Malaria and the evolution of human beta-globin polymorphisms in southeastern Asia.

Abstract

This dissertation investigates the evolution of human $\beta$-globin polymorphisms (hemoglobin E and $\beta$-thalassemia) in southeastern Asia. Evidence is reviewed for the evolution of these polymorphisms under malarial selection. Human malarias probably originated in southern or southeastern Asia during the terminal Pleistocene or early Holocene, based on parasite evolution, the ecology of mosquito vectors, and prehistoric human ecology. Diverse malarial ecology associated with prehistoric human habitats is reconstructed for southeastern Asia. The population genetics theory of hemoglobin E and $\beta$-thalassemia evolution under malarial selection is studied, with the conclusion that hemoglobin E is most likely replacing $\beta$-thalassemia over the long term. The frequency heterogeneity of hemoglobin E is explained in ecological and demographic terms, over its range of distribution from Greater Assam to archipelago southeastern Asia. The origins and diffusion of this genetic mutation on different $\beta$-globin frameworks common in southeastern Asia is proposed. Differential malarial selection and local demographic movements within southeastern Asia are the prime causes determining the current frequency distribution of hemoglobin E. A hypothesis connecting the frequency heterogeneity of hemoglobin E in southeastern Asia to the invasion of the Tai people from southern China during the early second millennium AD is improbable on ethnohistorical grounds. An analysis of genetic differentiation between 15 populations of Thailand (comprising 7 ethnic groups) is performed, based on allele frequencies at 15 genetic loci. The genetic data was collected and provided by Professor Donald L. Rucknagel, University of Cincinnati, and his collaborators. The Thai are genetically much more affiliated with Austroasiatic natives of southeastern Asia than with various ethnic groups from southern China. This evidence contradicts the hypothesis of a mass invasion of the Tai people from the latter geographic area. The pattern of allele frequency differentiation for hemoglobin E correlates with that for G-6PD deficiency (the other genetic variants probably evolving under malarial selection) and with the pattern of differential malarial endemicity. The genetic diversity is greater for hemoglobin E and G-6PD deficiency than for most other genetic markers. These results suggest the evolution of hemoglobin E under differential malarial selection in the studied populations.