Modern-day amphibians are known to be suffering rates of extinction that far exceed any other class of vertebrates, including those experienced by mammals and birds, and nearly one third of amphibian species are threatened. The question of why amphibians are going extinct at these accelerated rates has puzzled scientists for three decades. A clue to the mystery came about when scientists working in Central America and Australia noted that the declines in amphibian biodiversity were spreading in a wave-like manner, from a point source. These patterns of decline were caused by an emerging infectious disease, and in 1997 researchers discovered the fungal pathogen and named it Batrachochytrium dendrobatidis (Bd). Since then, our research has been focused on finding out where the fungus is, where it is spreading to and what its effect is on amphibian biodiversity. We have made a mapping tool at www.bd-maps.net and this has shown that Bd occurs on all continents with amphibians. However, not all species and populations infected with Bd die, suggesting to us that there may be more than one strain (or lineage) of Bd and that these are not all equally destructive. Confirmation of this came when we used new whole genome sequencing technology to sequence isolates of Bd from around the world. We discovered three lineages of Bd, and showed that only one of them is responsible for mass mortalities and species declines. We named this lineage BdGPL for 'Bd Global Panzootic Lineage' and showed that it occured in Africa, Europe, Australia and America. Currently, several lines of argument suggest that BdGPL evolved in Africa. We will investigate this 'Bd Out-of-Africa' hypothesis by sequencing the genomes of Bd isolates widely across Africa and Europe, and undertaking fine-scale studies of the pathogens impact where it has been introduced into new environments. Our project will investigate both broad- and fine-scale processes, by characterising the genome diversity of Bd at the continental-level, but also focusing on fine-scale evolutionary patterns in Africa, the Pyrenees, the Alps and the UK. We will twin these genomic approaches with experimental approaches in order to determine whether invasive 'outbreak' lineages have altered their virulence and infectivity owing to accelerated evolution by the action of natural selection. Here, our expectation is that outbreak lineages that are adapting to new environments and hosts will have increased virulence and transmission rates when compared against the ancestral lineage in its original geographic background. These experiments will not only give us added certainty when determining the geographic origins of these infections, but will also allow us to assess why BdGPL is so much more virulent, and transmittable, than the other lineages of Bd. More widely, our research will inform us about the risk that new pathogens pose to uninfected environments. Currently, we are seeing many emerging pathogenic fungi causing untold destruction to forests, bats and frogs. Perhaps there are common processes that underlie these emergences of disease - not only global trade in infected goods but also genome-level processes that are unique to fungi? Projects such as that described here hold the key to answering these important questions before losses of biodiversity increase further.

Bt-crops, engineered to express a variety of toxins derived from Bacillus thuringensis, are an efficient method for controlling agricultural insect pests, particularly moth caterpillars. However, as with conventional insecticides, several insect populations around the globe have found ways to evolve mechanisms of resistance to Bt. Therefore, the sustainable use of Bt-crops is dependent on preventing, or at least greatly slowing, the rate at which resistance evolves, and by developing new Bt-crop varieties that target one or more weak points in the pest defences. Resistance spreads through a population much more slowly when the resistance trait is fully recessive (as opposed to partially recessive or dominant), and when the proportion of susceptible individuals in the population is high (which prevents two copies of the resistance alleles coming together in the same individual). This is why Bt-crops are engineered to deliver a high dose of toxin that is supposed to kill all individuals outright, and they are grown together with non-Bt plants, to sustain a sufficiently large number of susceptible individuals. The problem is that, for various reasons, the assumptions on which this resistance management strategy is based rarely apply to field conditions. This project is about putting these assumptions under the microscope by studying the genetics of Bt resistance in two major moth pests of maize, and incorporating this information into a predictive model to provide a more nuanced basis for designing insect resistance management strategies. The primary focal species is the African maize stalkborer, the major insect pest of maize and sorghum in sub-Saharan Africa. This project aims to discover the genetic changes that have occurred in the African maize stalkborer population in South Africa to confer dominant resistance to Bt maize, which led to the economic failure and replacement of the original Bt-crop variety. Surveys of genetic diversity will also allow us to assess the risk of Bt-resistance evolving in east African countries, where Bt-maize is close to being released. The secondary focal species is the Fall armyworm, a major pest of maize and cotton in the Americas, where it has evolved resistance to some Bt toxins. This species colonised west and central Africa in 2016, and has now spread to eastern and southern Africa, where it has elicited emergency large scale pesticide spraying of maize fields. By establishing the degree of tolerance (and its genetic basis) in the South African Fall armyworm population to the Bt-maize currently in use, and plugging this information into our model, we will provide a timely evaluation of how this non-native pest species is likely to cope with the current Bt-resistance management regime in a new ecological setting. The benefits of this research are that specific knowledge about the genetic identity and diversity of Bt resistance and tolerance mechanisms, when put together with a more realistic model, will aid in making more reliable predictions about the rate of appearance and spread of resistance under alternative refuge design approaches. The results, including comparative analysis of two major pest species, will also contribute to developing new Bt crops that provide longer-term lepidopteran pest control. Finally, the outputs will both provide general scientific insights and be directly relevant to addressing a regional food security problem urgently in need of solutions.

