ERC FUNDED PROJECTS

Here we propose a first step toward a direct reconstruction of the evolutionary history of human infectious disease agents by obtaining genome wide data of historic pathogens. Through an extensive screening of skeletal collections from well-characterized catastrophe, or emergency, mass burials we plan to detect and sequence pathogen DNA from various historic pandemics spanning at least 2,500 years using a general purpose molecular capture method that will screen for hundreds of pathogens in a single assay. Subsequent experiments will attempt to reconstruct full genomes from all pathogenic species identified. The molecular fossil record of human pathogens will provide insights into host adaptation and evolutionary rates of infectious disease. In addition, human genomic regions relating to disease susceptibility and immunity will be characterized in the skeletal material in order to observe the direct effect that pathogens have made on the genetic makeup of human populations over time. The results of this project will allow a multidisciplinary interpretation of historical pandemics that have influenced the course of human history. It will provide priceless information for the field of history, evolutionary biology, anthropology as well as medicine and will have direct consequences on how we manage emerging and re-emerging infectious disease in the future.

1 474 560 €

Start date: 2013-01-01, End date: 2017-12-31

Horizontal gene transfer (HGT) is a fundamental process of bacterial evolution, accelerating adaptation to novel environments and providing access to new ecological niches. However, two of the three mechanisms of HGT, transduction and conjugation, both rely on semi-autonomous vectors (lysogenic phages and conjugative plasmids, respectively), creating the potential for coadaptation between microbe and vector. I here focus on conjugative plasmids. These encode their own replication and transfer, and as such are capable of pursuing their own fitness interests, which need not be aligned with those of their bacterial host. My thesis is that bacterial adaptation by conjugation must therefore be viewed as a co-evolutionary, rather than simply an evolutionary process as achieved to date. In this proposal I take an experimental evolution approach to derive an empirically founded understanding of bacteria-plasmid coevolutionary processes. In particular, I focus on the effects (on the pattern and process of bacteria-plasmid coevolution) of ecological variables identified in population models as crucial to the persistence of conjugative plasmids: environmental heterogeneity, spatial structure, and between-species transfer. Drawing on coevolutionary theory, I highlight that the ecological conditions expected to favour plasmid persistence may often drive the breakdown of bacteria-plasmid coadaptation. Additionally, I will determine the consequences of bacteria-plasmid coevolution for the structuring of microbial communities.

1 233 610 €

Start date: 2013-02-01, End date: 2018-01-31

Evolutionary change of gene copy number through gene duplication is a relatively pervasive phenomenon in eukaryotic genomes. However, for a subset of genes such changes are deleterious because they result in imbalances in the cell. Such dosage-sensitive genes have been increasingly implicated in disease, particularly through the association of copy number variants (CNVs) with pathogenicity. In my lab we have previously discovered that many genes in the human genome which were retained after whole genome duplication (WGD) are refractory to gene duplication both over evolutionary timescales and within populations. These are expected characteristics of dosage-balanced genes. Many of these genes are implicated in human disease. I now propose to take a computational (dry-lab) approach to examine the evolution of dosage-balanced genes further and to develop a sophisticated model of evolutionary constraint of copy number. These models will enable the identification of dosage-balanced genes and their consideration as novel candidate disease loci. Recognising and interpreting patterns of constraint is the cornerstone of molecular evolution. Through careful analysis of genome sequences with respect to gene duplication over evolutionary times and within populations, we will develop a formal and generalised model of copy-number evolution and constraint. We will use these models to identify candidate disease loci within pathogenic CNVs. We will also study the characteristics of known disease genes in order to identify novel candidate loci for dosage-dependent disease. This is an ambitious and high impact project that has the potential to yield major insights into gene copy-number constraint and its relationship to complex disease.

1 358 534 €

Start date: 2013-01-01, End date: 2018-12-31

"Multidrug-resistant bacteria are a global threat to public health and the economy. Studies in model organisms suggest compensatory evolution and epistatic interactions between drug resistance-conferring mutations are important drivers of drug resistance. However, the relevance of these factors for the emergence and transmission of human pathogenic bacteria has not been established. To bridge the gap between laboratory experimentation and epidemiology, I propose a multidisciplinary approach focusing on Mycobacterium tuberculosis, the etiologic agent of human tuberculosis (TB). Specifically, I shall combine experimental evolution and fitness assays in vitro and in human macrophages with comparative genome sequencing, RNAseq-based transcriptomics, and population-based molecular epidemiology to: 1) Identify and characterize compensatory mutations in M. tuberculosis resistant to rifampicin, streptomycin, and ofloxacin; 2) Detect epistasis between drug resistance-conferring mutations in different strain genetic backgrounds; 3) Investigate the effect of drug resistance-conferring mutations, compensatory mutations, and their epistatic interactions on the M. tuberculosis transcriptome. The strength of my approach lies in the integration of an experimentally tractable model system (Mycobacterium smegmatis) with targeted validation experiments in clinically relevant M. tuberculosis, and comprehensive molecular epidemiological data collected prospectively in Georgia, a country with a high-burden of multidrug-resistant TB. Through its multidisciplinary nature, this project will simultaneously test predictions from ecological theory and experimental models, generate new insights into the biology and epidemiology of multidrug-resistant TB, and ultimately contribute to the control of one of humankind’s most important infectious diseases."

