TBGENAfrica: An integrated approach to unraveling susceptibility to tuberculosis in Africa
Africa has the highest level of genetic diversity amongst all human populations. It also has the highest level of genetic diversity amongst populations of the pathogen that causes tuberculosis. Phylogenetic analysis shows that Mycobacterium tuberculosis (MTB) emerged with modern humans in Africa ~70 thousand years ago, and has spread and diversified in close association with humans during their migration out of Africa. We propose that the long history of co-evolution of host and pathogen genomes contributes to the diverse outcome following MTB infection, as reflected in the variable percentage of individuals progressing to active tuberculosis and varying efficiencies of ongoing transmission. To test this hypothesis, we will map the distribution of MTB genotypes
alongside the genotypes of genetically-distinct human populations in four African countries. Comparison of paired host and bacterial genomes will identify loci that have co-evolved. This information will have fundamental importance in understanding the influence of host genetics on disease susceptibility and will highlight novel factors that impact on tuberculosis pathogenesis and pathology. We anticipate that the influence of coevolutionary adaptation will be over-ridden in the context of HIV-induced immunosuppression. Loss of host-pathogen associations in HIV-infected populations will therefore provide a further test of our hypothesis.
Although tuberculosis is common and infectious, only 10% of infected individuals become sick. Understanding why this is the case could help develop better vaccines and drugs against TB. Recent analysis of the genetic make-up of the bacteria that cause TB suggests that TB first appeared when humans were evolving in Africa. It then accompanied them as they dispersed around the world. We think that during this time particular variants of the bacteria became adapted to particular human populations. Meanwhile, humans over many generations adapted to become more resistant to the TB bacteria and stay well. Thus, we think that to get TB disease you need the right combination of human and TB genetic make-ups. We will investigate this theory by collecting genetic material (DNA) from people with TB and from the bacteria that are infecting them. We will analyse them together to try to detect patterns of variation in humans that correlate with patterns of variation in bacteria. This could help identify new targets for vaccines and TB drugs. In parallel, we will build research capacity in cutting-edge science and carry out educational activities related to ethical issues associated with genome science in the African communities where we will work.