Tibetan Mastiff Research Articles

Genomic selection analysis of morphological and adaptation traits in Chinese indigenous dog breeds.

The significant morphological differences and abundant germplasm resources of Chinese indigenous dog breeds can be attributed to the diverse geographical environment, including plateaus, mountains, and a long history of raising dogs. The combination of both natural and artificial selection during the past several thousand years has led to hundreds of dog breeds with distinct morphological traits and environmental adaptations. China is one of the earliest countries to domesticate dogs and there are more than 50 ancient indigenous dog breeds. In this study, the run of homozygosity (ROH) and proportion of the autosomal genome covered by ROHs (FROH) were calculated for 10 dog breeds that are the most representative Chinese indigenous dogs based on 170K SNP microarray. The results of FROH showed that the Chuandong hound dogs (HCSSC) have the highest level of inbreeding among the tested breeds. The inbreeding in HCSSC occurred more recently than the Liangshan dogs (SCLSQ) dogs because of more numbers of long ROHs in HCSSC dogs, and the former also have higher inbreeding degree. In addition, there are significant differences in the inbreeding degree among different subpopulations of the same breed, such as the Thin dogs from Shaanxi and Shandong province. To explore genome-wide selection signatures among different breeds, including coat color, ear shape, and altitude adaptability, we performed genome selection analyses of FST and cross population extended haplotype homozygosity (XP-EHH). For the coat color, the FST analysis between Xiasi dogs (XSGZ) and HCSSC dogs was performed and identified multiple genes involved in coat color, hair follicle, and bone development, including MC1R, KITLG, SOX5, RSPO2, and TBX15. For the plateau adaptability, we performed FST and XP-EHH analyses between dogs from Tibet (Tibetan Mastiffs and Nyingchi dogs) and plain regions (Guangxi Biwei dogs GXBWQ and Guandong Sharpei dogs). The results showed the EPAS1 gene in dogs from Tibet undergo strong selection. Multiple genes identified for selection signals based on different usage of dogs. Furthermore, the results of ear shape analyses showed that MSRB3 was likely to be the main gene causing the drop ear of domestic dogs. Our study provides new insights into further understanding of Chinese indigenous dogs.

Issue Information

Molecular Ecology ResourcesVolume 23, Issue 5 p. i-ii ISSUE INFORMATIONFree Access Issue Information First published: 06 June 2023 https://doi.org/10.1111/1755-0998.13636AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract Cover Illustration: A Tibetan Mastiff in Tianzhu, Gansu, China. Photo Credit: Ru-Nian Wu. Volume23, Issue5July 2023Pages i-ii RelatedInformation

Origin and population structure of native dog breeds in the Korean peninsula and East Asia

To study the ancestry and phylogenetic relationships of native Korean dog breeds to other Asian dog populations, we analyzed nucleotide variations in whole-genome sequences of 205 canid individuals. Sapsaree, Northern Chinese indigenous dog, and Tibetan Mastiff were largely related to West Eurasian ancestry. Jindo, Donggyeongi, Shiba, Southern Chinese indigenous (SCHI), Vietnamese indigenous dogs (VIET), and Indonesian indigenous dogs were related to Southeast and East Asian ancestry. Among East Asian dog breeds, Sapsaree presented the highest haplotype sharing with German Shepherds, indicating ancient admixture of European ancestry to modern East Asian dog breeds. SCHI showed greater haplotype sharing with New Guinea singing dogs, VIET, and Jindo than with other Asian breeds. The predicted divergence time of East Asian populations from their common ancestor was approximately 2,000 to 11,000 years ago. Our results expand understanding of the genetic history of dogs in the Korean peninsula to the Asian continent and Oceanic region.

Raising Dogs that Bite: How Pastoralists and Breeders Care for Tibetan Mastiffs

Abstract Tibetan pastoralists have long been using dogs as guards. Since the late 1980s, the same dogs, called “Tibetan Mastiffs,” have become valuable pets for Han Chinese consumers. This paper discusses how commodification transforms the value of these dogs, and the care relationship between humans and dogs. Tibetan pastoralists and dogs participate in a reciprocal yet distanced care relationship through raising and guarding, which is not confined to a pursuit of dogs’ ferocity. In contrast, a taste for ferocity prevails in the Tibetan Mastiff market, and breeders care for dogs in a more dedicated, and yet more unilateral and dangerous, way. The unintended consequence of breeders’ care is that they raise dogs that sometimes bite; this is explained based on a process of value transformation in dogs’ guarding abilities, from ethical virtue to commercial price.

