Evolutionary patterns of MHC class II B in owls and their implications for the understanding of avian MHC evolution

Owing to its special mode of evolution and central role in the adaptive immune system, the major histocompatibility complex (MHC) has become the focus of diverse disciplines such as immunology, evolutionary ecology, and molecular evolution. MHC evolution has been studied extensively in diverse vertebrate lineages over the last few decades, and it has been suggested that birds differ from the established mammalian norm. Mammalian MHC genes evolve independently, and duplication history (i.e., orthology) can usually be traced back within lineages. In birds, this has been observed in only 3 pairs of closely related species. Here we report strong evidence for the persistence of orthology of MHC genes throughout an entire avian order. Phylogenetic reconstructions of MHC class II B genes in 14 species of owls trace back orthology over tens of thousands of years in exon 3. Moreover, exon 2 sequences from several species show closer relationships than sequences within species, resembling transspecies evolution typically observed in mammals. Thus, although previous studies suggested that long-term evolutionary dynamics of the avian MHC was characterized by high rates of concerted evolution, resulting in rapid masking of orthology, our results question the generality of this conclusion. The owl MHC thus opens new perspectives for a more comprehensive understanding of avian MHC evolution.

Probabilistic evidential assessment of gunshot residue particle evidence (Part II) : Bayesian parameter estimation for experimental count data.

Part I of this series of articles focused on the construction of graphical probabilistic inference procedures, at various levels of detail, for assessing the evidential value of gunshot residue (GSR) particle evidence. The proposed models - in the form of Bayesian networks - address the issues of background presence of GSR particles, analytical performance (i.e., the efficiency of evidence searching and analysis procedures) and contamination. The use and practical implementation of Bayesian networks for case pre-assessment is also discussed. This paper, Part II, concentrates on Bayesian parameter estimation. This topic complements Part I in that it offers means for producing estimates useable for the numerical specification of the proposed probabilistic graphical models. Bayesian estimation procedures are given a primary focus of attention because they allow the scientist to combine (his/her) prior knowledge about the problem of interest with newly acquired experimental data. The present paper also considers further topics such as the sensitivity of the likelihood ratio due to uncertainty in parameters and the study of likelihood ratio values obtained for members of particular populations (e.g., individuals with or without exposure to GSR).

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

The CD209 gene family that encodes C-type lectins in primates includes CD209 (DC-SIGN), CD209L (L-SIGN) and CD209L2. Understanding the evolution of these genes can help understand the duplication events generating this family, the process leading to the repeated neck region and identify protein domains under selective pressure. We compiled sequences from 14 primates representing 40 million years of evolution and from three non-primate mammal species. Phylogenetic analyses used Bayesian inference, and nucleotide substitutional patterns were assessed by codon-based maximum likelihood. Analyses suggest that CD209 genes emerged from a first duplication event in the common ancestor of anthropoids, yielding CD209L2 and an ancestral CD209 gene, which, in turn, duplicated in the common Old World primate ancestor, giving rise to CD209L and CD209. K(A)/K(S) values averaged over the entire tree were 0.43 (CD209), 0.52 (CD209L) and 0.35 (CD209L2), consistent with overall signatures of purifying selection. We also assessed the Toll-like receptor (TLR) gene family, which shares with CD209 genes a common profile of evolutionary constraint. The general feature of purifying selection of CD209 genes, despite an apparent redundancy (gene absence and gene loss), may reflect the need to faithfully recognize a multiplicity of pathogen motifs, commensals and a number of self-antigens

Evolutionary history and its relevance in understanding and conserving southern African biodiversity

