Core A: Mouse Genetics. Abstract: Understanding the mechanisms through which host genetic variation impacts Mycobacterium tuberculosis (Mtb) susceptibility and disease pathologies requires optimized and flexible model systems through which genetic variants affecting Mtb can be identified, characterized and manipulated across a range of genetic backgrounds. We propose usage of the highly diverse Collaborative Cross mouse panel to identify naturally occurring genetic polymorphisms driving variation in Mtb disease outcomes, and then investigate the mechanisms of these variants across a range of genetic backgrounds. We will assist the projects by analyzing genetic association studies to identify genetic variants driving differences between mouse lines, creating mouse crosses with which to assess how variation in gene transcription affects downstream Mtb disease outcomes, and also generate mutant mouse lines whereby putative genetic variants are swapped between mouse lines to assess their disease impact. We will provide the human genetics core with sets of genes containing variants affecting Mtb disease in mice for testing in human cohorts. This provides a direct tie from experimental data to clinical relevance. Lastly we will be responsible for curation, archiving and dissemination of the data generated throughout this program to publically available repositories.
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