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Comparative Genomics of Canine Hemoglobin Genes Reveals Primacy of Beta Subunit Delta in Adult Carnivores Sara Zaldívar-López1,2,5, Jennie L

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Comparative Genomics of Canine Hemoglobin Genes Reveals Primacy of Beta Subunit Delta in Adult Carnivores Sara Zaldívar-López1,2,5, Jennie L Zaldívar-López et al. BMC Genomics (2017) 18:141 DOI 10.1186/s12864-017-3513-0 RESEARCH ARTICLE Open Access Comparative genomics of canine hemoglobin genes reveals primacy of beta subunit delta in adult carnivores Sara Zaldívar-López1,2,5, Jennie L. Rowell1,3,6, Elise M. Fiala1, Isain Zapata1, C. Guillermo Couto2,7 and Carlos E. Alvarez1,2,4* Abstract Background: 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. Results: 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. Conclusions: 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. Keywords: Canine, Hemoglobin, Globin, Genetics, Comparative genomics, HBH, HBD, HBB Background dogs an alternative to mice, but rather a complementary Dog models are rapidly rising in diverse areas of bio- organism with many similarities to human research. How- medical research [1, 2]. Although they can be used ever, dogs have the immense advantage of having approxi- experimentally, the advantages that are gaining interest mately 400 isolated populations or breeds – each on the are related to the facts that they are natural models of order of 100-fold genetically simpler than the dog or complex traits with epidemiology and extremely powerful human population. As a result, canine investigations have translational genetics. Most investigators do not consider begun yielding important new understanding of complex- genetic traits that have been difficult to study in humans, * Correspondence: [email protected] who have vastly greater heterogeneity. Examples of major 1Center for Molecular and Human Genetics, The Research Institute at successes include diverse morphological traits [3, 4], germ ’ Nationwide Children s Hospital, Columbus, OH, USA line risk of rare cancers [5, 6] and anxiety- and aggression- 2College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA related behaviors [7]. In the last year, the first major Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zaldívar-López et al. BMC Genomics (2017) 18:141 Page 2 of 13 genome wide association study of canine blood traits was their repertoire of β-globin genes [12]. β-globin genes were published. Using 353 clinically healthy dogs, White, Boyko present in early vertebrates and their numbers were ex- and colleagues found significant loci for alanine transfer- panded through duplications within separate lineages. The ase, amylase, segmented neutrophils, urea nitrogen, glu- stem eutherian contained five β-globin genes in one cluster, cose and mean corpuscular hemoglobin [8]. Yet, while in the order 5′-ε-γ-η-δ-β-3′;thesewerederivedbyduplica- canine genetics are exceptionally powerful, one major tions of a single ancestral embryonic-like globin (resulting bottleneck is gene annotation. in ε, γ, η) and one adult-like globin (resulting in δ, β). Some Hemoglobin (Hb) is among the most highly studied β-globin genes were lost or duplicated in different species proteins because of its central role in physiology and its (some are extant as pseudogenes). The obscure η-globin alteration in hemoglobinopathies, some of which are very gene is only extant in Laurasiatheria and its expression is common (e.g., sickle-cell disease). Hb proteins were only known for goat (embryonic [14]); however, the gene among the first to be characterized by structure and func- was lost in rodents and rabbits, and is a pseudogene in pri- tion, and comparative studies were among the earliest mates. γ-globin has the opposite pattern, where it is extant tools used by biochemists to try to understand normal in Euarchontoglires (primates, rodents and rabbits), but and disease-mutant Hb in the 1950’s [9]. In the pre- absent or a pseudogene in Laurasiatheria. genomics DNA era, β-globin genes were some of the earli- Laurasiatheria is a very large and diverse suborder that est prototypes of gene duplication, gene/protein evolution, together with Euarchontoglires makes up Boreoeutheria and tissue- and developmental-specific transcriptional (the two other superorders of eutherians are Xenartha and regulation [10]. The gene for a human Hb subunit (HBB) Afrotheria) [15]. The two suborders are closely related ac- from β-thalassemia patients was one of the earliest to be cording to genetic sequences, and it is believed they split targeted in the nascent field of gene editing [11]. There is ~85 MYA, after the break-up of the supercontinent Pangea a wealth of knowledge on Hb gene regulation and protein into Laurasia (which includes North America, Europe and function in humans, mice, and chickens [10]. However, Asia) and Gondwana (Antarctica, South America, Africa, despite fine comparative genetic studies of Hb genes in Madagascar, Australia, the Arabian Peninsula and the In- placental mammals and animals in general, there is a gap dian subcontinent). In addition to carnivores such as dogs, in the understanding of Hb biology in the placental mam- cats and bears, Laurasiatheria includes shrews, hedgehogs, mal superorder of Laurasiatheria. most hoofed animals (including horses, pigs, ruminants, From its emergence, plants and animals adapted the camels, rhinos and hippos), pangolins, whales, and bats. porphyrin ring for diverse functions in both chlorophyll Laurasiatherians are thus in an excellent position to shed and heme proteins (e.g., O2 transport). That evolution, light on the ancestral functions of Boreoeutherian β-globin which led to the creation and expansion of Hb genes, con- genes, such as η-globin discussed above. Another mystery tinues to be pronounced to this day. Based on homology that they may help resolve is the significance of δ-globin. In between invertebrates and vertebrates, the ancestral humans, the δ-globin protein sequence has diverged signifi- heme-containing globin gene present ~800 million years cantlymorethanβ-globin from the common δ/β-ancestor, ago (MYA) appears to be Neuroglobin [12]. Since that and it is expressed at very low levels as a subunit of the time, gene duplications have resulted in a total of five gene minor adult Hb (HbA2, 3% of total adult Hb) [16]. Human families in tetrapods (amphibians, reptiles, birds, and δ-globin is thought to be physiologically irrelevant because mammals): neuroglobin, α-globin, β-globin, myoglobin, it shows no clinical manifestations when mutant (and, and cytoglobin. Evolutionary adaptation of Hb genes is despite having similar function to HbA, HbA2 levels are recognized in fish, amphibians, reptiles, birds and mam- too low to replace HbA function in β-thalassemia mals [9]. Additional understanding of Hb protein func- major) [16, 17]. However, the δ-globin gene HBD has tion, gene regulation, and evolution comes from studies of reduced diversity levels in humans, and it and the prox- diverse species in which known environmentally-induced imal pseudogene HBBP1 have the strongest signatures of adaptations occurred [12], including extinct species such purifying selection at the β-globin locus [18, 19]. The facts as the woolly mammoth [13]. discussed above have led Moleirinho et al. to propose that The α-globin genes of amniotes are ζ-, μ-, and α- globin, the evolutionary selection at HBD has to do with conser- plus θ-globin in marsupials/placental mammals [12]. ζ- vation of regulatory functions on other β-globin genes globin is expressed in embryonic erythroid cells and α- rather than δ-globin protein function [18]. globin is expressed in fetal and adult erythroid cells. μ-and Due to the high prevalence of hemoglobinopathies in θ- globin are transcribed in tetrapods, but their protein people, α-andβ- globin gene clusters of humans, and of products have not been detected in mammals (whereas the animal models, mouse and chicken are well character- birds express μ-globin protein in adult erythroid cells).
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