ERC FUNDED PROJECTS

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown. Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps. This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

1 999 750 €

Start date: 2017-03-01, End date: 2022-02-28

"The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."

1 196 701 €

Start date: 2014-02-01, End date: 2018-01-31

"This project explores the concept of agricultural spread as analogous to enforced climate change and asks how cereals adapted to new environments when agriculture was introduced into Europe. Archaeologists have long recognized that the ecological pressures placed on crops would have had an impact on the spread and subsequent development of agriculture, but previously there has been no means of directly assessing the scale and nature of this impact. Recent work that I have directed has shown how such a study could be carried out, and the purpose of this project is to exploit these breakthroughs with the goal of assessing the influence of environmental adaptation on the spread of agriculture, its adoption as the primary subsistence strategy, and the subsequent establishment of farming in different parts of Europe. This will correct the current imbalance between our understanding of the human and environmental dimensions to the domestication of Europe. I will use methods from population genomics to identify loci within the barley and wheat genomes that have undergone selection since the beginning of cereal cultivation in Europe. I will then use ecological modelling to identify those loci whose patterns of selection are associated with ecogeographical variables and hence represent adaptations to local environmental conditions. I will assign dates to the periods when adaptations occurred by sequencing ancient DNA from archaeobotanical assemblages and by computer methods that enable the temporal order of adaptations to be deduced. I will then synthesise the information on environmental adaptations with dating evidence for the spread of agriculture in Europe, which reveals pauses that might be linked to environmental adaptation, with demographic data that indicate regions where Neolithic populations declined, possibly due to inadequate crop productivity, and with an archaeobotanical database showing changes in the prevalence of individual cereals in different regions."

2 492 964 €

Start date: 2014-02-01, End date: 2019-01-31

"Electrical motors consume about 40 % of the electrical energy produced in the European Union. About 90 % of this energy is converted to mechanical work. However, 0.5-2.5 % of it goes to so called additional load losses whose exact origins are unknown. Our ambitious aim is to reveal the origins of these losses, build up numerical tools for modeling them and optimize electrical motors to minimize the losses. As the hypothesis of the research, we assume that the additional losses mainly result from the deterioration of the core materials during the manufacturing process of the machine. By calorimetric measurements, we have found that the core losses of electrical machines may be twice as large as comprehensive loss models predict. The electrical steel sheets are punched, welded together and shrink fit to the frame. This causes residual strains in the core sheets deteriorating their magnetic characteristics. The cutting burrs make galvanic contacts between the sheets and form paths for inter-lamination currents. Another potential source of additional losses are the circulating currents between the parallel strands of random-wound armature windings. The stochastic nature of these potential sources of additional losses puts more challenge on the research. We shall develop a physical loss model that couples the mechanical strains and electromagnetic losses in electrical steel sheets and apply the new model for comprehensive loss analysis of electrical machines. The stochastic variables related to the core losses and circulating-current losses will be discretized together with the temporal and spatial discretization of the electromechanical field variables. The numerical stochastic loss model will be used to search for such machine constructions that are insensitive to the manufacturing defects. We shall validate the new numerical loss models by electromechanical and calorimetric measurements."

2 489 949 €

Start date: 2014-03-01, End date: 2019-02-28