title: Characterization of the -16C>G sequence variation in the promoters of both HBG1 and HBG2: convergent evolution of the human gamma-globin genes.
abstract: We encountered a homozygous -16C>G mutation in cis at identical positions in the promoters of both human gamma-globin genes in a subject who was also homozygous for Hemoglobin C (HbC). Subsequent analysis of normal control individuals of African American ancestry revealed that both mutations were always present in cis with an allelic frequency of 3%. Furthermore, 10 out of 11 HbC subjects carried the -16C>G sequence variations, suggesting an association with HbC. The -16C>G mutation disrupts a putative CACCC box positioned between the TATA box and the transcriptional start site. However, the absence of high levels of HbF in HbC subjects homozygous and heterozygous for the -16C>G sequence variation suggested no effect of this mutation on gamma-globin gene expression in the adult stage of development. Further functional characterization by means of transient transfections in human erythroleukemic K562 cells showed that the -16C>G promoter sequence variation did not have an effect on gamma-globin expression in the fetal stage of development either. We therefore conclude that the -16C>G gamma-globin sequence variations are not beneficial to the clinical phenotype of HbC. The unique concurrent presence of this non-functional sequence variation is likely the result of a gene conversion event, and supports the concept of sequence homogenization between the two human gamma-globin genes.
authors.affiliation: Department of Clinical Chemistry and Haematology, Laboratory for Red Blood Cell Research, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Karen M K
authors.initials: KM
authors.lastname: de Vooght
authors.forename: Richard
authors.initials: R
authors.lastname: van Wijk
authors.forename: Hans K
authors.initials: HK
authors.lastname: Ploos van Amstel
authors.forename: Wouter W
authors.initials: WW
authors.lastname: van Solinge
mesh_terms: D000328:Adult; D001741:Black or African American; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000235:genetics*; D005914:Globins / Q000235:genetics*; D006444:Hemoglobin C / Q000235:genetics; D006720:Homozygote; D006801:Humans; D020014:K562 Cells; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D005914:Globins; D006444:Hemoglobin C