The phenotypic diversity of monogenic disease: lessons from the thalassemias

Clearly, the thalassemias are associated with a remarkably diverse series of phenotypes. Much of this heterogeneity can be explained at the molecular level by variability of the primary mutation of the beta globin genes, and the effects of genetic variability at two other loci, that is the alpha and gamma gene loci. When all these factors are taken into consideration there still remains a considerable amount of phenotypic diversity that is not explainable in this way. It is becoming clear that there is potential for further diversity at unrelated loci that may modify the major complications of the disease. And there is yet another layer of potential genetic variability that reflects the way in which these diseases have come under intense selection by malaria over a relatively short period of time. Finally, there are many environmental and cultural factors that may modify a patient's reaction to the disease. It is apparent, therefore, that this group of monogenic diseases are highly diverse and that, although much of this heterogeneity can be ascribed to the action of one or two major modifying loci, phenotypic variability also reflects the action of even further genetic diversity stemming from the way this disease has spread and its evolutionary background. It is apparent, therefore, that when we start to dissect disease due to the action of multiple loci, together with a major environmental component, the situation will be infinitely more complex. Of course this should not stop us from attempting to isolate the major genes involved, but it is telling us that we should be very careful about making assumptions that we will be able accurately to predict phenotypes from genotypes; although we have made considerable progress toward this end for the thalassemias, even here we have to deal with a large number of genetic and environmental factors that may modify the primary action of mutations of the beta globin genes. It is issues of this kind that will set the limit on our current reductionist approach to the study of human disease and will make it all the more important that we develop a more holistic way of analyzing disease processes in the future.