Negative Epistasis Between Α+ Thalassaemia and Sickle Cell Trait Can Explain Interpopulation Variation in South Asia

Abstract

Recent studies in Kenya and Ghana have shown that individuals who inherit two malaria-protective genetic disorders of haemoglobin—α+ thalassaemia and sickle cell trait—experience a much lower level of malaria protection than those who inherit sickle cell trait alone. We have previously demonstrated that this can limit the frequency of α+ thalassaemia in a population in which sickle cell is present, which may account for the frequency of α+ thalassaemia in sub-Saharan Africa not exceeding 50%. Here we consider the relationship between α+ thalassaemia and sickle cell in South Asian populations, and show that very high levels of α+ thalassaemia combined with varying levels of malaria selection can explain why sickle cell has penetrated certain South Asian populations but not others.

World Distribution, Population Genetics, and Health Burden of the Hemoglobinopathies

“…From the perspective of HbAS, this may be explained by the changes in the intracellular concentration of HbAS that accompany the coinheritance of a thalassemia (Brittenham et al 1980). This negative interaction between the two malariaprotective phenotypes could well explain why both are held at intermediate frequencies in populations where both occur together (Williams et al 2005c;Hedrick 2011;Penman et al 2011). A similar hypothesis has more recently been advanced to explain the relative frequencies of HbAS and the a and b thalassaemias within the Mediterranean region (Penman et al 2009).…”

The spatial epidemiology of sickle-cell anaemia in India

“…A few of these excluded surveys offer data in areas where no surveys meeting our inclusion criteria were conducted. For instance, analyses carried out in the Tharu tribal group of the Terai region of Uttar Pradesh revealed a β S allele frequency of 10% 33 . This survey could not be georeferenced to the district level and was therefore excluded from the present study.…”

Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria

“…The occurrence of negative epistasis between HbS and HbF in malaria would have implications in our understanding of malaria protective mechanisms in areas with high prevalence of SCD and malaria. The interaction between these two haemoglobins and their effect on malaria may differ between populations with different levels of HbF, for example in Asia population where HbF levels are higher than African population [ 21 , 22 ]. Epistatic interactions between different malaria-protective haemoglobin variants may be one of the factors that determines their geographical distribution [ 22 ]…”