterns (PAMPs). PAMPs are specific for groups of related microorganisms and represent highly conserved, mostly non-protein molecules essential for the pathogens’ life cycles. Hence, escape mutants strongly reduce the pathogen’s fitness. An important task of the innate immune system is to distinguish between harmless antigens and potentially dangerous pathogens. Ideally, innate immune cells should activate the adaptive immune cells only in the case of invading pathogens. The evolutionarily rather new adaptive immune system, which can be found in jawed fish and higher vertebrates, needs several days to mount an efficient response upon its first encounter with a certain pathogen. As soon as antigen-specific lymphocyte clones have been expanded, they powerfully fight the pathogen. Importantly, memory lymphocytes can often protect us from reinfections. During the development of T and B lymphocytes, many millions of different receptors are generated by somatic recombination and hypermutation of gene segments making up the antigen receptors. This process carries the inherent risk of autoimmunity, causing most inflammatory rheumatic diseases. In contrast, inadequate activation of the innate immune system, especially activation of the inflammasomes, may cause autoinflammatory syndromes.

The goal of our BARD proposal was to build both the necessary infrastructure and knowledge for using the CRISPR/Cas9-based gene drive system to control the whitefly Bemisia tabaci. Our research focused on achieving three main goals: (1) establishing a CRISPR/Cas9 gene-editing system for producing genetically-edited B. tabaci; (2) generating and testing CRISPR/Cas9-mediated mutations targeting genes that represent two gene drive strategies: population replacement and population suppression; (3) using computer modeling to optimize strategies for applying CRISPR/Cas9 to control B. tabaci populations in the field. CRISPR gene drive is one of the most promising strategies for diminishing the negative impacts of harmful insects. This technique can introduce mutations into wild populations of pests that reduce their ability to cause damage, reduce their population size, or both. In principle, this can be selfsustaining because mutations carried by relatively few insects can increase in frequency and spread quickly throughout wild populations. Because of this sustainability and the potential benefits to society, agricultural gene-drive systems are most likely to be funded by government agencies, foundations, and grower associations; as with sterile insect releases and most biocontrol programs. Although gene drives have received intensive study in Drosophila and mosquito vectors of human disease, we were one of the first teams pursuing this approach for crop pests. Our project was also one of the first to address CRISPR gene drive in the Hemiptera, an insect order that includes hundreds of pest species. We focused on developing and implementing CRISPR gene drive to reduce the massive damage caused by B. tabaci. This haplodiploid insect is one of the world's most devastating crop pests. Whereas extensive work by others explored CRISPR in diploid species, our project pioneered application of this revolutionary technology to haplodiploids, which have a distinct system of inheritance that presents special challenges and opportunities. Our project has achieved several breakthroughs, including publication of the first paper analyzing CRISPR gene drive in haplodiploids (Li et al. 2020, see next section). Our modeling results from this landmark study demonstrate that CRISPR gene drive can work in haplodiploids, especially if fitness costs associated with the driver allele are low or nil. Our paper was the first to provide a conceptual framework for evaluating and optimizing CRISPR gene drive strategies for managing B. tabaci and other haplodiploid pests. Our breakthroughs in the laboratory have created the infrastructure needed to develop CRISPR for controlling B. tabaci. We established a microinjection system enabling us to introduce CRISPR-derived mutations into B. tabaci embryos. We have used this system to generate and track inherited eye-color mutants of B. tabaci. We have identified and cloned germline promoters, and demonstrated their function in transgenic B. tabaci embryos and other hemipteran insects. We have also developed a tool to easily identify B. tabaci harboring CRISPR-mediated mutations by tagging target genes using a transgenic fluorescent marker. The successful completion of our project provides all the knowledge and infrastructure essential for developing a novel genetic approach for B. tabaci control, which can serve as a non-chemical "green" alternative for managing this global pest. We predict that our discoveries will accelerate the development of the CRISPR gene drive technique for reducing the numbers of this pest and the damage it causes. Still, realization of the benefits of gene-drive technology for pest control will require sustained attention to potential environmental and societal impacts, as well as regulatory and implementation challenges. Given the great promise of this technology and the urgent need for better control methods, we expect that guidance documents and regulations will be in place to allow the scientific community to safely move gene drives for pest control from the laboratory to field trials.