Long amplicon HiFi sequencing for mitochondrial DNA genomes.

Long-read sequencing technology is a powerful approach with application in various genetic and genomic research. Herein, we developed the pipeline for long amplicon high-fidelity (HiFi) sequencing and then applied it for sequencing mitochondrial DNA (mtDNA) genomes from pools of 79 Tibetan Mastiffs. We amplified the mtDNA genome with long-range PCR using two pairs of primers. Two rounds of circular consensus sequencing (CCS) were conducted and their accuracy was evaluated. The results indicate that the second round of CCS can improve the accuracy of HiFi reads. In addition, the analysis of 79 high-quality mtDNA genomes shows the Tibetan Mastiffs from outside of the Tibetan Plateau experienced hybridization with other dogs. The high quality reads generator (HQGR) software is provided to facilitate data analyses, which is publicly accessible on GitHub (https://github.com/Caizf-script/HQGR). Our long amplicon HiFi sequencing pipeline can also be applied in various target enrichment strategies for small genomes and candidate genes.

Impact of co-transfer of embryos produced by somatic cell nuclear transfer using two types of donor cells on pregnancy outcomes in dogs.

ObjectiveThe present study analyzed the influence of co-transferring embryos with high and low cloning efficiencies produced via somatic cell nuclear transfer (SCNT) on pregnancy outcomes in dogs.MethodsCloned dogs were produced by SCNT using donor cells derived from a Tibetan Mastiff (TM) and Toy Poodle (TP). The in vivo developmental capacity of cloned embryos was evaluated. The pregnancy and parturition rates were determined following single transfer of 284 fused oocytes into 21 surrogates and co-transfer of 47 fused oocytes into four surrogates.ResultsWhen cloned embryos produced using a single type of donor cell were transferred into surrogates, the pregnancy and live birth rates were significantly higher following transfer of embryos produced using TP donor cells than following transfer of embryos produced using TM donor cells. Next, pregnancy and live birth rates were compared following single and co-transfer of these cloned embryos. The pregnancy and live birth rates were similar upon co-transfer of embryos and single transfer of embryos produced using TP donor cells but were significantly lower upon single transfer of embryos produced using TM donor cells. Furthermore, the parturition rate for TM dogs and the percentage of these dogs that remained alive until weaning was significantly higher upon co-transfer than upon single transfer of embryos. However, there was no difference between the two embryo transfer methods for TP dogs. The mean birth weight of cloned TM dogs was significantly higher upon single transfer than upon co-transfer of embryos. However, the body weight of TM dogs did not significantly differ between the two embryo transfer methods after day 5.ConclusionFor cloned embryos with a lower developmental competence, the parturition rate and percentage of dogs that remain alive until weaning are increased when they are co-transferred with cloned embryos with a greater developmental competence.

Comparative genomic analysis of high-altitude adaptation for Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus

Tibetan Mastiff has adapted to the extreme environment of the Qinghai-Tibetan Plateau. Yet, the underlying mechanisms of its high-altitude-adaptation and origin remains elusive. Here, we generated the draft genomes of Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus. The phylogenetic tree uncovered that Tibetan Mastiff and Mongolia Mastiff were derived from Canis Lupus species. The comparative genomic analyses identified that the expansion of gene families related to DNA repair and damage response, and contraction related to ATPase activity revealed the genetic adaptations of Tibetan Mastiff and Canis Lupus to high altitude. In addition, the Tibetan Mastiff and Canis Lupus had signals of positive selection for genes involved in fatty-acid α/β- oxidation for highland adaptation. Notably, the positively selected TERT of Tibetan Mastiff should be an adaptive trait for correcting DNA damage. These findings suggested that the Tibetan Mastiff and Canis Lupus evolves basic strategies for adaptation to high altitude.