Abstract : Understanding how biodiversity is distributed is central to any conservation effort and has traditionally been based on niche modeling and the causal relationship between spatial distribution of organisms and their environment. More recently, the study of species' evolutionary history and relatedness has permeated the fields of ecology and conservation and, coupled with spatial predictions, provides useful insights to the origin of current biodiversity patterns, community structuring and potential vulnerability to extinction. This thesis explores several key ecological questions by combining the fields of niche modeling and phylogenetics and using important components of southern African biodiversity. The aims of this thesis are to provide comparisons of biodiversity measures, to assess how climate change will affect evolutionary history loss, to ask whether there is a clear link between evolutionary history and morphology and to investigate the potential role of relatedness in macro-climatic niche structuring. The first part of my thesis provides a fine scale comparison and spatial overlap quantification of species richness and phylogenetic diversity predictions for one of the most diverse plant families in the Cape Floristic Region (CFR), the Proteaceae. In several of the measures used, patterns do not match sufficiently to argue that species relatedness information is implicit in species richness patterns. The second part of my thesis predicts how climate change may affect threat and potential extinction of southern African animal and plant taxa. I compare present and future niche models to assess whether predicted species extinction will result in higher or lower V phylogenetic diversity survival than what would be experienced under random extinction processes. l find that predicted extinction will result in lower phylogenetic diversity survival but that this non-random pattern will be detected only after a substantial proportion of the taxa in each group has been lost. The third part of my thesis explores the relationship between phylogenetic and morphological distance in southern African bats to assess whether long evolutionary histories correspond to equally high levels of morphological variation, as predicted by a neutral model of character evolution. I find no such evidence; on the contrary weak negative trends are detected for this group, as well as in simulations of both neutral and convergent character evolution. Finally, I ask whether spatial and climatic niche occupancy in southern African bats is influenced by evolutionary history or not. I relate divergence time between species pairs to climatic niche and range overlap and find no evidence for clear phylogenetic structuring. I argue that this may be due to particularly high levels of micro-niche partitioning. Résumé : Comprendre la distribution de la biodiversité représente un enjeu majeur pour la conservation de la nature. Les analyses se basent le plus souvent sur la modélisation de la niche écologique à travers l'étude des relations causales entre la distribution spatiale des organismes et leur environnement. Depuis peu, l'étude de l'histoire évolutive des organismes est également utilisée dans les domaines de l'écologie et de la conservation. En combinaison avec la modélisation de la distribution spatiale des organismes, cette nouvelle approche fournit des informations pertinentes pour mieux comprendre l'origine des patterns de biodiversité actuels, de la structuration des communautés et des risques potentiels d'extinction. Cette thèse explore plusieurs grandes questions écologiques, en combinant les domaines de la modélisation de la niche et de la phylogénétique. Elle s'applique aux composants importants de la biodiversité de l'Afrique australe. Les objectifs de cette thèse ont été l) de comparer différentes mesures de la biodiversité, 2) d'évaluer l'impact des changements climatiques à venir sur la perte de diversité phylogénétique, 3) d'analyser le lien potentiel entre diversité phylogénétique et diversité morphologique et 4) d'étudier le rôle potentiel de la phylogénie sur la structuration des niches macro-climatiques des espèces. La première partie de cette thèse fournit une comparaison spatiale, et une quantification du chevauchement, entre des prévisions de richesse spécifique et des prédictions de la diversité phylogénétique pour l'une des familles de plantes les plus riches en espèces de la région floristique du Cap (CFR), les Proteaceae. Il résulte des analyses que plusieurs mesures de diversité phylogénétique montraient des distributions spatiales différentes de la richesse spécifique, habituellement utilisée pour édicter des mesures de conservation. La deuxième partie évalue les effets potentiels des changements climatiques attendus sur les taux d'extinction d'animaux et de plantes de l'Afrique australe. Pour cela, des modèles de distribution d'espèces actuels et futurs ont permis de déterminer si l'extinction des espèces se traduira par une plus grande ou une plus petite perte de diversité phylogénétique en comparaison à un processus d'extinction aléatoire. Les résultats ont effectivement montré que l'extinction des espèces liées aux changements climatiques pourrait entraîner une perte plus grande de diversité phylogénétique. Cependant, cette perte ne serait plus grande que celle liée à un processus d'extinction aléatoire qu'à partir d'une forte perte de taxons dans chaque groupe. La troisième partie de cette thèse explore la relation entre distances phylogénétiques et morphologiques d'espèces de chauves-souris de l'Afrique australe. ll s'agit plus précisément de déterminer si une longue histoire évolutive correspond également à des variations morphologiques plus grandes dans ce groupe. Cette relation est en fait prédite par un modèle neutre d'évolution de caractères. Aucune évidence de cette relation n'a émergé des analyses. Au contraire, des tendances négatives ont été détectées, ce qui représenterait la conséquence d'une évolution convergente entre clades et des niveaux élevés de cloisonnement pour chaque clade. Enfin, la dernière partie présente une étude sur la répartition de la niche climatique des chauves-souris de l'Afrique australe. Dans cette étude je rapporte temps de divergence évolutive (ou deux espèces ont divergé depuis un ancêtre commun) au niveau de chevauchement de leurs niches climatiques. Les résultats n'ont pas pu mettre en évidence de lien entre ces deux paramètres. Les résultats soutiennent plutôt l'idée que cela pourrait être I dû à des niveaux particulièrement élevés de répartition de la niche à échelle fine.

