ERC FUNDED PROJECTS

Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.

1 500 000 €

Start date: 2012-01-01, End date: 2016-12-31

The applicant will collaborate with Irish, European and U.S.-based colleagues to develop a sustainable biorefinery and bioenergy industry in Ireland and Europe. The focus of this ERC Starting Grant will be the application of classical microbiological, physiological and real-time polymerase chain reaction (PCR)-based assays, to qualitatively and quantitatively characterize microbial communities underpinning novel and innovative, low-temperature, anaerobic waste (and other biomass) conversion technologies, including municipal wastewater treatment and, demonstration- and full-scale biorefinery applications. Anaerobic digestion (AD) is a naturally-occurring process, which is widely applied for the conversion of waste to methane-containing biogas. Low-temperature (<20 degrees C) AD has been applied by the applicant as a cost-effective alternative to mesophilic (c. 35C) AD for the treatment of several waste categories. However, the microbiology of low-temperature AD is poorly understood. The applicant will work with microbial consortia isolated from anaerobic bioreactors, which have been operated for long-term experiments (>3.5 years), and include organic acid-oxidizing, hydrogen-producing syntrophic microbes and hydrogen-consuming methanogens. A major focus of the project will be the ecophysiology of psychrotolerant and psychrophilic methanogens already identified and cultivated by the applicant. The project will also investigate the role(s) of poorly-understood Crenarchaeota populations and homoacetogenic bacteria, in complex consortia. The host organization is a leading player in the microbiology of waste-to-energy applications. The applicant will train a team of scientists in all aspects of the microbiology and bioengineering of biomass conversion systems.

1 499 797 €

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

Homologous recombination (HR) is a conserved DNA double-strand breaks (DSB) repair pathway that uniquely uses an intact DNA molecule as a template. Genome-wide homology search is carried out by a nucleoprotein filament (NPF) assembled on the ssDNA flanking the DSB, and whose product is a “D-loop” joint molecule. Beyond accurate DSB repair, this capacity of HR to spatially associates homologous molecules is also harnessed for homolog pairing in meiosis. The goal of “3D-loop” is to tackle two long lasting conundrums: the fundamental homology search mechanism that achieves accurate and efficient identification of a single homologous donor in the vastness of the genome and nucleus, and how this mechanism is adapted for the purpose of homologs attachment in meiosis. I overcame the main hurdle to study these core steps of HR by developing a suite of proximity ligation-based methodologies and experimental systems to physically detect joint molecules in yeast cells. It revealed elaborate regulation controlling D-loop dynamics and a novel class of joint molecules. This proposal builds upon these methodologies and findings to first address basic properties of the homology sampling process by the NPF and the role of D-loop dynamics, with the long-term goal to establish a quantitative framework of homology search in mitotic cells (WP1). Second, the meiosis-specific regulation of homology search leading to homolog pairing likely integrates chromosomal-scale information. Genome re-synthesis and engineering approaches will be deployed to (i) achieve a quantitative and dynamic cartography of the cytological and molecular events of meiosis over a large chromosomal region, (ii) probe cis-acting regulations at the chromosomal scale, and (iii) revisit the molecular paradigm for crossover formation (WP2). We expect this project to shed light on the fundamental process of homology search and its involvement in the chromosome pairing phenomenon lying at the basis of sexual reproduction.

1 499 779 €

Start date: 2020-01-01, End date: 2024-12-31

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