Final Report Summary - EVOIMMUNOPOP (Human Evolutionary Immunogenomics: population genetic variation in immune responses) Unravelling the relative contribution of host, environmental and evolutionary factors to the observed levels of variability of the immune system is crucial to understand human susceptibility to infectious, inflammatory, and autoimmune diseases, the clinical manifestations of which vary between individuals and populations. The contribution of host genetic variants to variation in immune traits is increasingly being documented by genome-wide association studies; however, the variants detected tend to have small effect sizes, and the identification of functional causality remains challenging. In this context, the mapping of expression quantitative trait loci (eQTLs) has proved to be of considerable fundamental and biomedical value, as it increases our understanding of the extent of genetic control of gene expression variation and establishes links between intermediate phenotypes, such as gene expression, and organism traits, such as immunity to infection. Furthermore, the study of how natural selection has acted upon immune genes increases our understanding of the biological relevance of the functions concerned, complementing immunological, clinical, and epidemiological genetic studies. Nevertheless, the relationship between genetic variation and immune phenotype diversity, and the nature of the immunological mechanisms under selection remained largely unexplored. Using the “human model” and combing methods, approaches and concepts of population and statistical genetics, functional genomics and immunology, the EVOIMMUNOPOP project (i) explored how individuals and populations differ in the outcome that follows infection and immune stimulation, (ii) assessed the degree of genetic control of immune response variation, through the mapping of eQTLs, and (iii) delineated immunological mechanisms that have conferred an advantage to human adaptation, through analyses of natural selection. We have shown that marked differences in immune responses between Africans and Europeans exist, predominantly affecting antiviral and inflammation-related genes, and demonstrated that common regulatory variants (i.e. cis- and trans-eQTLs) largely contribute to such population differences. For example, one of the strongest hits is a trans-eQTL at the TLR1 locus, associated with a large network of genes that decrease the inflammatory response specifically in Europeans. We have also shown that genetic variants associated with gene expression changes upon immune stimulation (i.e. response eQTLs) have been privileged targets of population-specific selection, allowing us to uncover mechanisms, such as the avoidance of excessive inflammatory responses, which have conferred a selective advantage in a population-specific manner. Notably, our analyses revealed that admixture of the ancestors of Europeans with ancient hominins, such as Neanderthals, introduced regulatory variants into European genomes, which affect today gene expression variation and, preferentially, responses to viral challenges. By exploring another layer of transcriptional diversity (splicing variation), we have shown that infection and immune stimulation have a profound impact on isoform usage of both protein-coding genes and microRNAs. Lastly, our evolutionary and population genetics analyses have established that immune genes evolving under positive Darwinian selection are enriched in functional variants associated with immune traits or diseases, informing the relationship between past selection and current benign and disease-related phenotypic variation. Our work has also identified highly-constrained genes (i.e. evolving under purifying selection) that fulfil essential, non-redundant functions in host survival, and revealed others (i.e. evolving under positive selection) that are more permissive to change — containing advantageous variants in specific human populations — improving our understanding of the relative biological importance of immune pathways in natural conditions. Collectively, the EVOIMMUNOPOP project, which combined population, evolutionary and functional genomics approaches, has provided a comprehensive view of the impact of population genetic differences on transcriptional responses to innate immunity activation, and highlighted evolutionary important genes, functions, and mechanisms involved in immune-related phenotypic variation. Furthermore, the regulatory variants identified constitute a useful resource for evaluating the role of these variants in the molecular and cellular mechanisms underlying host immunity to infection and susceptibility to disease, both at the individual and population levels.