Identification and Characterization of a Novel Type of Cartilage Stem/ Progenitor Cells from Tibetan Mastiff

Identification and Characterization of a Novel Type of Cartilage Stem/ Progenitor Cells from Tibetan Mastiff

Bromide toxicosis (bromism) secondary to a decreased chloride intake after dietary transition in a dog with idiopathic epilepsy: a case report

BackgroundBromide is a halide ion of the element bromine usually administered in the form of potassium salt as monotherapy or add-on treatment in epileptic dogs. It is excreted unchanged in the urine and undergoes tubular reabsorption in competition with chloride. Thus, dietary chloride content affects serum bromide concentrations. This is the first published clinical report of bromide toxicosis secondary to a dietary modification of chloride content in an epileptic dog treated with potassium bromide.Case presentationA 3-year-old 55-kg neutered male Tibetan Mastiff was evaluated because of a 1-month history of progressive signs including ataxia, lethargy and behaviour changes. The dog was successfully treated for idiopathic epilepsy since the age of 1-year-old with phenobarbital and potassium bromide. Two months prior to presentation, the owners decided to change the dog’s diet without veterinary advice. Physical examination was unremarkable. A 12-kg weight gain was recorded since last follow-up (8 months). Neurological examination revealed severe symmetric 4-limbs ataxia with altered vigilance and intermittent episodes of hyperactivity and aggressive behaviour without significant abnormality of cranial nerves. Serum bromide concentration was high and increased by 103 % since last follow-up. Nutritional evaluation revealed a 53 % decrease of chloride content in the diet before and after dietary transition. Bromide toxicosis was suspected, due to bromide reduced clearance secondary to the decreased dietary chloride content. Potassium bromide treatment was lowered by 15 % without further dietary changes. Neurologic signs progressively improved over the next month, without any seizure. After two months, the serum bromide concentration lowered to the same level measured before dietary modification. After four months, neurological examination was unremarkable.ConclusionsDietary chloride content can directly influence serum bromide concentrations, therefore affecting seizure control or contributing to unexpected adverse effects. In the present case, a reduction in chloride intake markedly increased serum bromide concentrations causing bromism. Dietary changes should be avoided in dogs treated with potassium bromide to maintain stable serum bromide levels.

Sequence analysis of the coding regions of the apolipoprotein C2 (APOC2) gene in Miniature Schnauzers with idiopathic hypertriglyceridemia

It has been hypothesized that idiopathic hypertriglyceridemia in Miniature Schnauzers is hereditary, but the gene responsible has yet to be identified. The objective of this study was to determine if there were coding variants in the apolipoprotein C2 (APOC2) gene in Miniature Schnauzers with idiopathic hypertriglyceridemia. Blood samples from 12 Miniature Schnauzers with idiopathic hypertriglyceridemia were analyzed. Genomic DNA was extracted from whole blood, and the three coding exons of APOC2 were amplified by PCR. The PCR amplicons were sequenced and analyzed for variants relative to the canine reference genome (CanFam3.1 assembly). A second objective was to determine the extent of variation in coding exons of APOC2 in a large and diverse canine population using the Dog Biomedical Variant Database Consortium variant catalog, comprised of whole genome sequencing variant calls from 582 dogs of 126 breeds and eight wolves. There were no variants detected in the coding exons of APOC2 for any of the 12 Miniature Schnauzers with idiopathic hypertriglyceridemia. Variants in the coding exons of APOC2 were also rare in the Dog Biomedical Variant Database Consortium variant catalog; a single synonymous variant was identified in a heterozygous state in a Tibetan Mastiff. Thus, we concluded that coding variants in APOC2 are unlikely to be a major cause of idiopathic hypertriglyceridemia in North American Miniature Schnauzers and furthermore, that such coding variants are rare in the canine population.

The Fatal Case of an Autochthonous Heartworm Disease in a Dog from a Non-endemic Region of South-eastern Slovakia.

SummaryDuring the past few years, several localities with increasing Dirofilaria immitis occurrences have been identified in Slovakia; particularly in areas regarded as endemic for Dirofilaria repens up until now. In terms of that, dogs with clinically manifested heartworm disease have been referred to the veterinary ambulances more frequently. We report in this study, two autochthonous cases of D. immitisinfections diagnosed in two seven-year-old siblings of Tibetan Mastiff dogs from the Košice region of south-eastern Slovakia. The course of the disease in both dogs were very different. The female dog did not manifest any unusual findings, however the male dog exhibited severe clinical signs of heartworm disease that lead to his death. The subsequent autopsy revealed adult D. immitis worms in the right heart ventricle and pulmonary arteries.

