The human genome: what's in it for parasitologists?

Abstract

The sequencing of the human genome 1xInitial sequencing and analysis of the human genome. International Human Genome Sequencing Consortium. Nature. 2001; 409: 860–921Crossref | PubMed | Scopus (12778)See all References, 2xThe sequence of the human genome. Venter, J.C. et al. Science. 2001; 291: 1304–1351Crossref | PubMed | Scopus (8198)See all References is a wonderful achievement and a landmark in the history of science. Much has been written about the implications for biology and medicine, especially for research on the causes, diagnosis and treatment of genetic diseases. Yet when most commentators talk about ‘genetic diseases’ they mean heritable, non-communicable diseases – infectious diseases receive far less attention. So how can parasitologists use the information contained in the three billion base pairs that make up the human genome?The genome contains some 30 000–40 000 genes in total. Many of these are polymorphic: 1.42 million single nucleotide polymorphisms (SNPs) are mapped already 3xA map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. International SNP Map Working Group. Nature. 2001; 409: 928–933Crossref | PubMed | Scopus (1987)See all References3. Of the 60 000 SNPs in exons, probably only a small fraction result in amino acid substitutions, but some SNPs will surely be relevant to parasitic diseases. Many polymorphisms affecting susceptibility to parasite infection and disease are already identified and well understood. These include polymorphisms of genes relevant to immune function; for example, a polymorphism of the gene encoding tumor necrosis factor-α influences susceptibility to malaria. But other kinds of genes are involved as well; for example, a polymorphism of the gene encoding glucose-6-phosphate dehydrogenase also influences susceptibility to malaria. Undoubtedly, there are many other such polymorphisms waiting to be characterized and mapped. Each of these will not only increase our understanding of the genetic basis of parasitic diseases but, now that the entire genome is mapped, will also pinpoint host proteins involved in the processes of parasite infection and pathogenesis.A different challenge is to identify genes involved in host–parasite interactions that are not polymorphic. There are several ways to approach this problem, including the detection of differential gene expression in the absence and presence of the parasite. Eventually, it might be possible to use proteomics to identify the human gene ‘targets’ (such as those encoding cell surface receptors) of individual parasite genes. This gene-for-gene or protein-for-protein matching will be facilitated by the parasite genome mapping and sequencing projects now under way for malaria, schistosomes, trypanosomes, theileria, leishmania, giardia, eimeria, cryptosporidia, toxoplasma and filarial worms. These projects could well turn out to be synergistic, with different parasite genomes interacting with human (or other host) genomes in analogous ways.The importance of single genes for host–parasite interactions has long been recognized. But we also need to understand the effects of multiple interacting genes – epistatis – on parasitic diseases (and all other aspects of human genetics as well). Thirty thousand genes mean a huge 900 million possible two-way gene–gene interactions and effectively unlimited numbers of multi-way interactions. These higher-order effects could well turn out to be at least as important as those ascribed to single genes. Unraveling the effects of multiple genes on susceptibility to infectious diseases represents a formidable challenge for the future.Finally, by no means all factors contributing to risks of parasitic disease have a genetic basis. Environmental effects, everything from distance from a clinic to maternal education, strongly influence the risks associated with human parasitic diseases, especially in developing countries. Ultimately, the sequencing of the human genome should contribute to a better understanding of, and better treatments for, many different diseases. But the increased attention now being paid to the genetic basis of human disease must continue to be balanced by research efforts aimed at improving understanding of all aspects of the host–parasite interaction.