The observation that most eukaryotic species are sexual and that asexual species are rare and recent remains one of the greatest puzzles of contemporary evolutionary biology. This puzzle is a theoretical one because sex involves very strong costs relative to asexual reproduction (e.g., the famous twofold cost of males). Yet, it is also an empirical challenge as performing experiments aimed at understanding the maintenance of sex have proven extremely difficult, despite very intensive effort over several decades. Recently, population genomics approaches have increasingly been used to study asexuality. They have started to provide answers on a number of questions, such as the ages of clones and differentiation from related sexual species. While these studies have improved of our understanding of asexuality, they were nonetheless unable to overcome two major empirical limitations: First, asexuals sampled in nature represent a highly selected subset of the most successful lineages, which strongly complicates the interpretation of any results obtained on them. Second, the inability to perform crosses and to study segregating variation in asexuals by their very definition (they reproduce without crossing) largely makes classical genetics unavailable for asexuals. This is problematic because, even after the advent of genomics, classical genetics remains an extremely powerful tool for understanding the inheritance of characters, notably because crosses allow manipulating genotypes rather than performing correlations on existing variation. To overcome both limitations, we propose three innovative empirical breakthroughs: (1) Clone engineering is a method to generate new clones in the laboratory (already designed and tested by us and others on two model organisms, Daphnia and Artemia). (2) Asexual mapping is a new technique to study the linkage map of asexuals. This technique takes advantage of so-called “rare males” in asexual lineages, making it possible to study asexuals with classical and modern genetic/genomic tools that rely on crosses. We already obtained pilot results with this method, and this project will use it at a full scale. (3) An estimation of genetic load in asexuals using inbreeding depression in asexuals, assessed via back-crosses. The experimental studies will be complemented by a population genomic and theoretical approach. These key innovations and their combination will allow us to address three outstanding questions, each corresponding to one of the three objectives of the project: What is the genetic basis of asexuality (objective 1)? What are the genomic consequences of asexuality and the genome structure of asexuals (objective 2)? What are the fitness consequences of asexuality (objective 3)? Together, this project offers a highly original, powerful, and novel (because hitherto largely unexplored) approach to the study of asexuality, and answering these questions will represent a very large step forward in our understanding of the maintenance of sex, in particular by determining how much of the “cost of males” can be paid by the accumulation of deleterious mutations in asexuals.

Fronto Temporal Dementia (FTD) is a devastating pre-senile dementia characterized by the progressive deterioration of the frontal and anterior temporal lobes. The most common symptoms include severe changes in social and personal behaviour as well as a general blunting of emotions. Clinically, genetically and pathologically there is considerable overlap with a wide spectrum of neurodegenerative diseases. FTD has a very strong genetic influence. Up to 40% of cases have a positive family history and this has been the key to the remarkable progress in our understanding of the molecular basis of FTD. Currently, seven genes have been identified of which MAPT, GRN and C9Orf72 explain >50% of familial cases, but how these different genes lead to a very similar clinical phenotype despite very distinct pathologies, is still an unanswered question. For sporadic FTD the role of genetic factors and their interplay with environmental risk factors is largely unknown. Currently, there is no cure for FTD and the strategies for the development of successful therapies will depend on whether a single therapy can be applied to all patients or if specific approaches are needed for the distinct genetic, clinical and pathological subgroups. Therefore it is essential to identify all major genetic risk factors and find both common environmental and genetic modifiers important in the pathogenesis of the disease as well as factors that are specific for subgroups of patients. To reach these goals we aim to use the extensive genetic and pathological knowledge that already exists for FTD, including newly identified from our whole exome/genome sequencing and GWAS efforts, as a starting point to decode common and distinctly affected processes and pathways in different groups of Mendelian and sporadic FTD patients using a multi level approach based on a range of “omics” data sets from selected patient groups as well as corresponding animal and cellular model systems. This approach will allow us to work in a model guided and hypothesis driven fashion. Based on the generated data, testable hypotheses on affected common and distinct gene networks will be generated and the biological significance of identified networks will be validated in our cellular and animal models in a targeted fashion and these experiments will pinpoint potential pathomechanisms that are specific to a single FTD-subtype or common to all forms. The results will be utilized to refine theoretical disease models and improve the quality of our approaches towards targeted intervention.