DNA methylation (DNAm) is an epigenetic mechanism that plays a central role in gene regulation. It helps to define how cells respond to genetic and environmental signals and, ultimately, contributes to whole system health and disease status. Levels of DNAm differ from one person to another. However, it is unclear how much of the variation in DNAm levels is caused by genetic or environmental factors and if such effects also relate to human phenotypes. Understanding the relationships between DNAm, genetics and environment is essential for both understanding pathways of health and disease and disease consequences. Prior research has been limited to populations of European ancestry, restricting understanding of DNAm variation to limited contexts. This is a crucial knowledge gap because there are known genetic and environmental differences in drug response and disease risk factors across population groups worldwide which may be attributable to DNAm variation. Evaluating DNAm variation in diverse population groups allows comparison across varying genetic and environmental exposure profiles. Identification of disease pathways common to all populations will represent mechanisms of health and disease that are common across all humans. This allows identification of drug targets that will be effective in any population group. Identification of disease pathways restricted to specific genetic and/or environmental exposure profile will reflect adaptation to environmental and genetic context. This will allow identification of molecular mechanisms that underpin the disease discordance that we observe across global populations and highlight opportunities for targeted treatments. Our first project aim is to map genetic and environmental determinants of human DNAm variation to understand mechanisms of DNAm variability. We will generate a catalog of genetic associations with DNAm across populations worldwide. This catalog will be used to assess which of the identified genetic associations with DNAm are also associated with human complex traits. This is important because the findings can inform the functional role of phenotype-associated genetic variation, and ultimately - our understanding of the mechanisms underlying human phenotype variation. The second aim of the project is to understand mechanisms of disease and disease discordance observed between population groups for childhood and cardiometabolic disease related phenotypes. This project focusses on childhood and cardiometabolic disease for which there is substantial disease discordance and health disparity across populations. For example, diabetes risk is substantially higher in individuals of South Asian origin even after accounting for known genetic and environmental risk factors. Identification of DNAm variation associated with type 2 diabetes that is context specific will contribute to explaining excess type 2 diabetes risk in the South Asian population group. In doing so, Identification of disease pathways restricted to specific genetic and/or environmental exposure profiles brings the opportunity to target treatment or intervention where it is effective. This research builds a global partnership of teams to bring together genetic and epigenetic data collected from individuals worldwide. A key aspect of this proposal is building equitable partnerships between these teams. This is essential in order to build capacity for research in genetically diverse datasets and to provide internationally relevant research on cardiometabolic and child health phenotypes Identification of common and context specific mechanisms of health and disease mediated by DNAm is of high health impact because it will enable actions to reduce global health disparity and inequity via targeted interventions or treatments.

Biomass burning aerosol (BBA) exerts a considerable impact on climate by impacting regional radiation budgets as it significantly reflects and absorbs sunlight, and its cloud nucleating properties perturb cloud microphysics and hence affect cloud radiative properties, precipitation and cloud lifetime. However, BBA is a complex and poorly understood aerosol species as it consists of a complex cocktail of organic carbon and inorganic compounds mixed with black carbon and hence large uncertainties exist in both the aerosol-radiation-interactions and aerosol-cloud-interactions, uncertainties that limit the ability of our current climate models to accurately reconstruct past climate and predict future climate change. The African continent is the largest global source of BBA (around 50% of global emissions) which is transported offshore over the underlying semi-permanent cloud decks making the SE Atlantic a regional hotspot for BBA concentrations. While global climate models agree that this is a regional hotspot, their results diverge dramatically when attempting to assess aerosol-radiation-interactions and aerosol-cloud-interactions. Hence the area presents a very stringent test for climate models which need to capture not only the aerosol geographic, vertical, absorption and scattering properties, but also the cloud geographic distribution, vertical extent and cloud reflectance properties. Similarly, in order to capture the aerosol-cloud-interactions adequately, the susceptibility of the clouds in background conditions; aerosol activation processes; uncertainty about where and when BBA aerosol is entrained into the marine bundary layer and the impact of such entrainment on the microphysical and radiative properties of the cloud result in a large uncertainty. BBA overlying cloud also causes biases in satellite retrievals of cloud properties which can cause erroneous representation of stratocumulus cloud brightness; this has been shown to cause biases in other areas of the word such as biases in precipitation in Brazil via poorly understood global teleconnection processes. It is timely to address these challenges as both measurement methods and high resolution model capabilities have developed rapidly over the last few years and are now sufficiently advanced that the processes and properties of BBA can be sufficiently constrained. This measurement/high resolution model combination can be used to challenge the representation of aerosol-radiation-interaction and aerosol-cloud-interaction in coarser resolution numerical weather prediction (NWP) and climate models. Previous measurements in the region are limited to the basic measurements made during SAFARI-2000 when the advanced measurements needed for constraining the complex cloud-aerosol-radiation had not been developed and high resolution modelling was in its infancy. We are therefore proposing a major consortium programme, CLARIFY-2016, a consortium of 5 university partners and the UK Met Office, which will deliver a suite of ground and aircraft measurements to measure, understand, evaluate and improve: a) the physical, chemical, optical and radiative properties of BBAs b) the physical properties of stratocumulus clouds c) the representation of aerosol-radiation interactions in weather and climate models d) the representation of aerosol-cloud interactions across a range of model scales. The main field experiment will take place during September 2016, based in Walvis Bay, Namibia. The UK large research aircraft (FAAM) will be used to measure in-situ and remotely sensed aerosol and cloud and properties while advanced radiometers on board the aircraft will measure aerosol and cloud radiative impacts. While the proposal has been written on a stand-alone basis, we are closely collaborating and coordinating with both the NASA ORACLES programme (5 NASA centres, 8 USA universities) and NSF-funded ONFIRE programme (22 USA institutes).