β-globin genes: mutation hot-spots in the global thalassemia belt

The concurrence of malaria and hemoglobinopathies, observed in malaria endemic regions, reflects the phenomenon of natural selection. Since the life cycle of the malaria parasite has an erythrocytic stage, abnormalities in the red blood cells (RBCs) hinder the parasite's survival in the human host. Hemoglobin (Hb) variants affect the life span of RBCs and thus lower the chance of infection by the parasite. While a change in just one of the Hb genes offers some protection against malaria, change in both alleles results in β-thalassemia major (β-TM). A striking geographical heterogeneity of β-thalassemia (β-thal) has been observed. Moving from Mexico in the west to China towards the east, the spectrum of mutations in the β-globin gene has been seen to vary. In the western end of the thalassemia belt, defects in the first intervening sequence (IVS-I) and exon 2 of the β-globin gene are more common, while on the eastern coast, IVS-II and exon 1 are also vulnerable to mutations. The worldwide increase in the incidence of β-TM mandates the need for efficient measures to reduce β-thal births, and the geographical heterogeneity of β-thal alleles reduces the burden of genetic testing of fetuses suspected of carrying a mutant allele. In the present review, the common mutations in the global thalassemia belt have been illustrated, and the possible factors that affect the mutagenicity of sites have been discussed. A biogeographic analysis that may provide insight into the non biological factors influencing different loci in the β-globin gene in different geographical regions is suggested.