Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep

Caihong Wei,James W Kijas,Mingming Wu,Gang Liu,Youji Ma,Jiaxue Cao,Fuping Zhao,Zhen Liu,Li Zhang,Lixin Du,Huihua Wang,Guangkai Wang,Shuzhen Zhang,Chousheng Liu,Ruizao Liu,Jian Lu

doi:10.1038/srep26770

Abstract

Tibetan sheep have lived on the Tibetan Plateau for thousands of years; however, the process and consequences of adaptation to this extreme environment have not been elucidated for important livestock such as sheep. Here, seven sheep breeds, representing both highland and lowland breeds from different areas of China, were genotyped for a genome-wide collection of single-nucleotide polymorphisms (SNPs). The FST and XP-EHH approaches were used to identify regions harbouring local positive selection between these highland and lowland breeds, and 236 genes were identified. We detected selection events spanning genes involved in angiogenesis, energy production and erythropoiesis. In particular, several candidate genes were associated with high-altitude hypoxia, including EPAS1, CRYAA, LONP1, NF1, DPP4, SOD1, PPARG and SOCS2. EPAS1 plays a crucial role in hypoxia adaption; therefore, we investigated the exon sequences of EPAS1 and identified 12 mutations. Analysis of the relationship between blood-related phenotypes and EPAS1 genotypes in additional highland sheep revealed that a homozygous mutation at a relatively conserved site in the EPAS1 3′ untranslated region was associated with increased mean corpuscular haemoglobin concentration and mean corpuscular volume. Taken together, our results provide evidence of the genetic diversity of highland sheep and indicate potential high-altitude hypoxia adaptation mechanisms, including the role of EPAS1 in adaptation.

Highlights

The Tibetan Plateau represents 25% of the landmass of China
To assess the relationships between the animals and breeds under investigation, we applied multidimensional scaling (MDS) to analyze 122 individuals genotyped at 20,632 autosomal single-nucleotide polymorphisms (SNPs)
The individuals were representative of seven native Chinese sheep breeds: Hu sheep (HUS), Tong sheep (TON), Large-tailed Han sheep (LTH), Lop sheep (LOP), Tibetan sheep of the Qinghai (TIBQ), Sichuan (TIBS) and Nagqu (TIBN). (Figure 1A, Supplemental Table S1)

Summary

Introduction

The Tibetan Plateau represents 25% of the landmass of China. It is the largest high-altitude area on earth, with an average altitude exceeding 4,500 m1. Compared with neighbouring and lowland populations, the native people and animals have adapted to this habitat, which has a 43% lower partial pressure of oxygen[2] and 40% higher ultraviolet radiation[3] Several animals, such as Tibetan antelopes[4] and Tibetan Mastiffs[5,6], have recently been shown to exhibit adaptation to living in this challenging environment. China has many sheep breeds, such as Tibetan and Mongolian sheep, that are widely distributed from the highlands to lowlands, many of which have evolved over centuries or even millennia[7,8] They represent ideal organisms to study plateau adaptability. We identified candidate genes using selective sweep mapping and revealed potential genetic mechanisms of high-altitude adaptation in sheep compared with other species. We more deeply analyzed gene evolution by investigating genes and networks as well as the genetic diversity of EPAS1

Methods

Results

Conclusion