Genetic variability within the human population gives rise to a remarkable diversity of responses across various phenotypes, including conditions such as inflammatory bowel diseases (IBD) and psoriasis. However, most genetic variations occur in non-coding regions of the genome, impacting enhancers, and complicating the correlation between changes in DNA and phenotypic variations. Genome-wide association studies (GWAS) are highly valuable tools for understanding the genetic basis of phenotypes, enabling us to directly map genetic differences to observable traits. However, to date, there have been no studies investigating genome-wide associations between nutrition, microbiota, and macrophages in the gut or skin. In recent years, a remarkable genetic approach has emerged, known as the Collaborative Cross, which provides an accurate reflection of the genetic structure of human populations. Comprising a large panel of about 70 recombinant inbred strain of mice, this resource serves as a standardized reference panel for the integrative analysis of complex systems. Each strain within the Collaborative Cross is highly diverse from the others, yet inbred and homozygous, with fully sequenced genomes. Consequently, this model offers enormous potential for studying genome-wide associations. Utilizing mice from the Collaborative Cross will enable us to map genetic regions associated with the response to nutrition and the microbiome, expanding our understanding of the genotype-phenotype relationship in macrophages in the skin and gut.
Our laboratory will utilize this powerful genetic resource and conduct GWAS in naïve mice from the Collaborative Cross that are fed different diets or associated with commensal bacteria, allowing to investigate changes in macrophage phenotypes in the intestine and the skin. We employ state-of-the-art analysis methods, aiming to map the identified genetic regions to a minimal number of genes. In the long term, the laboratory will conduct in-depth analyses of genes associated with macrophage responses, examining both the founder strains and a subset of the Collaborative Cross strains by employing sequencing assays, pharmaceutical interventions, and genetic gain/loss of function approaches. This investigation will provide a deep understanding of the specific genetic factors influencing macrophage behavior in response to the microbiome and diet.