Yak genome database: a multi-omics analysis platform.

BACKGROUND: The yak (Bos grunniens) is a large ruminant species that lives in high-altitude regions and exhibits excellent adaptation to the plateau environments. To further understand the genetic characteristics and adaptive mechanisms of yak, we have developed a multi-omics database of yak including genome, transcriptome, proteome, and DNA methylation data. DESCRIPTION: The Yak Genome Database ( http://yakgenomics.com/ ) integrates the research results of genome, transcriptome, proteome, and DNA methylation, and provides an integrated platform for researchers to share and exchange omics data. The database contains 26,518 genes, 62 transcriptomes, 144,309 proteome spectra, and 22,478 methylation sites of yak. The genome module provides access to yak genome sequences, gene annotations and variant information. The transcriptome module offers transcriptome data from various tissues of yak and cattle strains at different developmental stages. The proteome module presents protein profiles from diverse yak organs. Additionally, the DNA methylation module shows the DNA methylation information at each base of the whole genome. Functions of data downloading and browsing, functional gene exploration, and experimental practice were available for the database. CONCLUSION: This comprehensive database provides a valuable resource for further investigations on development, molecular mechanisms underlying high-altitude adaptation, and molecular breeding of yak.

Genome-wide comparison of DNA methylation patterns between yak and three cattle strains and their potential association with mRNA transcription.

Yak has evolved specific adaptative mechanisms to high-altitude environment. Up to date, only a few studies reported the DNA methylation in yak. In the present study, genome-wide DNA methylome and transcriptome profiles in lung, mammary, and biceps brachii muscle tissues were compared between yak and three cattle breeds (Tibetan cattle, Sanjiang cattle, and Holstein cattle). The association between differentially expressed genes (DEGs) and differentially methylated regions (DMRs) was analyzed, and the biological functions of DEGs potentially driven by DMRs were explored by KEGG enrichment analysis. Finally, we found that yak-specific DMRs-driven DEGs were mainly involved in neuromodulation, respiration, lung development, blood pressure regulation, cardiovascular protection, energy metabolism, DNA repair, and immune functions. The higher levels of the key genes associated with these functions were observed in yak than in cattle, suggesting that DNA methylation might regulate these genes. Overall, the present study contributes basic data at the DNA methylation level to further understand the physiological metabolism in yak.

Differences in proteomic profiles between yak and three cattle strains provide insights into molecular mechanisms underlying high-altitude adaptation.

Yaks display unique properties of the lung and heart, enabling their adaptation to high-altitude environments, but the underlying molecular mechanisms are still largely unknown. In the present study, the proteome differences in lung and heart tissues were compared between yak (Bos grunniens) and three cattle strains (Bos taurus, Holstein, Sanjiang and Tibetan cattle) using the sequential window acquisition of all theoretical mass spectra/data-independent acquisition (SWATH/DIA) proteomic method. In total, 51,755 peptides and 7215 proteins were identified. In the lung tissue, there were 162, 310 and 118 differential abundance proteins (DAPs) in Tibetan, Holstein and Sanjiang cattle compared to yak respectively. In the heart tissue, there were 71, 57 and 78 DAPs in Tibetan, Holstein and Sanjiang cattle compared to yak respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the DAPs were enriched for the retinol metabolism and toll-like receptor categories in lung tissue. The changes in these two pathways may regulate hypoxia-induced factor and immune function in yaks. Moreover, DAPs in heart tissues were enriched for cardiac muscle contraction, Huntington's disease, chemical carcinogenesis and drug metabolism-cytochrome P450. Further exploration indicated that yaks may alter cardiac function through regulation of type 2 ryanodine receptor (RyR2) and Ca2+ -release channels. The present results are useful to further develop an understanding of the mechanisms underlying adaptation of animals to high-altitude conditions.

Whole-genome resequencing provides insights into the evolution and divergence of the native domestic yaks of the Qinghai-Tibet Plateau.

