The Role of Genomics in Studying Genetic Susceptibility to Infectious Disease

The notion that selection during epidemics or longer periods of exposure to infectious diseases may have had a major effect in modifying the constitution of the human genome is not new. It was proposed, at least in outline, by A.E. Garrod in 1931. In his remarkable book, The Inborn Factors in Disease, he suggested that infectious diseases may have been a major selective force in human evolution and in shaping our biochemical individuality. In 1948, J.B.S. Haldane, unimpressed with the idea that the extremely high frequency of thalassemia in certain racial groups from the Mediterranean region might reflect an unusually high mutation rate in these populations, proposed that these diseases might have come under intense selection because of heterozygote advantage against malaria. It was, in effect, Haldane’s remarkable insight that opened up the field of the investigation of genetic susceptibility to infection.

Although considerable progress was made in relating the frequency and distribution of different protein polymorphisms to past or present infection, until recently the field was bedeviled by difficulties relating to population homogeneity, founder effects, and gene drift. However, with an increasing ability to analyze human variability at the DNA level, progress has been much more rapid. Comparing the sequences of genes common to rodents and humans, Murphy (1993), found that host defense genes are much more diverse than those for other families of proteins, an observation suggesting that selection in many species has resulted from exposure to different infectious agents. The way in which DNA analysis is transforming our understanding of the reasons for the distribution and high frequency of the human hemoglobin variants, the problem first posed by Haldane, is reviewed by Flint et al. (1993). Clearly, an analysis of the human genome with respect to variable susceptibility to infection is already beginning to provide …