Population and molecular genetics of susceptibility to tuberculosis

Genetic influences on the course of mycobacterial infections during epidemics and in the endemic areas have always been suspected, but the precise nature of such genetic control and of the inherited mechanisms of susceptibility has been unknown. We have used the methods of population genetics in the mouse to discover a single dominant autosomal gene which controls the susceptibility to tuberculosis. The phenotypic expression of this gene has been defined as the nonspecific macrophage activation for bactericidal function. Using recombinant inbred strains we have mapped this gene to the centromeric part of Chromosome 1, and we have identified closely linked DNA polymorphisms (RFLP sites) which can be used as biochemical markers of innate susceptibility. It has recently become obvious that a homologous linkage group of RFLP sites is conserved in the bovine genome and also on the long arm (2q) of human Chromosome 2, suggesting the existence of a human homologue of the mouse host resistance gene. Experiments currently in progress test this hypothesis by linkage analysis of the trait of resistance and susceptibility to tuberculosis with the allelic forms of the 2q DNA markers. The identification of the human gene for susceptibility would be of major importance in the search for genetically susceptible individuals and in the development of novel strategies of specific prevention and treatment.