BACKGROUND: On the Qinghai-Tibet Plateau, known as the roof ridge of the world, the yak is a precious cattle species that has been indispensable to the human beings living in this high-altitude area. However, the origin of domestication, dispersal route, and the divergence of domestic yaks from different areas are poorly understood. RESULTS: Here, we resequenced the genome of 91 domestic yak individuals from 31 populations and 1 wild yaks throughout China. Using a population genomics approach, we observed considerable genetic variation. Phylogenetic analysis suggested that the earliest domestications of yak occurred in the south-eastern QTP, followed by dispersal to the west QTP and northeast to SiChuang, Gansu, and Qinghai by two routes. Interestingly, we also found potential associations between the distribution of some breeds and historical trade routes such as the Silk Road and Tang-Tibet Ancient Road. Selective analysis identified 11 genes showing differentiation between domesticated and wild yaks and the potentially positively selected genes in each group were identified and compared among domesticated groups. We also detected an unbalanced pattern of introgression among domestic yak, wild yak, and Tibetan cattle. CONCLUSIONS: Our research revealed population genetic evidence for three groups of domestic yaks. In addition to providing genomic evidence for the domestication history of yaks, we identified potential selected genes and introgression, which provide a theoretical basis and resources for the selective breeding of superior characters and high-quality yak.

Signature of high altitude adaptation in the gluteus proteome of the yak.

Yak is the unique Bovidae species in the Qinghai-Tibetan Plateau. A previous proteomic study has compared the yak muscle tissue to one cattle strain using the isobaric tags for relative and absolute quantification approach. In this study, to further investigate the molecular mechanisms underlying yak adaptation, the proteomic profiles of gluteus were compared between yak and one moderate-altitude cattle strain (Tibetan cattle) and two low-altitude cattle strains (Holstein and Sanjiang cattle) using a label-free quantitative method. The comparisons identified 20, 364, 143 upregulated proteins and 4, 6, 37 downregulated proteins in yak, compared with Tibetan, Holstein, and Sanjiang cattle, respectively. Protein-protein interaction analysis indicated that these differentially expressed proteins were mainly related to "oxidative phosphorylation" and "electron transport chain." Further analysis revealed that NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4, cytochrome C oxidase subunit 6A2, mitochondrial and cytochrome c oxidase subunit NDUFA4 were all increased in the yak, suggesting that yak might increase mitochondrial capacity to sustain metabolic rates under high altitude conditions, which might be a long-term adaptive mechanism underlying adaptation to high altitude environments. Yak increased the level of thioredoxin reductase 2 to protect themselves from oxidative damages. Moreover, the increased expression levels of phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform and caveolin-1 in yak suggested that yaks promoted glucose uptake for adaptation to high altitude. These results provided more information to better understand the molecular mechanisms underlying yak adaption.

[Genetic diversity of DNA microsatellite for Tibetan Yak].

To assess the genetic diversity and relationship of the Tibetan yak breeds. The genetic diversity and phylogenies of a total of 480 individual from 11 Tibetan yak groups were analyzed using PCR and multiplex gel electrophoresis of silver staining technology with eight pairs of microsatellite markers.The result showed that these markers were highly polymorphic loci with rich genetic diversity in the Tibetan yak populations.The average polymorphic information content (PIC) in 11 groups of yak were higher than 0.5. The highest HEL13 was 0.8496, and the lowest TGLA57 was 0.7349. Among them, the PICof Dingqing yak was minimum (0.7505), indicating that the group is relatively pure.Sangri Yak had the highest PIC value (0.7949) indicating greater genetic variationwithinthe groups. Among the 11 groups examined, the order of heterozygosity size wasSangri(0.8193)>Jiangda(0.8190)>Sangsang(0.8157)>Baqing(0.8150)>Kangbu(0.8123)> Jiali(0.8087)>Gongbujiangda(0.8054)>Sibu(0.8041)>Leiwuqi(0.8033)>Pali(0.8031)>Dingqing(0.7831). The groups from eastern Tibet had grater genetic diversity than those from Western Tibet, which indicate that Tibet may be one of the cradles of the yak.According to the genetic distance, the cluster relationship constructed with UPGMA and NJ methods showed that 11 yak groups in Tibet could be divided into three forms. In summary,Tibet yak has abundant genetic diversity and the selected microsatellite markers can be used to evaluategenetic diversity of Tibetan yak.

