Objective Understanding the process of spontaneous mutation is fundamental for understanding the genetic basis of quantitative variation, the threat posed by declining population size in conservation biology and the distribution of nucleotide variation in the genome. I will address these and other unanswered questions concerning the evolutionary impact of spontaneous mutation using the house mouse as a model system. With the first, highly replicated mutation accumulation (MA) experiment in any vertebrate, I will study the impact of mutation accumulation on fitness and other quantitative traits and on genomic variation. I will pay particular attention to the effects of mutations in the heterozygous state, since this is important for resolving two important questions: 1. The threat posed by deleterious mutation accumulation in humans, where natural selection has weakened in many populations, and in endangered species, where declining effective population size has made selection less effective, and 2. The extent by which new mutations sustain response to artificial selection. By characterizing many thousands of mutation events by genome sequencing of MA lines and wild mice, I will determine the molecular spectrum and the factors explaining mutation rate variation across the genome. I will exploit this new knowledge to address the long-unanswered question of the causes of correlations between nucleotide diversity and the recombination rate and the density of conserved genomic elements. I will develop new approaches, incorporating the simultaneous action of mutation, selection, drift and recombination, to determine the contributions of background selection and selective sweeps to variation in nucleotide diversity, and to quantify the contributions of coding and noncoding mutations to fitness variation. The project will lead to substantial advances in the understanding of the role of new mutations in explaining phenotypic and molecular diversity in mammals. Fields of science natural sciencesbiological sciencesevolutionary biologynatural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesgeneticsnucleotidesnatural sciencesbiological scienceszoologymammalogynatural sciencesbiological sciencesgeneticsgenomes Keywords DENOVOMUT Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-ADG-2015 - ERC Advanced Grant Call for proposal ERC-2015-AdG See other projects for this call Funding Scheme ERC-ADG - Advanced Grant Host institution THE UNIVERSITY OF EDINBURGH Net EU contribution € 1 680 706,72 Address OLD COLLEGE, SOUTH BRIDGE EH8 9YL Edinburgh United Kingdom See on map Region Scotland Eastern Scotland Edinburgh Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 680 706,72 Beneficiaries (2) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE UNIVERSITY OF EDINBURGH United Kingdom Net EU contribution € 1 680 706,72 Address OLD COLLEGE, SOUTH BRIDGE EH8 9YL Edinburgh See on map Region Scotland Eastern Scotland Edinburgh Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 680 706,72 MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV Germany Net EU contribution € 818 624,28 Address HOFGARTENSTRASSE 8 80539 Munchen See on map Region Bayern Oberbayern München, Kreisfreie Stadt Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 818 624,28