Genomic analysis of malaria resistance

Malaria is one of humankind‘s most persistent and deadly foes, and is a significant determinant of global poverty - causing debilitating illness in approximately half a billion people each year. The greatest burden of the disease falls on African children - over a million die each year of malaria.

This project hinges on a key observation. Many people survive malaria infection and, after repeated exposure, develop some level of immunity.

Our challenge is to answer this question. What are the natural immune responses that protect people from dying or becoming ill due to malaria? Here are two examples of what we mean by an immune response: (1) the person makes antibodies that attach to molecule X on the surface of the parasite; (2) when white blood cells come into contact with a malaria parasite they release chemical Y that kills the parasite. Knowing the answer to this question would help enormously in designing an effective malaria vaccine.

Researchers have been tackling this question for almost a century - why is it so difficult to answer? Part of the problem is that people who are infected with malaria make a vast range of immune responses that have no protective benefit and some that may even be harmful. Searching through all these different immune responses to find those that protect people from becoming ill or dying is like searching for a needle in a haystack. To complicate matters further, much of the immune battle against the malaria parasite happens in the spleen and other inaccessible parts of the body that are very difficult to study in living people.

Recent advances in human genome research are revolutionising the way that we tackle complex problems of this sort. The key observation is that most human genes show variation between individuals. By investigating how this natural genetic variation affects the ability of people to resist infection, we can get deep insights into molecular mechanisms of protective immunity.

Why is this such a powerful approach? Firstly, because it doesn‘t require us to measure proteins directly, so we may be able to identify important mechanisms even if they are impossible to measure in living humans - e.g., if they are hidden away in the spleen. Secondly, because new technologies allow us to screen a vast number of genes without knowing anything about their function, making it possible to discover entirely novel mechanisms that are critical for protection against malaria.

A major obstacle to the development of a malaria vaccine, or improved treatments for severe malaria, is our poor understanding of the host responses that determine protective immunity. Genomic epidemiology offers a radically new approach to the problem, using natural human diversity as a tool to identify host genes that play a critical role in immunity and pathogenesis.

The long-term goal of this MRC Programme, which began in 1996, is to achieve a comprehensive understanding of malaria resistance genes in human populations. It has 3 key objectives:

1. establish epidemiological infrastructure to discover malaria resistance genes

2. develop effective strategies for high-resolution genomic association mapping

3. characterise functional genetic variants that affect immune gene regulation

All 3 areas have seen substantial progress over the past 5 years. We have established a unique epidemiological resource for large-scale genetic association analysis of malaria, which now contains more than 6000 cases of severe malaria plus parents and population controls. Building on the success of this MRC Programme, and on revolutionary advances in the science of human genomic diversity and genotyping technology, we have obtained funding from the Grand Challenges in Global Health initiative to establish a global network for genomic epidemiology of malaria (MalariaGEN) which will yield extremely large epidemiological collections across 14 malaria endemic countries, plus massive-throughput genotyping. Thus we expect to generate a vast amount of data over the next 5 years. However to achieve our long-term goal we need to do more than simply scale up sample size and genotyping capacity. Genomic epidemiology is a young science and there are many basic methodological issues to be addressed.

This proposal aims to tackle some of these fundamental problems.

First, the huge genetic diversity of African populations poses a major challenge for genetic association analysis due to population stratification - we will address this problem both by detailed population sampling and by analytical approaches.

Second, the complex haplotypic structure of the genome across different African populations greatly complicates the process of linkage disequilibrium mapping - this grant will fund an exceptionally high resolution survey of a single region of the genome, the MHC, across three populations.

Third, we remain at a very early stage in understanding the functional basis of genetic variation in immune gene regulation - a problem we will tackle using allele-specific transcript quantification, an emerging technology to which our group has made a significant contribution over the past 3 years.