High frequencies of α-thalassaemia are the result of natural selection by malaria

Abstract

The frequency of alpha+-thalassaemia, but not other unlinked DNA polymorphisms, exhibits an altitude- and latitude-dependent correlation with malaria endemicity throughout Melanesia, supporting the hypothesis that protection against this parasitic disease is the major factor responsible for the high frequencies of haemoglobinopathies in many parts of the world.

Population genetics of malaria resistance in humans

“…For example, there does not appear to be any of the common malariaresistant variants in native people of the new world (Livingstone, 1985), apparently because their Asian ancestors were not exposed to malaria and malaria was only brought to the new world by early Spanish explorers in the 1600s and 1700s. In addition, there are convincing examples of microgeographic variation in bthalassemia with higher frequencies at lower altitudes in Sardinia where malaria was historically endemic compared with higher altitudes (Siniscalco et al, 1961) and variation of a-thalassemia (Flint et al, 1986) and bthalassemia (Hill et al, 1988) in Melanesia correlated with altitude, which is highly correlated with malaria endemicity.…”

“…The distribution of both a and b thalassemia variants correspond closely to the regions that have historically had high rates of malaria (Weatherall and Clegg, 2001) and the local distribution of these variants also corresponds to endemic malaria (Siniscalco et al, 1961;Flint et al, 1986;Hill et al, 1988). In addition, several studies have shown protection from severe malaria for individuals with a þ thalassemia, compared with individuals without thalassemia (Allen et al, 1997;Mockenhaupt et al, 2004;Williams et al, 2005b).…”

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

“…1 One of the clearest manifestations of such genetic control is malaria, where the parasite seems to have influenced the gene pool of the human host in areas of endemic disease, including retention of otherwise deleterious, disease-causing alleles at erythroid-specific genes (reviewed in Fortin et al 2 ). These include polymorphisms in the Duffy gene at the GATA-1-binding site of the chemokine receptor (DARC, also known as Fy) expressed on erythrocytes, 3 sickle cell anemia, 4 a and b thalassemia, 5,6 glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency, 7,8 and alterations in proteins associated with red cell integrity, such as deletions in the erythrocytic band 3 protein 9 or in the erythrocytic structural protein glycophorin C. 10 Furthermore, Class I and II HLA haplotypes 11 and genetically controlled variations in the level of the proinflammatory cytokine TNFa 12 have been shown to affect the severity and outcome of malaria. Finally, genetic linkage studies by whole genome scanning have shown that several chromosomal regions additionally affect innate susceptibility, extent of host response, and type of disease, 2 although the individual genes involved have yet to be identified.…”

Selection and Mutation for α Thalassemia in Nonmalarial and Malarial Environments

“…The high frequency of hemoglobinopathies generally occurs in areas with historically endemic malaria and it appears that the alteration of the amount and/or type of globin molecules from these disorders confers protection from malarial parasites. In particular, the distribution of α + thalassemia variants corresponds closely with regions that have had historically high rates of malaria and the local distribution of these variants also corresponds to historically endemic malaria (Flint et al, 1986). Haldane (1949) first suggested that genetic variants were important for resistance to malaria and proposed that there may be heterozygote advantage for β thalassemia variants maintaining genetic variation at the β globin locus.…”

“…The haplotypes for the deletional chromosomes with 2, 1, and 0 α globin genes are indicated by αα, −α, and −−, respectively, and the homozygous genotypes for α + thalassemia and α 0 thalassemia are indicated by −α/−α and −−/−−. Heterozygotes for α + thalassemia have three normal genes, −α/αα, and are often difficult to distinguish from normal individuals while homozygotes for α + thalassemia have a mild anemia with little known fitness consequences in nonmalarial environments (Flint et al, 1986). Homozygotes for α 0 thalassemia have hydrops fetalis (fetal edema from anemia), do not survive, and are stillborn.…”