he developmental programming hypothesis posits that environmental insults in utero can have a major influence on adult-onset disease and phenotypic outcomes. We are interested in understanding the mechanistic basis of this phenomenon in mammals. In particular, identifying developmental programming-induced molecular perturbations, such as epigenetic marks, and then understanding how these perturbations influence phenotype. The project will be highly inter- disciplinary and will involve novel in vitro assays, followed by translation into a unique long-standing human cohort from the Gambia. The experimental work will be underpinned by bioinformatics/statistical analyses of (epi)genome-scale datasets. Developmental programming is the process by which the in utero environment influences phenotypic and disease outcomes in post-natal life. There is currently great interest in identifying the molecular mechanisms that underlie developmental programming, and modulation of epigenetic marks (e.g. DNA methylation) has emerged as potentially a key contributing factor. We recently analysed a mouse model in which pregnant females are exposed to a low protein (LP) diet and their offspring subjected to phenotypic and DNA methylation analyses when they reach adulthood (Holland et al 2016, Science). We found that in the LP-exposed offspring, body weight is linearly correlated with methylation dynamics at ribosomal DNA. Strikingly, the methylation response in these animals was also influenced by previously unappreciated genetic variation within the rDNA. Similar effects were also found in developmental programming models of high fat and obesogenic diet. Given the ubiquity of rDNA in all life forms, we propose that such gene- environment induced epigenetic dynamics also occur in humans. In this regard, we have a long- term study on a population in rural Gambia, wherein seasonal variations in food supply and metabolic demand provide a natural experiment by which to study the effect of periconceptional environment (including maternal nutritional status) on epigenetic development in the offspring. The PhD project will involve first developing an in vitro assay for identifying environmentally- responsive rDNA variants in humans. These will then be studied mechanistically in vitro, and also translated into The Gambian cohort. The work will also entail generation and bioinformatic analysis of (epi)genome-scale datasets. There will also be opportunities to visit The MRC center in The Gambia. Overall, the project will aim to deliver a molecular understanding of the in utero basis of complex diseases and phenotypes in mammals, and is best suited to candidates interested in developing both wet-lab and computational skills.

Throughout evolution, retroviruses invaded virtually all mammals and became integrated within their genomes. Although these so-called endogenous retroviruses (ERVs) lost their ability to produce viral particles, for a while they could still self-replicate within genomes and be passed on to the next generation. Eventually, most became inactive and could not expand further. Currently there are no known active ERVs in humans and only a relatively small number remain active in mice. Nevertheless, ERVs make up ~8% of the mouse and human genomes. It is thought that most ERVs serve no particular purpose. However, a small subset has been 'domesticated' by the species that host them to perform essential functions. Some have turned into genes, which produce proteins involved in, e.g., immunity and placental development. Others became important regulators of existing genes. That means that certain ERVs can determine whether a given gene is 'on' or 'off'. However, only few examples of this are known to date, and it remains unclear how important ERVs are for the regulation of gene activity. One particular place where ERVs seem to be important is in the placenta. Placental shape and structure varies extensively between different mammals, and it is thought that these differences might come, at least in part, from the influence that ERVs have on gene activity. In this proposal we aim to test this hypothesis by comparing how ERVs affect gene activity in the placenta of mice, rats and humans. First, we will look for differences in the location of ERVs between these species and how it correlates with gene activity in the placenta. This will tell us which ERVs are likely to be important. Next, we will test for causal relationships between ERVs and gene activity by manipulating selected ERVs with molecular tools. We will take several approaches, first inactivating multiple ERVs simultaneously, then removing individual ERVs from the genome. We will test whether these experiments resulted in genes turning 'on' or 'off' and ultimately, any change in the behaviour of placental cells. This proposal will provide clues as to whether ERVs may have played a role in placental evolution, and potentially impact on reproductive success.

This innovative project will provide a comparative cultural history of British and American colonial campaigns in Africa, South Asia and South East Asia, between 1885 and 1914. The project will provide a comprehensive study of what was known as ‘savage warfare’ that goes beyond the conventional military histories by examining the cultural assumptions and colonial knowledge that underwrote military practice. The project aims at making a substantial contribution beyond academia, and the historical exploration of colonial warfare cuts to the very heart of contemporary debates on the ‘war on terror’ and the continuing legacies of imperialism. The Experienced Researcher will expand his area of expertise on British imperial history to include American imperial and military history, as well as undertaking extensive archival research in Britain, the United States, India and the Philippines. The ER will spend 24 months during the outgoing phase at the History Department at George Washington University to receive training and gain new knowledge within the area of American imperial history. Following this, during the 12 months of the return phase, he will be hosted at Queen Mary, University of London, to transfer back the acquired knowledge and further consolidate his knowledge in the field. The deliverables of the project consist of two articles in per-reviewed journals and the completion of one book manuscript. The ER will furthermore organize two workshops in the United States and one major international conference at QMUL upon his re-integration into the ERA. The undertaking of this multidisciplinary project, that ties together European and American imperial history in a highly original manner, will significantly enhance the career opportunities of the ER and allow him to establish himself as a world-leading historian of imperialism and conflict.