Comparative genomics of canine hemoglobin genes reveals primacy of beta subunit delta in adult carnivores.
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. 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.



We 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.



We 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.
Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.|Present affiliation: SZL, Departamento. de Genetica, Facultad de Veterinaria, Universidad de Cordoba, Cordoba, Spain.
Sara
S
Zaldívar-López
Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|College of Nursing, The Ohio State University, Columbus, OH, USA.|Present affiliation: Center of Excellence in Critical and Complex Care, College of Nursing, The Ohio State University, Columbus, USA.
Jennie L
JL
Rowell
Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Elise M
EM
Fiala
Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Isain
I
Zapata
College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.|Present affiliation: Couto Veterinary Consultants, Hilliard, OH, USA.
C Guillermo
CG
Couto
Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA. alvarez.73@osu.edu.|College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA. alvarez.73@osu.edu.|College of Medicine, The Ohio State University, Columbus, OH, USA. alvarez.73@osu.edu.
Carlos E
CE
Alvarez
D000818:Animals; D001483:Base Sequence; D046528:Chimerism / Q000662:veterinary; D055028:Comparative Genomic Hybridization; D004285:Dogs; D019143:Evolution, Molecular; D056426:Genetic Loci; D006239:Haplotypes; D006454:Hemoglobins / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D006801:Humans; D005810:Multigene Family; D010802:Phylogeny; D011401:Promoter Regions, Genetic; D020836:Protein Structure, Quaternary; D055542:alpha-Globins / Q000737:chemistry / Q000145:classification / Q000235:genetics; D055544:beta-Globins / Q000737:chemistry / Q000145:classification / Q000235:genetics
D006454:Hemoglobins; D055542:alpha-Globins; D055544:beta-Globins
Canine; Comparative genomics; Genetics; Globin; HBB; HBD; HBH; Hemoglobin