In 1948, J. B. S. Haldane proposed that the selective agent for maintaining the high frequency of thalassemia in the Mediterranean races might be malaria. Thus was born what, in the human hemoglobin field at least, later became known as the malaria hypothesis. In this short essay, I examine the origins of this hypothesis, ask how it has stood the test of time, and summarize the broader field of research which it has spawned and which attempts to understand the genetic basis of variability in individual susceptibility to infection in general. Many of these issues have been reviewed in detail over recent years and are only summarized here.

THE MALARIA HYPOTHESIS

Although the first clinical descriptions of the thalassemias appeared in the 1920's, it only became apparent that these conditions follow a Mendelian recessive or co-dominant pattern of inheritance in the period immediately preceding World War II. At this time relatively simple methods for carrier screening became available and hence it was possible to carry out population studies to attempt to determine gene frequencies.

The extraordinarily high frequency of the genes for thalassemia puzzled population geneticists, particularly those who had become interested in mutation rates as a result of their studies of the survivors of the atomic bombs that had been dropped on Hiroshima and Nagasaki. Extensive studies of gene frequencies of thalassemia were carried out quite independently in the 1940's by workers in the United States and Italy (Neel and Valentine, 1947; Silvestroni and Bianco, 1947), but because of lack of communication during the war and its aftermath it was not until the early 1950's that this broad body of work could be integrated and assessed.