Human globin genes: What can we learn from their polymorphism?

Molecular analysis of human alpha and beta globin genes reveals extensive polymorphism at these loci. Worldwide distribution of the sickle cell trait has been well known for some time. However the molecular basis and distribution of thalassemia have been more recently studied. These are the commonest monogenic disorder. For most of them, beta-thalassemia is due to single nucleotide substitutions, small deletions or insertions They are very heterogeneous and widely dispersed in the Old World. alpha-thalassemia is mainly due to the deletion of one to four alpha genes. On the whole, their distribution is quite similar to beta-thalassemia. With some exceptions, both distributions coincide with present and past regions of malarious endemicity. On the other hand, when looking at individual mutations, no two regions are identical. The question of whether selection by malaria plays a role on observed allele frequencies is still a challenge. The only well clear instance is the beta(S) mutation, which causes sickle cell anaemia. The role of malaria is but one among other hypothesis for explaining thalassemia distribution and frequencies. A possible scenario could be the following: one (or a few) mutation happened in a population and spread because of its selective advantage, along with the founder effect and/or genetic drift. Migration, founder effect and genetic drift must be invoked to account for some observations. It is still difficult to say why a mutation is highly frequent in one population and not in another, even at equivalent malarial endemicity. On the other hand, many genes should contribute simultaneously or in synergy in the process of fighting against malaria. Fitness of each mutation could depend on its genetic background when the mutation arose. Selection must work on a set of genes. Populations who are living now, and genetically very different, could very well be the result of selection on many genes by many infectious agents.