A chromosome-scale reference genome and genome-wide genetic variations elucidate adaptation in yak.

Yak is an important livestock animal for the people indigenous to the harsh, oxygen-limited Qinghai-Tibetan Plateau and Hindu Kush ranges of the Himalayas. The yak genome was sequenced in 2012, but its assembly was fragmented because of the inherent limitations of the Illumina sequencing technology used to analyse it. An accurate and complete reference genome is essential for the study of genetic variations in this species. Long-read sequences are more complete than their short-read counterparts and have been successfully applied towards high-quality genome assembly for various species. In this study, we present a high-quality chromosome-scale yak genome assembly (BosGru_PB_v1.0) constructed with long-read sequencing and chromatin interaction technologies. Compared to an existing yak genome assembly (BosGru_v2.0), BosGru_PB_v1.0 shows substantially improved chromosome sequence continuity, reduced repetitive structure ambiguity, and gene model completeness. To characterize genetic variation in yak, we generated de novo genome assemblies based on Illumina short reads for seven recognized domestic yak breeds in Tibet and Sichuan and one wild yak from Hoh Xil. We compared these eight assemblies to the BosGru_PB_v1.0 genome, obtained a comprehensive map of yak genetic diversity at the whole-genome level, and identified several protein-coding genes absent from the BosGru_PB_v1.0 assembly. Despite the genetic bottleneck experienced by wild yak, their diversity was nonetheless higher than that of domestic yak. Here, we identified breed-specific sequences and genes by whole-genome alignment, which may facilitate yak breed identification.

Transcriptome analysis identified long non-coding RNAs involved in the adaption of yak to high-altitude environments.

The mechanisms underlying yak adaptation to high-altitude environments have been investigated using various methods, but no report has focused on long non-coding RNA (lncRNA). In the present study, lncRNAs were screened from the gluteus transcriptomes of yak and their transcriptional levels were compared with those in Sanjiang cattle, Holstein cattle and Tibetan cattle. The potential target genes of the differentially expressed lncRNAs between species/strains were predicted using cis and trans models. Based on cis-regulated target genes, no KEGG pathway was significantly enriched. Based on trans-regulated target genes, 11 KEGG pathways in relation to energy metabolism and three KEGG pathways associated with muscle contraction were significantly enriched. Compared with cattle strains, transcriptional levels of acyl-CoA dehydrogenase, acyl-CoA-binding protein, 3-hydroxyacyl-CoA dehydrogenase were relatively higher and those of glyceraldehyde 3-phosphate dehydrogenase, phosphoglycerate mutase 1, pyruvate kinase and lactate/malate dehydrogenase were relatively lower in yak, suggesting that yaks activated fatty acid oxidation but inhibited glucose oxidation and glycolysis. Besides, NADH dehydrogenase and ATP synthase showed lower transcriptional levels in yak than in cattle, which might protect muscle tissues from deterioration caused by reactive oxygen species (ROS). Compared with cattle strains, the higher transcriptional level of glyoxalase in yak might contribute to dicarbonyl stress resistance. Voltage-dependent calcium channel/calcium release channel showed a lower level in yak than in cattle strains, which could reduce the Ca2+ influx and subsequently decrease the risk of hypertension. However, levels of EF-hand and myosin were higher in yak than in cattle strains, which might enhance the negative effects of reduced Ca2+ on muscle contraction. Overall, the present study identified lncRNAs and proposed their potential regulatory functions in yak.

Evaluation of the economic impact of brucellosis in domestic yaks of Tibet.

