Overproduction of α chains provides a proton-insensitive component to the bluefish hemoglobin system

Expression of α and β chains and their post-translational assembly into α₂β₂ tetramers is fundamental to the formation and function of most vertebrate hemoglobins. There is a strong evolutionary bias that favors expression of equal amounts of the two types of chains, because coopexrativity, pH sensitivity, and anionic control of function occurs only for the α₂β₂ tetramers. Remarkably, an overproduction of α chains, as in the pathological condition known as β thalassemia in humans, is adaptive rather than pathological in the bluefish hemoglobin system. The thalassemia of the bluefish is a novel means of providing for oxygen uptake and delivery when low pH conditions incapacitate the highly pH-sensitive Root effect hemoglobins of the fish. Although fish often have pH-insensitive along with highly pH-sensitive hemoglobins, having pH-insensitive α chain monomers in circulation is an unusual structural variation. The role of bluefish α chains in oxygen transport is enabled by their remarkably lower oxygen affinity relative to human α chains. This is the first reported case of a thalassemic condition that is maintained in a species as an adaptive advantage.