The profusion of gene paralogues (gene families) that are observed in all genomes is the signature of the many gene duplication events that took place in the course of evolution. It has been postulated that “only when a redundant gene locus is created by duplication is it permitted to accumulate formerly forbidden mutations and emerge as a new gene with a hitherto unknown function” (Ohno, 1970). Thus, the question of how gene duplication and subsequent divergence contributes to genetic novelty and adaptation has become a hot topic in evolutionary studies. This is not only due to the role of gene duplications as a catalyser of genetic innovation, but also because the growing knowledge of gene networks and their intrinsic logic has revealed that many properties of these networks, such as redundancy, co-option and modularity must be rooted on ancient duplication events. Not surprisingly, for more than 30 years the question of how gene duplication and divergence contribute to genetic novelty and adaptation has been intensely debated. However, while many theoretical developments have greatly enriched the discussion, few experimental approaches have played a prominent role in the debate. We thus propose to develop a novel experimental contribution focusing on the analysis of a reduced set of gene duplicates originated during the evolution of the diptera lineage, with the double objective of characterising their roles, (i.e., their functional fates), and analysing the divergence of their promoter sequences, all in a highly amenable system for both genetic and cis-regulation analysis: the fly Drosophila melanogaster. For this, we have chosen to focus a novel family of Drosophila paralogues recently described by us, whose members code for different GPI-anchored proteins sharing a conserved extracellular motif called Three Finger Domain (TFD). Preliminary work carried out by the two groups involved in the proposal has already allowed to first, characterise the evolutionary history of the different TFD paralogues within the diptera lineage and, second, to establish that their expression patterns have undergone considerable changes during paralogue divergence. Thus, this experimental set-up constitutes a promising system to study cis-regulatory evolution, allowing direct evaluation of processes such as degeneration/conservation and/or co-option of specific regulatory modules. In parallel and using the large arsenal of genetic and technical resources available in Drosophila, we will also perform a functional analysis of the different TFD paralogues in order to establish their cellular role(s) during development. This particular combination of structural (sequence analysis) and functional (gene expression/mutant analysis) studies will serve as a platform for inferring on the evolutionary paths undertaken by each gene duplicate, namely their neo- and/or subfunctionalization. In addition, we expect that the data set stemming from this project will be suitable to approach the nature and genesis of some of the properties of gene regulation and structure, such as modularity and its internal logic, enhancer sharing and co-option.

The physiologic function of the immune system is the defense against infectious microbes. Inflammation, the extravasation, accumulation and activation of leukocytes at the site of the infection is initiated in changes in blood vessels that promote leukocyte recruitment. Local innate and adaptive immune responses can promote inflammation. Although the inflammation serves a protective function in controlling infections, it can also cause tissue damage and disease. The primary role of neuroinflammation is to protect the central nervous system (CNS) from invasion and attack by infectious agents, i.e. parasites, bacteria and viruses. The invasion is hindered by the immune system and by physical barriers between the blood and the CNS, which main function is to preserve brain homeostasis. However, inflammatory molecules released to prevent neuroinvasion may be detrimental to the integrity of the physical barriers and thus to the brain function. In Neuinf project we will study the neuroinflammation processes due to three different parasitic infections of the brain: Malaria, Toxoplasmosis, and African trypanosomiasis. Each of these infections constitute a heavy health burden. Five research partners groups in 4 European countries will study these diseases using mouse models that mimic many features of the human disease. In common to these infections is that these parasites are recognized by innate immune response and generate a parasite specific immunity that might be detrimental. We will study how these parasites are recognized by the immune system and what are the specific requirements for the adaptive “parasite specific” immune repsonses to mediate brain damage. The rabies virus inhibits neuroinflammation as a strategy to promote its own survival. We have discovered one molecule of rabies virus that has anti-inflammatory properties and will test its efficacy as an anti parasitic drug in the models of Malaria, Toxoplasmosis and African trypanosomiasis that induce neuroinflammation.