1 498 614 €

Start date: 2013-04-01, End date: 2018-03-31

How important are environmental barriers between species and populations now and in the future? Currently, environmental barriers to movement across habitats that have persisted since the last ice age are breaking down, resulting in gene flow among previously isolated populations and even hybridization between species. What are the consequences of this gene flow? Local genetic adaptations to the specific conditions of a habitat are though to be threatened when gene flow occurs, but we know little about the long-term evolutionary effects such events have on species. Recent ancient DNA work on polar and brown bears even suggests that gene flow may be beneficial, rather than detrimental for the adaptation and survival of species during times of rapid climate change. This project aims to investigate the extent of gene flow among and its effect upon the survival, adaptation and evolutionary history of temporarily isolated populations of animal species during periods of rapid climate change. This goal will be achieved by looking back into the late Pleistocene, when our world experienced repeated and rapid periods of massive climatic change to which species had to adapt. The project will target the evolutionary history of four species (mammoth, spotted hyena, cave bear, and grey wolf) by sequencing large parts of the nuclear genome of each species across both time and space. In each species conflicting evolutionary histories are provided by morphological and mitochondrial DNA analyses, suggesting that (so far undetected) gene flow of nuclear DNA must have occurred. Undetected gene flow may explain aspects of their evolutionary history, and also the way these species adapted to the rapidly changing environmental conditions of the late Pleistocene.

1 449 380 €

Start date: 2012-12-01, End date: 2017-11-30

"The dramatic success of infectious agents comes from their ability to adapt to both immune and pharmaceutical selective pressures. To uncover the dynamics of bacterial adaptation, experimental evolution has been widely used, focusing mostly on organismal fitness. Many of the observation derived from these experiments have been captured by Fisher's Geometric model of Adaptation (FGMA). Despite its success, this top-down phenotypic model is relatively abstract. In fact, its most important parameter, the number of independent phenotypes an organism expose to the action of natural selection, or phenotypic complexity, remains completely disconnected from a genetic perspective. More recently, bottom-up genotype to phenotype maps from system biology have provided an alternative to unravel the constraints regulating bacterial evolution. In the present project, I want to connect these different approaches. The interpretation of system biology models in terms of FGMA will (i) uncover the genetic determinants of phenotypic complexity, giving more genetic context to FGMA, and, (ii) transpose our understanding of evolution through FGMA to complex genotype to phenotype maps. Four different levels of integration will be used: the gene, the metabolic network, the organism and the species. I will use -antibiotic resistance gene, TEM1, to connect thermodynamic models of protein evolution to FGMA, and characterize the phenotypic complexity of a single gene, -computational models of metabolic network and experimental modification of a biochemical pathway regulation to assess the meaning of phenotypic complexity in networks, -in vitro and in vivo experimental evolution coupled with genome sequencing and mutant reconstruction to assess the molecular bases of changes in beneficial mutation rates during organismal adaptation, - faeces of well characterised human twins to assess the factors of the human gut's environment that shape the genetic diversity of the Escherichia coli species."

1 485 600 €

Start date: 2013-05-01, End date: 2018-04-30

INCORALS will establish a novel conceptual model that introduces a transition of symbiotic algae from a nutrient limited to a nutrient starved state as a process that renders reef building corals more susceptible to heat stress. Elevated temperatures have been identified as the key driver for coral bleaching, which is the often fatal loss of corals’ symbiotic algae. Thus, studies have estimated that reefs will be lost within the next one hundred years as a result of global warming. High temperatures undoubtedly play a major role in triggering coral bleaching. However, observations made for instance during the 1998 bleaching event, suggest also a connection between the susceptibility of corals to heat stress and anthropogenically elevated nutrient levels. Here, I present evidence that unbalanced ratios of dissolved inorganic nitrogen to phosphorus in the water column perturb the lipid composition of photosynthetic membranes of zooxanthellae and result in an increased susceptibility to thermal bleaching. I have developed a novel conceptual model of coral bleaching that introduces nutrient starvation as a cause for increased heat stress susceptibility. The model clarifies the previously unexplained correlation between the reduction of the thermal bleaching threshold of corals and their exposure to coastal run-off with elevated concentrations of dissolved inorganic nitrogen. INCORALS will conduct an in-depth study of nutrient starvation of reef corals, comparing the impact of nitrogen, phosphorus and iron. INCORALS will combine physiological experiments under tightly controlled laboratory conditions and field-based studies, using a suite of optical methods and cutting-edge molecular techniques to study this yet unexplored cause of coral bleaching and define its relevance for coral ecosystems. The improved understanding of coral bleaching gained during this project is urgently required to develop knowledge-based management strategies to support coral reef resilience.

