Identical Mutations in the Paralogous Human γ-Globin Genes Leading to Hemoglobin Variants and Nondeletional Hereditary Persistence of Fetal Hemoglobin

Abstract

The human fetal globin genes are highly similar at the DNA sequence level, resulting in a single amino acid difference between the Gγ- and Aγ-globin chains. A large proportion of hemoglobin (Hb) variants of the Gγ- and Aγ-globin chains result from an identical mutation in the HBG2 and HBG1 genes, respectively, while the same is true for a fraction of mutations leading to nondeletional hereditary persistence of fetal Hb (HPFH). In particular, 11 different Hb variants result from identical mutations on either one of the two human γ-globin paralogous genes, while seven other promoter substitutions result either in nondeletional HPFH or are benign polymorphisms. In the former case, the percentage of the Hb variants due to an HBG2 gene mutation was significantly higher than the percentage of Hb variants due to the same HBG1 gene mutation, following the Gγ/Aγ-globin chain ratio seen in wild-type individuals. These γ-globin chain variants have most likely occurred via recurrent mutations, gene conversion events or both and, contrary to the situation observed in the human α-globin genes, these mutations lead to distinct variant Hb molecules.