Brian Hodgson's Tibetan Mastiffs: twice presented to the Zoological Society of London

In November 1828, King George IV presented to the menagerie of the Zoological Society of London a pair of Tibetan Mastiffs (Canis lupus familiaris) sent from Nepal by Brian Houghton Hodgson, the Assistant Resident at the British Residency in Kathmandu. The dogs' stay was brief: within weeks of their arrival, both dogs had succumbed to distemper, a disorder which periodically ran rampant through the Society's collections. However, during their short lives they caught the imagination of those naturalists fortunate enough to see them, and they live on in a number of watercolours commissioned by Hodgson before they started on their journey to Britain. This paper traces the brief existence of the “Thibet watch dogs” in London, paying close attention to their intended and abortive use as a gift to gain favour with the King, and places their portraits within the wider context of Hodgson's work in Nepal.

Adaptive Changes in Hemoglobin Function in High-Altitude Tibetan Canids Were Derived via Gene Conversion and Introgression.

A key question in evolutionary biology concerns the relative importance of different sources of adaptive genetic variation, such as de novo mutations, standing variation, and introgressive hybridization. A corollary question concerns how allelic variants derived from these different sources may influence the molecular basis of phenotypic adaptation. Here, we use a protein-engineering approach to examine the phenotypic effect of putatively adaptive hemoglobin (Hb) mutations in the high-altitude Tibetan wolf that were selectively introgressed into the Tibetan mastiff, a high-altitude dog breed that is renowned for its hypoxia tolerance. Experiments revealed that the introgressed coding variants confer an increased Hb–O2 affinity in conjunction with an enhanced Bohr effect. We also document that affinity-enhancing mutations in the β-globin gene of Tibetan wolf were originally derived via interparalog gene conversion from a tandemly linked β-globin pseudogene. Thus, affinity-enhancing mutations were introduced into the β-globin gene of Tibetan wolf via one form of intragenomic lateral transfer (ectopic gene conversion) and were subsequently introduced into the Tibetan mastiff genome via a second form of lateral transfer (introgression). Site-directed mutagenesis experiments revealed that the increased Hb–O2 affinity requires a specific two-site combination of amino acid replacements, suggesting that the molecular underpinnings of Hb adaptation in Tibetan mastiff (involving mutations that arose in a nonexpressed gene and which originally fixed in Tibetan wolf) may be qualitatively distinct from functionally similar changes in protein function that could have evolved via sequential fixation of de novo mutations during the breed’s relatively short duration of residency at high altitude.

Biological Characteristics and Multilineage Differentiation of Kidney Mesenchymal Stem Cells Derived from the Tibetan Mastiff

Of all the significant researches that have taken place in isolation, culture and characterization of mesenchymal stem cells (MSCs), the field of kidney-derived mesenchymal stem cells (KMSCs) in Tibetan mastiff is still a blank. Therefore, the purpose of this study is to isolate, culture and characterize the Tibetan mastiff KMSCs. The KMSCs were successfully isolated from one-day year old Tibetan mastiff kidney, cultured for 16 passages and distinguished by two methods: immunofluorescence staining and RT-PCR. The Tibetan mastiff KMSCs expressed specific surface marker genes (VIM, CD44, FN1, CD90, CD109, CD73, FN1) and kidney marker gene PAX2. The proliferation ability of Tibetan mastiff KMSCs was measured through cell count and clonality. Furthermore, cells differentiated into different cell types (hepatocellular cells, osteogenic cells, adipogenic cells and chondrogenic cells) under special induced medium, and the marker genes of induced cells were identified with Immunofluorescence staining and RT-PCR. All of these results indicated that the Tibetan mastiff KMSCs were obtained successfully, which possessed certain characteristics of multipotent stem cells. Therefore, MSCs in Tibetan mastiff kidney hold potential for clinical applications for regenerative therapy and their further studies are waiting to be required to investigate their functions.

Improvement of Sperm Motility Within One Month Under Selenium and Vitamin E Supplementation in Four Infertile Dogs with Low Selenium Status.

