Danish and American researchers find that HbD is not a “Peter Pan” protein that historically never grew up and retained its ancestral embryonic function
Nov. 9, 2012 — Nearly all vertebrate animals rely on the respiratory protein hemoglobin to ensure the efficient transport of oxygen from the lungs or gills to cells throughout the body. Most vertebrates express distinct types of hemoglobin during different stages of development. These different types of hemoglobin (called “isoforms”) have different biochemical properties that are tailored to the specific oxygen-transport challenges that are encountered during embryonic development and adult life. In placental mammals, for example, fetal hemoglobin has a much higher affinity for oxygen than adult hemoglobin, and this affinity difference is critically important for facilitating oxygen transfer across the placental barrier during pregnancy.
Gene Duplication and the Evolution of Hemoglobin Isoform Differentiation in Birds
Background: The functional significance of hemoglobin heterogeneity remains a mystery.
Results: In adult birds, the HbD isoform (related to embryonic hemoglobin) exhibits distinct oxygenation properties relative to the major HbA isoform.
Conclusion: Substitutions that distinguish HbD from HbA are not shared with embryonic hemoglobin.
Significance: Differences between isoforms stem from derived (nonancestral) changes in duplicated genes, not from the retention of an ancestral condition.
The physiological division of labor among hemoglobin isoforms that are expressed at different stages of development have been well-characterized in mammals and birds. However, many vertebrate groups also express different hemoglobin isoforms during postnatal life, and in most cases the nature of the physiological division of labor between these co-expressed isoforms remains a mystery. Whereas humans and most other mammals express a single hemoglobin isoform during adult life, birds express two functionally distinct isoforms, called HbA and HbD. Hemoglobins are composed of distinct subunits, and the HbA and HbD isoforms of birds just differ in their “alpha-chain” subunits. The alpha-chains of HbA are products of the alphaA-globin gene, whereas the corresponding subunits of HbD are products of the alphaD-globin gene. Intriguingly, the alphaD-globin gene is a duplicate copy of a hemoglobin gene that is exclusively expressed during early embryonic development in all vertebrates. This suggests the possibility that functional differences between HbA and HbD may be attributable to a retained ancestral character in HbD that harkens back to a primordial embryonic function.
In a publication in a recent issue of The Journal of Biological Chemistry, an American/Danish research team led by Jay F. Storz (University of Nebraska) and Roy E. Weber (Aarhus University, Denmark) report findings that shed light on the evolutionary origins of the differences between the avian HbA and HbD isoforms. The team conducted a functional analysis of the avian HbA and HbD isoforms in conjunction with an evolutionary analysis of the underlying genes. The team found that HbD is characterized by a consistently higher oxygen affinity than the HbA isoform, a property consistent with its heritage as an embryonic hemoglobin. However, after identifying all the mutational differences that distinguish the alpha-chain subunits of HbA and HbD, the researchers discovered that the functional differences between the two isoforms are attributable to mutational changes that are not shared with embryonic hemoglobin. Thus, HbD is not a “Peter Pan” protein that never grew up and retained its ancestral embryonic function. Instead, the functional differences that evolved between HbA and HbD are attributable to more recent mutational changes that occurred in the alphaD gene long after it originated via duplication from an embryonic hemoglobin gene. This study of bird hemoglobins suggests that not all proteins are prisoners of their evolutionary past.