Abstract
BackgroundThe main function of hemoglobin (Hb) is to transport oxygen in the circulation. It is among the most highly studied proteins due to its roles in physiology and disease, and most of our understanding derives from comparative research. There is great diversity in Hb gene evolution in placental mammals, mostly in the repertoire and regulation of the β-globin subunits. Dogs are an ideal model in which to study Hb genes because: 1) they are members of Laurasiatheria, our closest relatives outside of Euarchontoglires (including primates, rodents and rabbits), 2) dog breeds are isolated populations with their own Hb-associated genetics and diseases, and 3) their high level of health care allows for development of biomedical investigation and translation.ResultsWe established that dogs have a complement of five α and five β-globin genes, all of which can be detected as spliced mRNA in adults. Strikingly, HBD, the allegedly-unnecessary adult β-globin protein in humans, is the primary adult β-globin in dogs and other carnivores; moreover, dogs have two active copies of the HBD gene. In contrast, the dominant adult β-globin of humans, HBB, has high sequence divergence and is expressed at markedly lower levels in dogs. We also showed that canine HBD and HBB genes are complex chimeras that resulted from multiple gene conversion events between them. Lastly, we showed that the strongest signal of evolutionary selection in a high-altitude breed, the Bernese Mountain Dog, lies in a haplotype block that spans the β-globin locus.ConclusionsWe report the first molecular genetic characterization of Hb genes in dogs. We found important distinctions between adult β-globin expression in carnivores compared to other members of Laurasiatheria. Our findings are also likely to raise new questions about the significance of human HBD. The comparative genomics of dog hemoglobin genes sets the stage for diverse research and translation.
Highlights
The main function of hemoglobin (Hb) is to transport oxygen in the circulation
Comparative genomics of the canine α- and β- globin gene-cluster loci Using the relevant proteins and genes from humans and several other mammals to computationally align with the dog genome (BLAST/BLAT algorithms; canFam3.1 assembly), the canine α and β globin gene clusters were identified in chromosomes 6 and 21, respectively
The α-globin gene cluster is formed by three embryonic-like (HBZ1, HBZ2 and HBM) and two adult-like (HBA1 and HBA2) genes (Fig. 1a, Additional file 1)
Summary
The main function of hemoglobin (Hb) is to transport oxygen in the circulation It is among the most highly studied proteins due to its roles in physiology and disease, and most of our understanding derives from comparative research. Dog models are rapidly rising in diverse areas of biomedical research [1, 2]. They can be used experimentally, the advantages that are gaining interest are related to the facts that they are natural models of complex traits with epidemiology and extremely powerful translational genetics. Hb proteins were among the first to be characterized by structure and function, and comparative studies were among the earliest tools used by biochemists to try to understand normal and disease-mutant Hb in the 1950’s [9]. Despite fine comparative genetic studies of Hb genes in placental mammals and animals in general, there is a gap in the understanding of Hb biology in the placental mammal superorder of Laurasiatheria
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