Multi-omics Analysis Reveals The Molecular Mechanism Underlying High-altitude Adaptation And Cashmere Traits In Domestic Goat

The goat was one of the first domesticated animals,and goats have adapted to diverse and adverse climates without the aid of man-made shelters.Cashmere goat,being native to the Inner Mongolia and Tibetan,is well acclimatized to the and cold climate.Tibetan goat is especially well adapted to the high altitude environment which with cold temperatures and low oxygen pressures.In the present study,the molecular mechanisms underlying adaptation to high altitude and the traits of cashmere were studied using multi-omic method.Firstly,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 regionsin 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.Secondly,we identified a total of 2,377 potential lincRNA transcripts overlapping 1,451 lincRNA genes.These lincRNAs exhibited a tissue-specific pattern.Specifically,327 lincRNAs were expressed exclusively in only one tissue,and 92 ha:ir follicle-specific lincRNAs were identified.In addition,more than one thousand time-specific mRNAs and 47 lincRNAs were identified in the skin of goat,with the majority exhibiting the most significantly differential expression in the transition of the secondary hair follicle from the early anagen phase to the anagen phase.Fundamental biological processes,such as hair/skin/nail development,were significantly enriched in these genes.Furthermore,we identified seven spatiotemporal hair follicle-specific lincRNAs that exhibited not only a co-expression with the key factors to the hair follicle development but also activated expression in the transition from the early anagen phase to the anagen phase.Intriguingly,one of the seven spatiotemporal lincRNAs,linc-chig1020 could be a potential regulator of distal-less homeobox 3 expression during SHF growth.Finally,we generated whole-genome sequences from 15 goat breed,with an average effective sequencing depth of-5x for 117 samples.Genetic variation,population structure and selective sweeps related to speccial traits of goat were conducted.Selection signals which related to high altitude and cashmere traits were detected with four different methods,and 514 and 377 selected windows were detected within highland goat population and cashmere goat population,respectively.A Indel polymorphism in the FGF5 locus was found between the cashmere and non-cashmere goat population.The major allele in the cashmere goat population is "deletion",while the major allele in the non-cashmere goat is "insertion".The result of dual-luciferase activity assay showed that the inserted sequence had enhancer-like role for the expression in of FGF5.In the present study,the molecular mechanisms underlying adaptation to high altitude and the traits of cashmere were studied using multi-omic method.Our study provides insights concerning the molecular mechanisms of high-altitude adaptation and cashmere traits in cashmere goat populations in China.The variants in cardiovascular system-related genes may explain the observed phenotypic adaptation of the Tibetan cashmere goat.lincRNAs playing an important role in the development of hair follicle,and this study will facilitate future studies aimed at unraveling the function of lincRNAs in hair follicle development.FGF5 locus showed a big differentiation between cashmere and non-cashmere goat,and we provide a new marker for cashmere goat molecular breeding.