Evolutionary analysis of genes of two pathways involved in placental malaria infection

Placental malaria is a special form of malaria that causes up to 200,000 maternal and infant deaths every year. Previous studies show that two receptor molecules, hyaluronic acid and chondroitin sulphate A, are mediating the adhesion of parasite-infected erythrocytes in the placenta of patients, which is believed to be a key step in the pathogenesis of the disease. In this study, we aimed at identifying sites of malaria-induced adaptation by scanning for signatures of natural selection in 24 genes in the complete biosynthesis pathway of these two receptor molecules. We analyzed a total of 24 Mb of publicly available polymorphism data from the International HapMap project for three human populations with European, Asian and African ancestry, with the African population from a region of presently and historically high malaria prevalence. Using the methods based on allele frequency distributions, genetic differentiation between populations, and on long-range haplotype structure, we found only limited evidence for malaria-induced genetic adaptation in this set of genes in the African population; however, we identified one candidate gene with clear evidence of selection in the Asian population. Although historical exposure to malaria in this population cannot be ruled out, we speculate that it might be caused by other pathogens, as there is growing evidence that these molecules are important receptors in a variety of host-pathogen interactions. We propose to use the present methods in a systematic way to help identify candidate regions under positive selection as a consequence of malaria.

Evolutionary and biomedical consequences of internal melanins.

The adaptive function of melanin located in the integument is well known. Although pigments are also deposited in various internal organs, their function is unclear. A review of the literature revealed that 'internal melanin' protects against parasites, pollutants, low temperature, oxidative stress, hypoxemia and UV light, and is involved in the development and function of organs. Importantly, several studies have shown that the amount of melanin deposited on the external body surface is correlated with the amount located inside the body. This finding raises the possibility that internal melanin plays more important physiological roles in dark than light-colored individuals. Internal melanin and coloration may therefore not evolve independently. This further emphasizes the major role played by indirect selection in evolutionary processes.

Patterns of evolutionary constraints on genes in humans

Background: Different regions in a genome evolve at different rates depending on structural and functional constraints. Some genomic regions are highly conserved during metazoan evolution, while other regions may evolve rapidly, either in all species or in a lineage-specific manner. A strong or even moderate change in constraints in functional regions, for example in coding regions, can have significant evolutionary consequences. Results: Here we discuss a novel framework, 'BaseDiver', to classify groups of genes in humans based on the patterns of evolutionary constraints on polymorphic positions in their coding regions. Comparing the nucleotide-level divergence among mammals with the extent of deviation from the ancestral base in the human lineage, we identify patterns of evolutionary pressure on nonsynonymous base-positions in groups of genes belonging to the same functional category. Focussing on groups of genes in functional categories, we find that transcription factors contain a significant excess of nonsynonymous base-positions that are conserved in other mammals but changed in human, while immunity related genes harbour mutations at base-positions that evolve rapidly in all mammals including humans due to strong preference for advantageous alleles. Genes involved in olfaction also evolve rapidly in all mammals, and in humans this appears to be due to weak negative selection. Conclusion: While recent studies have identified genes under positive selection in humans, our approach identifies evolutionary constraints on Gene Ontology groups identifying changes in humans relative to some of the other mammals.

Differentiated evolutionary rates in alternative exons and the implications for splicing regulation

Background: Alternatively spliced exons play an important role in the diversification of gene function in most metazoans and are highly regulated by conserved motifs in exons and introns. Two contradicting properties have been associated to evolutionary conserved alternative exons: higher sequence conservation and higher rate of non-synonymous substitutions, relative to constitutive exons. In order to clarify this issue, we have performed an analysis of the evolution of alternative and constitutive exons, using a large set of protein coding exons conserved between human and mouse and taking into account the conservation of the transcript exonic structure. Further, we have also defined a measure of the variation of the arrangement of exonic splicing enhancers (ESE-conservation score) to study the evolution of splicing regulatory sequences. We have used this measure to correlate the changes in the arrangement of ESEs with the divergence of exon and intron sequences. Results: We find evidence for a relation between the lack of conservation of the exonic structure and the weakening of the sequence evolutionary constraints in alternative and constitutive exons. Exons in transcripts with non-conserved exonic structures have higher synonymous (dS) and non-synonymous (dN) substitution rates than exons in conserved structures. Moreover, alternative exons in transcripts with non-conserved exonic structure are the least constrained in sequence evolution, and at high EST-inclusion levels they are found to be very similar to constitutive exons, whereas alternative exons in transcripts with conserved exonic structure have a dS significantly lower than average at all EST-inclusion levels. We also find higher conservation in the arrangement of ESEs in constitutive exons compared to alternative ones. Additionally, the sequence conservation at flanking introns remains constant for constitutive exons at all ESE-conservation values, but increases for alternative exons at high ESE-conservation values. Conclusion: We conclude that most of the differences in dN observed between alternative and constitutive exons can be explained by the conservation of the transcript exonic structure. Low dS values are more characteristic of alternative exons with conserved exonic structure, but not of those with non-conserved exonic structure. Additionally, constitutive exons are characterized by a higher conservation in the arrangement of ESEs, and alternative exons with an ESE-conservation similar to that of constitutive exons are characterized by a conservation of the flanking intron sequences higher than average, indicating the presence of more intronic regulatory signals.

