Proportion of hemoglobin G Philadelphia (alpha 268 Asn leads to Lys beta 2) in heterozygotes is determined by alpha-globin gene deletions.

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Abstract
In humans the .alpha.-globin (.alpha.G) genes are duplicated and closely linked. Whereas individuals heterozygous for most .alpha.-chain mutations possess approximately 25% abnormal Hb, heterozygotes for the .alpha.-chain variant Hb G Philadelphia synthesize either 33% or 50% Hb G. Both variable gene dosage and interaction with .alpha.-thalassemia may explain this observation. To differentiate between these models, restriction endonuclease mapping and hematological studies were performed on individuals with Hb G from 4 families. In every case the .alpha.G locus was carried on an EcoRI or EcoRI + BamHI fragments approximately 4 kbases shorter than that bearing the 2 linked .alpha.A loci of hematologically normal individuals. Bgl II digestion revealed that the .alpha.G gene is the only .alpha. locus on the affected chromosome. Erythrocyte indicates and .alpha./.beta. synthesis ratios indicated that the .alpha.G chromosome confers .alpha.-thalassemia. In addition to the .alpha.G gene, subjects who synthesized 33% Hb G possessed 2 .alpha.A genes on the homologous chromosome and exhibited the mild form of .alpha.-thalassemia trait (silent carrier). Subjects who synthesized 50% HbG possessed a single .alpha.A gene trans to the .alpha.G locus and displayed the more pronounced form of .alpha.-thalassemia trait. One subject, who synthesized 100% .alpha.G chains and had Hb G-Hb H disease, had a single nonfunctional .alpha. gene trans to the .alpha.G gene. The proportion of Hb G synthesized by heterozygotes is determined by interaction with .alpha.-globin gene deletions cis and trans to the .alpha.G locus.