ERC FUNDED PROJECTS

It has long been understood that genes contribute to phenotypes that are then the basis of selection. However, the nature and process of this relationship remains largely theoretical, and the relative contribution of change in gene expression and coding sequence to phenotypic diversification is unclear. The aim of this proposal is to fuse information about sexually dimorphic phenotypes, the mating systems and sexually antagonistic selective agents that shape sexual dimorphism, and the sex-biased gene expression patterns that encode sexual dimorphisms, in order to create a cohesive integrated understanding of the relationship between evolution, the genome, and the animal form. The primary approach of this project is to harnesses emergent DNA sequencing technologies in order to measure evolutionary change in gene expression and coding sequence in response to different sex-specific selection regimes in a clade of birds with divergent mating systems. Sex-specific selection pressures arise in large part as a consequence of mating system, however males and females share nearly identical genomes, especially in the vertebrates where the sex chromosomes house very small proportions of the overall transcriptome. This single shared genome creates sex-specific phenotypes via different gene expression levels in females and males, and these sex-biased genes connect sexual dimorphisms, and the sexually antagonistic selection pressures that shape them, with the regions of the genome that encode them. The Galloanserae (fowl and waterfowl) will be used to in the proposed project, as this clade combines the necessary requirements of both variation in mating systems and a well-conserved reference genome (chicken). The study species selected from within the Galloanserae for the proposal exhibit a range of sexual dimorphism and sperm competition, and this will be exploited with next generation (454 and Illumina) genomic and transcriptomic data to study the gene expression patterns that underlie sexual dimorphisms, and the evolutionary pressures acting on them. This work will be complemented by the development of mathematical models of sex-specific evolution that will be tested against the gene expression and gene sequence data in order to understand the mechanisms by which sex-specific selection regimes, arising largely from mating systems, shape the phenotype via the genome.

1 350 804 €

Start date: 2011-01-01, End date: 2016-07-31

Wide field panoramic telescopes will become a major force in astronomy over the next decade. They will address a rich set of scientific problems, from ``killer asteroids'' to the cosmic dark energy. Pan-STARRS-1 (PS1), built by the University of Hawaii, is the first of this new generation of telescopes. European astronomers in Germany and the UK, including in the PI's host institute, make up a large fraction of the Science Consortium that, over the next 4 years, will exploit the data. This proposal is focused on the use of PS1 for cosmology. I propose a programme that combines state-of-the-art cosmological simulations and modelling with high-level analyses of the data. The goal is to test core assumptions of the standard cosmogonic model, LCDM, on scales and at epochs where it has not been tested before and where it can, in principle, be ruled out. At the same time, these tests will advance our understanding of the main constituents of our universe (dark matter and dark energy) and of the processes of galaxy formation and evolution. Two types of structure at opposite ends of the cosmological scale, the Milky Way and the large-scale distribution of galaxies at redshifts z<1.5, are ideally suited to this purpose. Studies of the Milky Way will test LCDM predictions for the hierarchical assembly of galaxies and the structure of their dark matter halos. Studies of the galaxy distribution will test LCDM predictions for the growth of structure and the connection between galaxies and dark matter. To link theory and data, I will construct mock catalogues using very large cosmological simulations and sophisticated modelling techniques. These catalogues will have a much broader applicability that just PS1 and I will make them publicly available using e-science techniques.

2 266 850 €

Start date: 2011-05-01, End date: 2017-04-30

The human genome is highly transcribed, with over 90% of sequences contributing to the production of RNA. The function of the vast majority of these RNAs is unknown. Evidence over many years has revealed that transcription factors and chromatin regulators are associated with a variety of non-coding (nc)RNAs, but their function remains largely unknown. There are a few cases where a role has been ascribed for ncRNAs in transcription, but no clear mechanistic insight has been defined yet. We predict that many of the newly identified ncRNAs emanating from the genome will play a role in transcriptional processes. We intend to identify and characterise such ncRNAs. This will take place in two phases. In the first phase we will use biochemical approaches to identify ncRNAs involved in the regulation of chromatin and transcription. Our investigations will focus on proteins leading to the induction of pluripotency and oncogenesis. ncRNAs associated with such proteins will be identified using targeted screens. In the second phase, the importance of these RNAs in determining pluripotency and oncogenesis will be analysed. In addition, a variety of molecular approaches will be used to investigate the mechanism by which these ncRNAs regulate the function of the proteins or complexes they associate with. One particular hypothesis we will explore is that such ncRNAs play a role in guiding proteins to DNA sequences, via the formation of RNA/DNA triplexes. This concerted and focused analysis will provide mechanistic insights into the functions of ncRNAs in transcriptional regulation and validate their role in key biological processes. The identification of such new ncRNA-regulated pathways may open up new avenues for therapeutic intervention.

2 141 470 €

Start date: 2011-05-01, End date: 2017-04-30

The prime objective for every life form is to deliver its genetic material, intact, to the next generation. Each human cell receives tens-of-thousands of DNA lesions per day. These lesions can block genome replication and transcription, and if not repaired or repaired incorrectly, they lead to mutations or wider genome aberrations that threaten cell viability. To counter such threats, life has evolved the DNA-damage response (DDR), to detect DNA damage, signal its presence and mediate its repair. DDR events impact on many cellular processes and, crucially, prevent diverse human diseases that include cancer, neurodegenerative diseases, immune-deficiencies and premature ageing. While much progress has been made in identifying DDR proteins, much remains to be learned about the molecular and cellular functions that they control. Furthermore, the frequent reporting of new DDR proteins in the literature suggests that many others await identification. The main goals for the proposed research are to: identify important new DDR-proteins and DDR-modulators, particularly those responding to DNA double-strand breaks (DSBs); provide mechanistic insights into how these proteins function; and determine how DDR events are affected by chromatin structure, by molecular chaperones and components of the Ubiquitin and Sumo systems. To achieve these ends, we will use molecular biology, biochemical, cell-biology and molecular genetics approaches, including synthetic-lethal and phenotypic-suppression screening methods in human cells and in the nematode worm. This work will not only be of academic importance, but will also indicate how DDR dysfunction can cause human disease and how such diseases might be better diagnosed and treated.

2 482 492 €

Start date: 2011-05-01, End date: 2016-04-30