IntroductionSignificant improvement of sperm motility within one month effected by oral supplementation of selenium and vitamin E was described in four infertile male dogs which failed to conceive in their last three matings with different bitches.Material and MethodsThe dogs (a Golden Retriever, an English Cocker Spaniel, and two Tibetan Mastiffs) were supplemented daily with selenium (Se) (0.6 mg/kg organic Se yeast) and vitamin E (vit. E) (5 mg/kg) per os for 60 days. Semen was collected on days 0, 30, 60, and 90. The sperm concentration and motility parameters were evaluated by the CASA system, sperm morphology was explored by Diff-Quick staining, and live and dead spermatozoa were differentiated by eosin/nigrosin staining. The concentrations of Se and vit. E were measured in peripheral blood serum on semen collection days.ResultsBefore administration, the concentrations of Se in blood plasma were low (86.0–165.0 μg/L). After 30 days of treatment there was an observable improvement in total and progressive sperm motility and kinematic parameters (VAP, VSK, VCL, ALH, BCF, and RAPID). The percentages of live and normal morphology sperm cells were also higher. There was also an observable increase in Se and vitamin E concentrations in blood serum. Bitches were successfully mated and delivered four to six puppies.ConclusionSupplementation with Se and vit. E improved rapid sperm motility and restored fertility in infertile dogs with low Se status.

Isolation, Culture and Biological Characteristics of Tibetan Mastiff (Canis lupus Familiaris) Muscle Satellite Cells

With the ability of self-renewal and multipotenntial differentiation, muscle satellite cells (MSCs) are recognized as a population of tissue-specific progenitors which play an important role in the growth, repair and regeneration of muscles. Satellite cells have been isolated for a very long time, but the techniques of isolation are still to be improved. In this study, MSCs were obtained from aborted Tibetan mastiff fetuses (about 60 days) under sterile conditions. Primary MSCs were sub-cultured to passage 25 in vitro. The gene of C-met, MyoD1, Desmin and Pax7 were detected by RT-polymerase chain reaction and immunofluorescence assays. The result showed that they were positive in MSCs of Tibetan mastiff. The growth of different passages cells typically appeared in S curve. Furthermore, myogenic, osteogenic and adipogenic differenciation of MSCs were successfully induced. The results denoted that the MSCs obtained from Tibetan Mastiffs exhibited the characteristics of multipotent stem cells. Therefore, this work provided a theoretical and technical basis for Tibetan mastiff, even its genetic resources preservation and laid a solid foundation for studying the mechanism of skeletal muscle growth and development in future.

Characteristics and multi‑lineage differentiation of bone marrow mesenchymal stem cells derived from the Tibetan mastiff.

Bone marrow mesenchymal stem cells (BM-MSCs) are pluripotent stem cells that are regarded as ideal resources for the reconstruction of tissues and organs. The Tibetan mastiff is a breed of domesticated Chinese native dog that is well-adjusted to the high-altitude environments of Tibet. To the best of our knowledge, the biological characterization and multi-lineage differentiation of Tibetan mastiff BM-MSCs have not been reported previously. Therefore, the present study aimed to investigate the biological characteristics and therapeutic potential of Tibetan mastiff BM-MSCs. A cell culture system was constructed and cells were cultured to 23 passages in vitro. Growth curves and colony formation studies suggested that BM-MSCs had a high self-renewal capacity and that their proliferation rate declined with age. Karyotype analysis demonstrated that BM-MSCs were diploid and genetically stable. Semi-quantitative polymerase chain reaction analysis revealed that BM-MSCs positively expressed cluster of differentiation (CD)73, CD90, CD105, CD166 and vimentin, although they were negative for the endothelial cell marker CD31. Additionally, immunofluorescence staining revealed that the cells expressed CD29, CD44, CD90, CD105 and vimentin. Flow cytometric analysis revealed that the rates of positive expression of vimentin, CD44, CD90 and CD105 were all >97%. BM-MSCs were able to differentiate into adipocytes, osteoblasts, cartilage cells, hepatocytes and functional insulin-secreting cells. In conclusion, Tibetan mastiff BM-MSCs may be purified successfully using a whole bone marrow culture method. The findings of the current study suggested important potential applications of BM-MSCs as a source for regenerative therapies.