Brucellosis is considered as an endemic disease in yaks (Bos grunniens) in China, but few economic analyses describing the cost of the disease and potential benefits of control have been reported. The aim of the study was to estimate the economic cost of brucellosis in yaks and the economic value of three control strategies: (a) vaccination; (b) test-and-slaughter; and (c) a combination of vaccination and test-and-slaughter programs in Damxung and Maizhokunggar counties and Pali township of Yadong county in Tibet. Using data from a cross-sectional seroprevalence survey conducted in 2015, combined with financial data, the predicted costs and benefits of the different control strategies were simulated over a 6-year period. The annual estimated cost of brucellosis in yaks within the study area was US$ 521,043 (95% CI: US$ 334,441; US$ 759,862), with an annual average cost per yak estimated at US$ 1.42 (95% CI: US$ 0.91, US$ 2.07). The benefit-cost analysis predicted that vaccination was the most effective control method with a benefit-cost ratio (BCR) of 3.19 (95% CI: 2.17, 4.66) and a net present value (NPV) of US$ 313,355 (95% CI: US$ 157,679, US$ 541,062) over a 6-year period. A sensitivity analysis found the NPV was most sensitive to the loss from a female yak aborting in the vaccination control program. In contrast, the price of yaks that were slaughtered had the largest influence on the NPV for both the test-and-slaughter control program and the combination control program. These estimates provide valuable information and establish a foundation for formulating and implementing cost-effective measures for controlling the disease in yaks on the Tibetan plateau, and more broadly in China.

Comparisons of lung and gluteus transcriptome profiles between yaks at different ages.

The yak, Bos grunniens, is the only large mammal in the Qinghai-Tibet Plateau and has been bred to provide meat, milk, and transportation. Previous studies indicate that the immune system contributes to the yak's adaptation to high-altitude environments. In order to further investigate changes in immune function during yak development, we compared the transcriptome profiles of gluteus and lung tissues among yaks at 6, 30, 60, and 90 months of age. Analyses of significantly differentially expressed genes (DEGs) in lung tissues revealed that immune function was more activated at 6-months and less activated at 90-months than in the 30 and 60-month-old animals. DEG exploration in gluteal tissues revealed that immune functions were more highly activated at both 6 and 90-months, compared with 30 and 60-months. Immune system activation in the muscle and lung tissues of 30-month-old yaks may increase their resistance to infections, while decreased may be due to aging. Furthermore, the higher immune activation status in the gluteal tissues in 90-month-old yaks could be due to muscle injury and subsequent regeneration, which is supported by the fact that 5 unigenes related with muscle injury and 3 related to muscle regeneration displayed greater expression levels at 90-months than at 30 and 60-months. Overall, the present study highlights the important role of the immune system in yak development, which will facilitate future investigations.

Transcriptome profiles revealed the mechanisms underlying the adaptation of yak to high-altitude environments.

The yak is a valuable species in the Qinghai-Tibet Plateau of China. Nevertheless, the molecular mechanisms underlying its adaptation to high-altitude environments remain largely unknown. In the present study, comparative transcriptome sequencing was performed for lung and gluteus tissues from two species of low-altitude cattle (Sanjiang and Holstein cattle), Tibetan cattle (living at a moderate altitude), and yak (living at a high altitude) and the differentially expressed genes were validated using real-time quantitative PCR. The results showed that CD36 antigen was up-regulated and CD59 antigen was down-regulated in yak in comparison to the other animals, which might promote the development of red blood cells and inhibit the development of lymphocytes in yak. In addition, thrombospondin type 1, coagulation factor 5/8, and fibronectin were all down-regulated, but serpin and alpha 2-macroglobulin (A2M) were up-regulated. These differences would inhibit blood coagulation, thus reducing the risk of pulmonary edema. The expression levels of the calcium-release, potassium, and transient receptor potential channels decreased in yak, minimizing membrane depolarization and the harmful effects of pulmonary edema. Eleven KEGG pathways associated with innate immunity were more activated in yak and Tibetan cattle than in other cattle strains, which should reduce their risk of infection and disease. These changes together might facilitate the adaptation of yak and Tibetan cattle to live in high-altitude habitats.