ERC FUNDED PROJECTS

Animal welfare is a topic of highest societal and scientific priority. Here, I propose to use genomic and epigenetic tools to provide a new perspective on the biology of animal welfare. This will reveal mechanisms involved in modulating stress responses. Groundbreaking aspects include new insights into how environmental conditions shape the orchestration of the genome by means of epigenetic mechanisms, and how this in turn modulates coping patterns of animals. The flexible epigenome comprises the interface between the environment and the genome. It is involved in both short- and long-term, including transgenerational, adaptations of animals. Hence, populations may adapt to environmental conditions over generations, using epigenetic mechanisms. The project will primarily be based on chickens, but will also be extended to a novel species, the dog. We will generate congenic chicken strains, where interesting alleles and epialleles will be fixed against a common background of either RJF or domestic genotypes. In these, we will apply a broad phenotyping strategy, to characterize the effects on different welfare relevant behaviors. Furthermore, we will characterize how environmental stress affects the epigenome of birds, and tissue samples from more than 500 birds from an intercross between RJF and White Leghorn layers will be used to perform an extensive meth-QTL-analysis. This will reveal environmental and genetic mechanisms affecting gene-specific methylation. The dog is another highly interesting species in the context of behavior genetics, because of its high inter-breed variation in behavior, and its compact and sequenced genome. We will set up a large-scale F2-intercross experiment and phenotype about 400 dogs in standardized behavioral tests. All individuals will be genotyped on about 1000 genetic markers, and this will be used for performing an extensive QTL-analysis in order to find new loci and alleles associated with personalities and coping patterns.

2 499 828 €

Start date: 2013-03-01, End date: 2018-02-28

Many animals – including birds, sea turtles and insects – perform spectacular long-distance migrations across the surface of the Earth. Remarkably some, like birds, can accurately migrate between highly specific locations thousands of kilometres apart, a navigational feat that requires an external compass cue and a robust sensory system to detect it. The Earth’s magnetic field is one such compass cue. But exactly how the magnetic field is sensed, and which receptor cells are involved, remains a mystery and its discovery is one of the greatest “holy grails” in modern sensory physiology, and also the main aim of this proposal. Fortuitously, I have made a pioneering discovery that a migratory insect – the Australian Bogong moth – relies on the Earth’s magnetic field to navigate at night. Due to its tractable nervous system, this insect may thus hold the key to uncovering the identity of the enigmatic magnetosensor. By tethering flying migrating moths in a flight simulator, I will dissect for the first time how insects use magnetic cues to navigate, isolating which of the two current (contentious) hypotheses for magnetic sensation apply. The most likely of these involves the action of photoreceptor-based cryptochrome (Cry) molecules in the eyes. Having cloned genes for 4 visual opsins and 2 Cry in Bogong moths, I will use in situ hybridisation to localise putative magnetoreceptors in the eyes, targeting them with intracellular electrophysiology and magnetic stimulation in an attempt to describe the physiology of these elusive sensors for the first time. The project is ground breaking since it will elucidate how a migratory insect, despite its small eyes and brain, detects and uses the Earth’s magnetic field for navigation. The discovery of the enigmatic magnetoreceptor would be a sensation, opening the floodgates for international research on this little understood sense.

2 498 625 €

Start date: 2017-09-01, End date: 2022-08-31

This proposal describes a series of powerful experimental strategies to develop a completely novel treatment for mtDNA mutation disease based on identifying unknown mechanisms controlling mtDNA replication. Several hundred different mtDNA mutations affect tRNA genes and impair mitochondrial translation leading to human disease. There is typically heteroplasmy with a mixture of wild-type and mutated mtDNA, and the mutations are acting in a “recessive” (loss of function) way. Very high levels of mutated mtDNA are needed to cause disease in affected patients whereas maternal relatives with high, but sub-threshold levels of mutated mtDNA are completely healthy. The corollary of these observations is that even a small increase of wild-type mtDNA may efficiently counteract disease in affected patients. This hypothesis will be validated by a series of genetic experiments with mice harbouring single pathogenic mtDNA mutations. Furthermore, novel factors controlling mtDNA replication will be identified. In particular, we will elucidate the formation and function of the mammalian displacement (D) loop, which provides a switch between abortive and genome length mtDNA replication. This very fundamental problem in mammalian mitochondrial biology has remained unsolved for decades, but I feel that the innovative experimental strategies I present in this proposal are very powerful and should have a fair chance of being successful. In any circumstance, the project will provide important molecular insights into novel mechanisms relevant for mammalian mtDNA replication. Over the years I have been strongly convinced that congruent results from in vivo and in vitro studies are needed to obtain reliable mechanistic insights and this project is therefore based on the close integration of biochemistry, advanced proteomics and state-of-the-art mouse and fly genetics. Finally, I describe a powerful large-scale screening approach to develop small molecular stimulators of mtDNA replication.

2 500 000 €

Start date: 2018-01-01, End date: 2022-12-31