ERC FUNDED PROJECTS

By detailed evolutionary comparisons among multiple sequenced yeast genomes, we have identified several unusual regions where our preliminary evidence suggests that previously unknown molecular biology phenomena, involving rearrangement of genomic DNA, are occurring. I now propose to use a combination of dry-lab and wet-lab experimental approaches to characterize these regions and phenomena further. One region is a 24-kb section of chromosome XIV that appears to undergo recurrent 'flip/flop' inversion between two isomers at a fairly high rate in five species as diverse as Saccharomyces cerevisiae and Naumovia castellii, leading to a 1:1 ratio of the two isomers in each species. We hypothesize that this region is the site of a programmed DNA rearrangement analogous to mating-type switching. We have also identified two new genes related to the mating-type switching endonuclease HO, but different from it, that are potentially involved in rearrangement processes though not necessarily the inversion described above. We will determine the sites of action of these endonucleases. Separately, we have found evidence for a process of recurrent deletion of DNA from regions flanking the mating-type (MAT) locus in all yeast species that are descended from the whole-genome duplication (WGD) event, causing continual transpositions of genes from beside MAT to other locations in the genome. In related computational work, we propose to investigate an hypothesis that evolutionary loss of the MATa2 transcriptional activator may have been the cause of the WGD event.

1 516 960 €

Start date: 2011-06-01, End date: 2016-05-31

The genetic code was established at a very early stage during the evolution of life on Earth and is nearly universal. In eukaryotic nuclear genes, the only known examples of a sense codon that underwent an evolutionary change of meaning, from one amino acid to another, occur in yeast species. The codon CUG is translated as Leu in the universal genetic code, but it has long been known to be translated as Ser in some Candida species. In recent work, we discovered that this switch is one of three parallel reassignments of CUG that occurred in three closely related clades of yeasts. CUG was reassigned once from Leu to Ala, and twice from Leu to Ser, in three separate events. The meaning of sense codons in the nuclear genetic code has otherwise remained completely stable during all of eukaryotic evolution, so why was CUG so unstable in yeasts? CODEKILLER will test a radical new hypothesis that the genetic code changes were caused by a killer toxin that specifically attacked the tRNA that translated CUG as Leu. The hypothesis implies that the reassignments of CUG were not driven by selection in favor of their effects on the proteome, as commonly assumed, but by selection against the existence of a particular tRNA. As well as searching for this killer toxin, we will study the detailed mechanism of genetic code change by engineering a reversal of a CUG-Ser species back to CUG-Leu translation, and investigate translation in some species that naturally contain both tRNA-Leu and tRNA-Ser molecules capable of decoding CUG.

2 368 356 €

Start date: 2018-10-01, End date: 2023-09-30

The Mediterranean, a key socio-cultural, economic and political crossroads, has shifted its relative position recently, with profound effects for relations between the peoples associated with its diverse parts. Crosslocations is a groundbreaking theoretical approach that goes beyond current borders research to analyse the significance of the changes in relations between places and peoples that this involves. It does this through explaining shifts in the relative positioning of the Mediterranean’s many locations – i.e. the changing values of where people are rather than who they are. Approaches focusing on people’s identities, statecraft or networks do not provide a way to research how the relative value of ‘being somewhere in particular’ is changing and diversifying. The approach builds on the idea that in socio-cultural terms, location is a form of political, social, economic, and technical relative positioning, involving diverse scales that calibrate relative values (here called ‘locating regimes’). This means locations are both multiple and historically variable, so different types of location may overlap in the same geographical space, particularly in crossroads regions such as the Mediterranean. The dynamics between them alter relations between places, significantly affecting people’s daily lives, including their life chances, wellbeing, environmental, social and political conditions and status. The project will first research the locating regimes crossing the Mediterranean region (border regimes, infrastructures; digital technologies; fiscal, financial and trading systems; environmental policies; and social and religious structures); then intensively ethnographically study the socio-cultural dynamics of relative positioning that these regimes generate in selected parts of the Mediterranean region. Through explaining the dynamics of relative location, Crosslocations will transform our understanding of trans-local, socio-cultural relations and separations.

2 433 234 €

Start date: 2016-09-01, End date: 2021-08-31

This proposal seeks support for a research group led by James Heckman of the Geary Institute at University College Dublin to produce an integrated developmental approach to health that studies the origins and the evolution of health inequalities over the lifecourse and across generations, and the role played by cognition, personality, genes, and environments. Major experimental and nonexperimental international datasets will be analyzed. A practical guide to implementing related policy will be produced. We will build a science of human development that draws on, extends, and unites research on the biology and epidemiology of health disparities with medical economics and the economics of skill formation. The goal is to develop an integrated framework to jointly model the economic, social and biological mechanisms that produce the evolution and the intergenerational transmission of health and of the capabilities that foster health. The following tasks will be undertaken: (1) We will quantify the importance of early-life conditions in explaining the existence of health disparities across the lifecourse. (2) We will understand how health inequalities are transmitted across generations. (3) We will assess the health benefits from early childhood interventions. (4) We will examine the role of genes and environments in the aetiology and evolution of disease. (5) We will analyze how health inequalities emerge and evolve across the lifecourse. (6) We will give biological foundations to both our models and the health measures we will use. The proposed research will investigate causal channels for promoting health. It will compare the relative effectiveness of interventions at various stages of the life cycle and the benefits and costs of later remediation if early adversity is not adequately eliminated. It will guide the design of current and prospective experimental and longitudinal studies and policy formulation, and will train young scholars in frontier methods of research

2 505 222 €

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