Chromosomal rearrangements and genetic structure at different evolutionary levels of the Sorex araneus group.

Robertsonian (Rb) fusions received large theoretical support for their role in speciation, but empirical evidence is often lacking. Here, we address the role of Rb rearrangements on the genetic differentiation of the karyotypically diversified group of shrews, Sorex araneus. We compared genetic structure between 'rearranged' and 'common' chromosomes in pairwise comparisons of five karyotypic taxa of the group. Considering all possible comparisons, we found a significantly greater differentiation at rearranged chromosomes, supporting the role of chromosomal rearrangements in the general genetic diversification of this group. Intertaxa structure and distance were larger across rearranged chromosomes for most of the comparisons, although these differences were not significant. This last result could be explained by the large variance observed among microsatellite-based estimates. The differences observed among the pairs of taxa analysed support the role of both the hybrid karyotypic complexity and the level of evolutionary divergence.

Evolutionary origin and functions of retrogene introns.

Retroposed genes (retrogenes) originate via the reverse transcription of mature messenger RNAs from parental source genes and are therefore usually devoid of introns. Here, we characterize a particular set of mammalian retrogenes that acquired introns upon their emergence and thus represent rare cases of intron gain in mammals. We find that although a few retrogenes evolved introns in their coding or 3' untranslated regions (untranslated region, UTR), most introns originated together with untranslated exons in the 5' flanking regions of the retrogene insertion site. They emerged either de novo or through fusions with 5' UTR exons of host genes into which the retrogenes inserted. Generally, retrogenes with introns display high transcription levels and show broader spatial expression patterns than other retrogenes. Our experimental expression analyses of individual intron-containing retrogenes show that 5' UTR introns may indeed promote higher expression levels, at least in part through encoded regulatory elements. By contrast, 3' UTR introns may lead to downregulation of expression levels via nonsense-mediated decay mechanisms. Notably, the majority of retrogenes with introns in their 5' flanks depend on distant, sometimes bidirectional CpG dinucleotide-enriched promoters for their expression that may be recruited from other genes in the genomic vicinity. We thus propose a scenario where the acquisition of new 5' exon-intron structures was directly linked to the recruitment of distant promoters by these retrogenes, a process potentially facilitated by the presence of proto-splice sites in the genomic vicinity of retrogene insertion sites. Thus, the primary role and selective benefit of new 5' introns (and UTR exons) was probably initially to span the often substantial distances to potent CpG promoters driving retrogene transcription. Later in evolution, these introns then obtained additional regulatory roles in fine tuning retrogene expression levels. Our study provides novel insights regarding mechanisms underlying the origin of new introns, the evolutionary relevance of intron gain, and the origin of new gene promoters.

