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Malaria resistance genes: a natural selection

1992; Oxford University Press; Volume: 86; Issue: 3 Linguagem: Inglês

10.1016/0035-9203(92)90282-h

1878-3503

Adrian V. S. Hill,

Mosquito-borne diseases and control

Over the years there have been various ideas for dealing with malaria, from wormwood and cold water cures to genetically engineered vaccines and transgenic mosquitoes. Designing genes to resist malaria, the essence of these more recent approaches, is an attractive and exciting concept, but one which is not entirely original. For thousands of years natural selection has been tinkering with the same problem by altering our genome-to a surprising extent. We now know of far more genes which influence susceptibility to Plasmodium falciparum malaria than any other disease of humans, and the analysis of these has some timely implications when huge sums of money are being spent on mapping and sequencing the human genome, and much made of the potential this exercise may have for understanding other common polygenic diseases. Although malaria resistance genes remain the outstanding examples of natural selection acting in human populations, the impact that they have had on disease control and our understandinn of pathophysiology has been more measured. No& theless,recent work is revealing tantalizing leads. with several of the red cell defects now”appearing ib act ihrough iricreased parasite clearance by macrophages, and human leucocyte antigen (HLA) associations offering the prospect of a new route to identify protective immune responses in the sea of immune reactivity elicited by the parasite. From a broader perspective, malaria resistance genes continue to provide evidence on questions as diverse as the time depth and magnitude of malaria mortality amongst humans, the mechanisms of evolution of immune response genes, and the migration routes of prehistoric populations. In the terminology of gene mapping, malaria represents a triumph for the candidate gene approach. We still have no satisfactory comparison of identical to non-identical twins to es&&e the overall contribution of genetic factors to malaria susceptibility. Also, because of the age distribution of severe malaria in endemic regions, multigenerational studies are particularly difficult. The alternative sib-pair analysis ap roach, much used in studies of autoimmune disorders, ooks at the frequency of sharP ing of polymorphic alleles amongst sibs with the disease (DAY & SIMON?,, 1976). If large numbers of sibs with severe malaria could be recruited this would offer a new and powerful approach to analysing malaria susceptibility. Instead, almost all malaria resistance genes (Table)