High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski’s horses added for comparison. We find that Tibetan horses do not descend from Przewalski’s horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1, also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages.

The Tibetan cashmere goat (Capra hircus), one of the most ancient breeds in China, has historically been a critical source of meat and cashmere production for local farmers. To adapt to the high-altitude area, extremely harsh climate, and hypoxic environment that the Tibetan cashmere goat lives in, this goat has developed distinct phenotypic traits compared to lowland breeds. However, the genetic components underlying this phenotypic adaptation remain largely unknown. We obtained 118,700 autosomal SNPs through exome sequencing of 330 cashmere goats located at a wide geographic range, including the Tibetan Plateau and low-altitude regions in China. The great majority of SNPs showed low genetic differentiation among populations; however, approximately 2-3 % of the loci showed more genetic differentiation than expected under a selectively neutral model. Together with a combined analysis of high- and low-altitude breeds, we revealed 339 genes potentially under high-altitude selection. Genes associated with cardiovascular system development were significantly enriched in our study. Among these genes, the most evident one was endothelial PAS domain protein 1 (EPAS1), which has been previously reported to be involved in complex oxygen sensing and significantly associated with high-altitude adaptation of human, dog, and grey wolf. The missense mutation Q579L that we identified in EPAS1, which occurs next to the Hypoxia-Inducible Factor-1 (HIF-1) domain, was exclusively enriched in the high-altitude populations. Our study provides insights concerning the population variation in six different cashmere goat populations in China. The variants in cardiovascular system-related genes may explain the observed phenotypic adaptation of the Tibetan cashmere goat.

As large-scale genomic studies have progressed, it has been revealed that a single reference genome pattern cannot represent genetic diversity at the species level. While domestic animals tend to have complex routes of origin and migration, suggesting a possible omission of some population-specific sequences in the current reference genome. Conversely, the pangenome is a collection of all DNA sequences of a species that contains sequences shared by all individuals (core genome) and is also able to display sequence information unique to each individual (variable genome). The progress of pangenome research in humans, plants and domestic animals has proved that the missing genetic components and the identification of large structural variants (SVs) can be explored through pangenomic studies. Many individual specific sequences have been shown to be related to biological adaptability, phenotype and important economic traits. The maturity of technologies and methods such as third-generation sequencing, Telomere-to-telomere genomes, graphic genomes, and reference-free assembly will further promote the development of pangenome. In the future, pangenome combined with long-read data and multi-omics will help to resolve large SVs and their relationship with the main economic traits of interest in domesticated animals, providing better insights into animal domestication, evolution and breeding. In this review, we mainly discuss how pangenome analysis reveals genetic variations in domestic animals (sheep, cattle, pigs, chickens) and their impacts on phenotypes and how this can contribute to the understanding of species diversity. Additionally, we also go through potential issues and the future perspectives of pangenome research in livestock and poultry.

Through long term natural and artificial selection, domestic sheep (Ovis aries) have become adapted to a diverse range of agro-ecological environments and display multiple phenotypic traits. Characterization of diversity and selection signature is essential for genetic improvement, understanding of environmental adaptation, as well as utilization and conservation of sheep genetic resources. Here, we aimed to assess genomic diversity, population structure, and genomic selection among five Chinese native sheep breeds using 600K high density SNP genotypes. A total of 96 animals of the five breeds were selected from different geographical locations with extremely dry or humid conditions. We found a high proportion of informative SNPs, ranging from 93.3% in Yabuyi to 95.5% in Wadi, Hu, and Hetian sheep. The average pairwise population differentiation (F_ST) between the breeds was 0.048%, ranging from 0.022% to 0.054%, indicating their low to moderate differentiation. PCA, ADMIXTURE, and phylogenetic tree analyses revealed a clustering pattern of the five Chinese sheep breeds according to their geographical distribution, tail type, coat color, body size, and breeding history. The genomic regions under putative selection identified by F_ST and XP-EHH approaches frequently overlapped across the breeds, and spanned genes associated with adaptation to extremely dry or humid environments, innate and adaptive immune responses, and growth, wool, milk, and reproduction traits. The present study offers novel insight into genomic adaptation to dry and humid climates in sheep among other domestic animals and provides a valuable resource for further investigation. Moreover, it contributes useful information to sustainable utilization and conservation of sheep genetic resources.

The growth of cashmere exhibits a seasonal pattern arising from photoperiod change. However, the underlying molecular mechanism remains unclear. We profiled the skin transcriptome of six goats at seven time points during hair follicle cycling via RNA-seq. The six goats comprised three goats exposed to a natural photoperiod and three exposed to a shortened photoperiod. During hair cycle transition, 1713 genes showed differential expression, and 332 genes showed a pattern of periodic expression. Moreover, a short photoperiod induced the hair follicle to enter anagen early, and 246 genes overlapped with the periodic genes. Among these key genes, cold-shock domain containing C2 (CSDC2) was highly expressed in the epidermis and dermis of Cashmere goat skin, although its function in hair-follicle development remains unknown. CSDC2 silencing in mouse fibroblasts resulted in the decreased mRNA expression of two key hair-follicle factors, leading to reduced cell numbers and a lower cell density. Cashmere growth or molting might be controlled by a set of periodic regulatory genes. The appropriate management of short light exposure can induce hair follicles to enter full anagen early through the activation of these regulators. The CSDC2 gene is a potentially important transcription factor in the hair growth cycle.

The identification of genome-wide selection signatures can provide insights on the mechanisms of natural and/or artificial selection and uncover genes related to biological functions and/or phenotypes. Tibetan sheep are an important livestock in Tibet, providing meat and wool for Tibetans who are renown for breeding livestock that adapt well to high altitudes. Using whole-genome sequences with an effective sequencing depth of 5×, we investigated the genomic diversity and structure and, identified selection signatures of White Tibetan, Oula and Poll Dorset sheep. We obtained 30,163,679 Single Nucleotide Polymorphisms (SNPs) and 5,388,372 indels benchmarked against the ovine Oar_v4.0 genome assembly. Next, using F_ST, ZHp and XP-EHH approaches, we identified selection signatures spanning a set of candidate genes, including HIF1A, CAPN3, PRKAA1, RXFP2, TRHR and HOXA10 that are associated with pathways and GO categories putatively related to hypoxia responses, meat traits and disease resistance. Candidate genes and GO terms associated with coat color were also identified. Finally, quantification of blood physiological parameters, revealed higher levels of mean corpuscular hemoglobin measurement and mean corpuscular hemoglobin concentration in Tibetan sheep compared with Poll Dorset, suggesting a greater oxygen-carrying capacity in the Tibetan sheep and thus better adaptation to high-altitude hypoxia. In conclusion, this study provides a greater understanding of genome diversity and variations associated with adaptive and production traits in sheep.