Human genetic diversity and the epidemiology of parasitic and other transmissible diseases

Abstract

This paper aims to review human genetic studies that are generally poorly known by parasitologists and scientists working on other pathogenic agents. The key proposals of this paper are as follows: (i) human susceptibility to transmissible diseases may often have a complex, multigenic background; (ii) recent discoveries indicate that major genomic rearrangements may be involved, possibly more so than DNA sequence; (iii) it is crucial to have a general population genetics framework of the human species based on neutral/historical markers to analyse reliably genetic susceptibility to infectious diseases; and (iv) the population level is a key factor. Ethnic diversity, a highly adaptive genetically driven phenotypic diversity, is possibly a valuable source for exploring human genetic susceptibility to transmissible diseases, since different populations have been exposed to drastically different geographic/climatic environments and different pathogens and vectors for tens of thousands of years. Studies dealing with human genetic susceptibility to transmissible diseases have mostly been based on the hypothesis that this factor is driven by only one or a few genes, and considered the individual more than the population level. Two different approaches have been developed for identifying the genes involved: (i) candidate genes and (ii) blind association studies (linkage analysis), screening the genome with a large number of high-resolution markers. Some loci involved in susceptibility to leishmaniosis, malaria and schistosomosis, for example, have already been identified. South American trypanosomosis (Chagas disease) is reviewed in detail to show the methodological problems of this classical approach. Current knowledge on the general impact of transmissible diseases on human genetic diversity, mainly HLA polymorphism, and the hopes raised by recent major international programmes such as the Human Genome Project (HGP), Human Genome Diversity Project (HGDP), International Human Haplotype Map Project (Hap Map) and extended databases, networks and networks of networks will also be reviewed.