How mapping ancestral genes could help the fight against TB

The fight against tuberculosis (TB) has been extended through the use of a genetic mapping technique called admixture mapping. This could help uncover previously unknown genetic factors contributing to susceptibility to the disease.

To use this genetic technique, access to an admixed population that originated from two or more other populations (the so-called parental populations) is needed. These parental populations should have been separated for long periods of time and must differ in their genetic susceptibility to the disease.

Disease-causing variants in the at-risk ancestral population will be harboured in certain regions of the genome. Admixture mapping is based on the premise that these regions will be inherited more frequently by affected admixed individuals. The goal of admixture mapping is to identify these regions.

Researchers at Stellenbosch University have identified South Africa as an ideal location to perform an admixture mapping study. This is because the country has a recent history of admixture in its populations. In addition, research has suggested differences in genetic susceptibility to TB between parental populations.

The study identified regions of the genome that may well harbour informative and novel TB susceptibility candidate genes. Work is currently underway to investigate these findings.

Why genes are important

About one-third of the world’s population is infected with the TB bacterium, but only 5% to 10% progress to having the disease and its symptoms. Infection with Mycobacterium tuberculosis, which causes TB, can be contained by an individual’s immune system without acquiring symptoms of the disease. But when this does not happen, the person develops active TB.

There are various reasons why not everyone infected with TB goes on to develop the disease. These include the strain and disease-causing ability of mycobacteria, environmental factors such as population density and nutrition, as well as the person’s genetic make-up.

Research is exploring the possible genetic reasons why a patients' immune system does not rid the body of the bacterium. Studies on twins have shown that a patient’s immune response to TB is regulated by their genetic background and that between 36% to 80% of the total variation between individuals can be ascribed to genetic factors.

Some genes some of the time

A number of candidate genes have been identified through various analytical methods and case-control association studies.

Interferon gamma, an important cytokine that aids in immunity to pathogens (such as M. tuberculosis), and variants in this gene have been shown to confer an increase in susceptibility to TB. Other genes are HLA, TNF-alpha, Mannose binding factor, Vitamin D receptor, IL-10, IL-1, ICAM 1,IL-4, IL-6 and some chemokine receptors.

But genetic variants that have been identified explain only a small proportion of the estimated heritability of developing active TB. Much remains unexplained about the genetic factors thought to underlie TB susceptibility. For example, the effects of some genetic variants are not universal. Some appear to play a role in some population groups only. It is often unclear whether this means that the identified variants are false discoveries or that these genetic susceptibility factors differ between population groups.

This is where admixture mapping comes in handy.

It has been suggested that M. tuberculosis originated in Africa and that some lineages of the bacterium accompanied their human hosts during the out-of-Africa migration about 60,000 to 125,000 years ago. Modern lineages that evolved in Eurasia then spread throughout the world and back into Africa during the colonisation period.

Incidence of TB between 1800 and 1922.Center for the History of Medicine/Francis A. Countway Library of Medicine, Harvard Medical School

People of European descent may have a higher resistance to the disease in comparison to their African counterparts. This could be due to centuries of exposure to the modern form of the pathogen in densely populated European settlements.

This may have allowed natural selection to happen resulting in an increased resistance to the bacterium.

As the puzzle pieces come together we hope it will be possible to identify genes that determine susceptibility to TB. This would give us new clues on how to improve existing treatments, supplement or improve immune function in vulnerable populations, or change vaccinations to decrease the incidence of TB.

Caitlin Uren is a Masters student in Human Genetics at Stellenbosch University and assisted in the writing of this article.

Michelle Daya receives funding from the National Research Foundation of South Africa.