Causal explanations and scientific realism in particle physics

Particle physics studies highly complex processes which cannot be directly observed. Scientific realism claims that we are nevertheless warranted in believing that these processes really occur and that the objects involved in them really exist. This dissertation defends a version of scientific realism, called causal realism, in the context of particle physics. I start by introducing the central theses and arguments in the recent philosophical debate on scientific realism (chapter 1), with a special focus on an important presupposition of the debate, namely common sense realism. Chapter 2 then discusses entity realism, which introduces a crucial element into the debate by emphasizing the importance of experiments in defending scientific realism. Most of the chapter is concerned with Ian Hacking's position, but I also argue that Nancy Cartwright's version of entity realism is ultimately preferable as a basis for further development. In chapter 3,1 take a step back and consider the question whether the realism debate is worth pursuing at all. Arthur Fine has given a negative answer to that question, proposing his natural ontologica! attitude as an alternative to both realism and antirealism. I argue that the debate (in particular the realist side of it) is in fact less vicious than Fine presents it. The second part of my work (chapters 4-6) develops, illustrates and defends causal realism. The key idea is that inference to the best explanation is reliable in some cases, but not in others. Chapter 4 characterizes the difference between these two kinds of cases in terms of three criteria which distinguish causal from theoretical warrant. In order to flesh out this distinction, chapter 5 then applies it to a concrete case from the history of particle physics, the discovery of the neutrino. This case study shows that the distinction between causal and theoretical warrant is crucial for understanding what it means to "directly detect" a new particle. But the distinction is also an effective tool against what I take to be the presently most powerful objection to scientific realism: Kyle Stanford's argument from unconceived alternatives. I respond to this argument in chapter 6, and I illustrate my response with a discussion of Jean Perrin's experimental work concerning the atomic hypothesis. In the final part of the dissertation, I turn to the specific challenges posed to realism by quantum theories. One of these challenges comes from the experimental violations of Bell's inequalities, which indicate a failure of locality in the quantum domain. I show in chapter 7 how causal realism can further our understanding of quantum non-locality by taking account of some recent experimental results. Another challenge to realism in quantum mechanics comes from delayed-choice experiments, which seem to imply that certain aspects of what happens in an experiment can be influenced by later choices of the experimenter. Chapter 8 analyzes these experiments and argues that they do not warrant the antirealist conclusions which some commentators draw from them. It pays particular attention to the case of delayed-choice entanglement swapping and the corresponding question whether entanglement is a real physical relation. In chapter 9,1 finally address relativistic quantum theories. It is often claimed that these theories are incompatible with a particle ontology, and this calls into question causal realism's commitment to localizable and countable entities. I defend the commitments of causal realism against these objections, and I conclude with some remarks connecting the interpretation of quantum field theory to more general metaphysical issues confronting causal realism.

Towards robust network based complex systems : from evolutionary cellular automata to biological models

Abstract Sitting between your past and your future doesn't mean you are in the present. Dakota Skye Complex systems science is an interdisciplinary field grouping under the same umbrella dynamical phenomena from social, natural or mathematical sciences. The emergence of a higher order organization or behavior, transcending that expected of the linear addition of the parts, is a key factor shared by all these systems. Most complex systems can be modeled as networks that represent the interactions amongst the system's components. In addition to the actual nature of the part's interactions, the intrinsic topological structure of underlying network is believed to play a crucial role in the remarkable emergent behaviors exhibited by the systems. Moreover, the topology is also a key a factor to explain the extraordinary flexibility and resilience to perturbations when applied to transmission and diffusion phenomena. In this work, we study the effect of different network structures on the performance and on the fault tolerance of systems in two different contexts. In the first part, we study cellular automata, which are a simple paradigm for distributed computation. Cellular automata are made of basic Boolean computational units, the cells; relying on simple rules and information from- the surrounding cells to perform a global task. The limited visibility of the cells can be modeled as a network, where interactions amongst cells are governed by an underlying structure, usually a regular one. In order to increase the performance of cellular automata, we chose to change its topology. We applied computational principles inspired by Darwinian evolution, called evolutionary algorithms, to alter the system's topological structure starting from either a regular or a random one. The outcome is remarkable, as the resulting topologies find themselves sharing properties of both regular and random network, and display similitudes Watts-Strogtz's small-world network found in social systems. Moreover, the performance and tolerance to probabilistic faults of our small-world like cellular automata surpasses that of regular ones. In the second part, we use the context of biological genetic regulatory networks and, in particular, Kauffman's random Boolean networks model. In some ways, this model is close to cellular automata, although is not expected to perform any task. Instead, it simulates the time-evolution of genetic regulation within living organisms under strict conditions. The original model, though very attractive by it's simplicity, suffered from important shortcomings unveiled by the recent advances in genetics and biology. We propose to use these new discoveries to improve the original model. Firstly, we have used artificial topologies believed to be closer to that of gene regulatory networks. We have also studied actual biological organisms, and used parts of their genetic regulatory networks in our models. Secondly, we have addressed the improbable full synchronicity of the event taking place on. Boolean networks and proposed a more biologically plausible cascading scheme. Finally, we tackled the actual Boolean functions of the model, i.e. the specifics of how genes activate according to the activity of upstream genes, and presented a new update function that takes into account the actual promoting and repressing effects of one gene on another. Our improved models demonstrate the expected, biologically sound, behavior of previous GRN model, yet with superior resistance to perturbations. We believe they are one step closer to the biological reality.