1 285 671 €

Start date: 2012-11-01, End date: 2017-10-31

The American tropics – the Neotropics – comprise more species than any other region on Earth, including thousands of species used as crops, medicines and crafts. Understanding the evolution of this biodiversity and predicting the effects of climate and habitat changes on species losses constitute a major scientific challenge. This project will: 1) Estimate the rates of historical migration, speciation and extinction among and within all major Neotropical biomes and regions, thereby identifying key areas for ‘evolutionary’ conservation (i.e., those necessary for biotic interchange and vegetation shifts, and those that may function as ‘species pumps’ to the rest of the continent). 2) Test competing hypotheses of speciation (soil specialisation, temperature increases, polyploidy, habitat shifts, range expansion) for the two main centres of Neotropical biodiversity: the tropical Andes and Amazonia. 3) Produce new estimates on species losses due to on-going climate and habitat changes based on our new findings in 1) and 2) above. To achieve these goals we will develop novel bioinformatics pipelines that will greatly improve our use of biological databases. We will analyse DNA sequences, georeferences and biotic traits for tens of thousands of plant and animal species. Our tools will enable continuously up-to-date inferences and allow the easy integration of new data by students and researchers interested in the evolution of particular species groups or biomes. This is a multi-disciplinary project that requires a wide range of skills in molecular phylogenetics, bioinformatics, field botany, ecology and palaeontology. It will greatly profit from the well-established scientific network I have built up in my career, the vast collections of Neotropical species deposited at European natural history collections, and the excellent laboratory and cultivation facilities available in Gothenburg, Sweden.

1 499 855 €

Start date: 2013-01-01, End date: 2017-12-31

The origin of the eukaryotic cell represents an enigmatic yet dramatically incomplete evolutionary puzzle. The few pieces of this puzzle that we have managed to identify thus far indicate that the eukaryotic cell most probably emerged via a fusion of an archaeal and an alphaproteobacterial cell. Yet, beyond this, scientific debate is mainly engulfed by speculation, which, to a large extent, is fed by our poor understanding of the identity of these bacterial and archaeal fusion partners. In the current research proposal, I aim to identify contemporary relatives of the bacterial and archaeal lineages that once founded the eukaryotic cell using novel single-cell genomics and phylogenomics approaches. Till this end, environmental samples that are enriched for the target microbial lineages will be collected and analyzed at the single cell level. A novel microdroplet-based single-cell analysis platform will be implemented that allows for the analysis of millions of individual cells. After target cells have been identified, their genomic material will be amplified, and subjected to next-generation sequencing analysis. Subsequent state-of-the-art phylogenomic analyses will elucidate the taxonomic affiliation of these target cells in relation to other archaeal and bacterial lineages, as well as to eukaryotes. The proposed strategy will identify hundreds of novel prokaryotic lineages, some of which representing close contemporary relatives of the ‘parental’ lineages that founded the eukaryotic cell. The genomic exploration of these lineages will add the taxonomic resolution that is needed to start solving the evolutionary puzzle of the emergence of the eukaryotic cell.

1 721 440 €

Start date: 2012-11-01, End date: 2017-10-31

"Studies of cooperative animal societies have advanced understanding of social evolution but have also revealed great individual variation in cooperative behaviour and major life history traits, even among individuals of the same age, sex and social status. Research on laboratory mammals suggests that this variation may be explained by early life influences on development, but little is known about the function and mechanism of these developmental effects in wild mammals, or whether these effects are adaptive. We will address this shortfall in knowledge using both empirical and theoretical approaches. Our empirical work will use large-scale field experiments on a model cooperative mammal system, the banded mongoose Mungos mungo, to measure prenatal developmental impacts on offspring growth, care received, stress physiology, cooperation, health, cognition, aging and lifetime fitness. Our theoretical research will build on the recent economic theory of ‘skill formation’, and will generate new testable predictions about the coevolution of developmental responses and maternal and helper investment. The output of the research will be new insights into the evolutionary and proximate causes of individual variation in health, behaviour and life history in social mammals, and a new conceptual understanding of social development in cooperative organisms from insects to humans."

1 493 322 €

Start date: 2013-01-01, End date: 2017-12-31