The Role of Introgressive Hybridization in Hypoxia Adaptation of the Tibetan Mastiff

The role of introgressive hybridization as a source of adaptive genetic variation in animal populations is generally unclear, although recent findings suggest it may be more important than previously anticipated. While there are a number of tools to detect introgression, a major challenge is to experimentally confirm that it has played a role in adaptation by documenting the phenotypic effects of introgressed alleles. Animals native to high‐altitude are excellent models for such experimental studies, as it is often possible to formulate clear a priori hypotheses about the adaptive significance of particular changes in phenotype (for example, increases or decreases in the oxygen affinity of hemoglobin [Hb]). There is evidence to suggest that the high‐altitude adaptation of the Tibetan mastiff is, in part, the result of adaptive introgresssion with the Tibetan wolf. One of the introgressed regions between the Tibetan wolf and mastiff spans the entire β‐Hb gene cluster and the upstream cis‐regulatory elements. This has resulted in two non‐synonymous amino acid substitutions in the Tibetan mastiff, with respect to domestic dogs, in each of the adult expressed β‐type globin genes. To assess the functional effects of these mutations, we have measured the Hb‐O2 affinity of Tibetan wolves, Tibetan mastiffs and domestic dogs. These analyses revealed that the high‐altitude canids have Hb‐O2 affinity that is increased relative to domestic dogs (Figure 1). Thus, introgressive hybridization with the Tibetan wolf has resulted in a phenotypic change to the Tibetan mastiff that increases blood‐O2 saturation under hypoxia.Support or Funding InformationThis work is supported by the National Institutes of Health, the National Science foundation, and the Chinese Academy of Sciences.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Exploration of mtDNA control region sequences in Chinese Tibetan Mastiffs

The control region of mitochondrial DNA (mtDNA) was obtained from 40 purebred Chinese Tibetan Mastiffs (TMs). Sequence structure and genetic diversity were analyzed, and a phylogenetic tree was constructed. The TM mtDNA control region was composed of ETAS (extended termination associated sequences), CD (a central domain) and CSBs (conserved sequenced blocks) and sequence length showed some diversity, which was mainly caused by the number of 10 nucleotide repeat units [5′-GTA CAC GT (G/A) C-3′] between CSB I and CSB II, which ranged from 27 to 35 among individuals. Seventy-five polymorphic sites were identified, which defined 37 haplotypes; the haplotype diversity was 0.990, and the nucleotide diversity was 1.201. Based on the control region sequences, Chinese TMs were divided into three categories, which were consistent with the origin and geographical classification of TMs. Phylogenetic analysis of 538-bp HVR-I sequences revealed that TMs were most closely related to Labrador Retrievers.

EPAS1 variants in high altitude Tibetan wolves were selectively introgressed into highland dogs.

BackgroundAdmixture can facilitate adaptation. For example, black wolves have obtained the variant causing black coat color through past hybridization with domestic dogs and have higher fitness than gray colored wolves. Another recent example of the transfer of adaptive variation between the two species has been suggested by the similarity between high altitude Tibetan mastiffs and wolves at the EPAS1 gene, a transcription factor induced in low oxygen environments.MethodsHere, we investigate the directionality of admixture in EPAS1 between 28 reference highland gray wolves, 15 reference domestic dogs, and 21 putatively admixed highland wolves. This experimental design represents an expanded sample of Asian dogs and wolves from previous studies. Admixture was inferred using 17,709 publicly available SNP genotypes on canine chromosome 10. We additionally conducted a scan for positive selection in the highland dog genome.ResultsWe find an excess of highland gray wolf ancestry at the EPAS1 locus in highland domestic dogs, suggesting adaptive introgression from wolves to dogs. The signal of admixture is limited in genomic extent to a small region on chromosome 10, indicating that it is the focus of selection in an oxygen-limited environment.DiscussionOur results suggest that an adaptive variant of EPAS1 in highland wolves was transferred to highland dogs, carrying linked variants that potentially function in hypoxia response at high elevation. The intertwined history of dogs and wolves ensures a unique evolutionary dynamic where variants that have appeared in the history of either species can be tested for their effects on fitness under natural and artificial selection. Such coupled evolutionary histories may be key to the persistence of wild canines and their domesticated kin given the increasing anthropogenic modifications that characterize the future of both species.