Abstract
Sheep has successfully adapted to the extreme high-altitude Himalayan region. To identify genes underlying such adaptation, we genotyped genome-wide single nucleotide polymorphisms (SNPs) of four major sheep breeds living at different altitudes in Nepal and downloaded SNP array data from additional Asian and Middle East breeds. Using a di value-based genomic comparison between four high-altitude and eight lowland Asian breeds, we discovered the most differentiated variants at the locus of FGF-7 (Keratinocyte growth factor-7), which was previously reported as a good protective candidate for pulmonary injuries. We further found a SNP upstream of FGF-7 that appears to contribute to the divergence signature. First, the SNP occurred at an extremely conserved site. Second, the SNP showed an increasing allele frequency with the elevated altitude in Nepalese sheep. Third, the electrophoretic mobility shift assays (EMSA) analysis using human lung cancer cells revealed the allele-specific DNA-protein interactions. We thus hypothesized that FGF-7 gene potentially enhances lung function by regulating its expression level in high-altitude sheep through altering its binding of specific transcription factors. Especially, FGF-7 gene was not implicated in previous studies of other high-altitude species, suggesting a potential novel adaptive mechanism to high altitude in sheep at the Himalayas.
Highlights
IntroductionIt is suited for detecting selection specific to a particular breed, or subset of breeds, and isolating the direction of change
An earlier phylogenetic studies using blood proteins showed that Bhyanglung, as well as Tibetan and Changthangi sheep were derived from the Tibetan sheep group, and Baruwal belongs to Himalayan group, while Kage and Lampuchhre are associated with Indian group[5]
A number of responsible genes have been proposed by these reports and among them, the most prominent ones were EPAS1 and EGLN1
Summary
It is suited for detecting selection specific to a particular breed, or subset of breeds, and isolating the direction of change Using these methods, candidate genes that contributed to the high-altitude adaptation in human[12,13,14,15,16,17], yak[18], Tibetan antelope[19], grey wolf[20], dog[21,22,23], pig[24,25,26], chicken[27] and goat[28] have been identified. The genetic mechanism of high-altitude adaptation in sheep, one of the most commonly distributed livestock, remains perplexing To delve into these issues, we genotyped the four major Nepalese sheep breeds comprising of two high-altitude breeds (Bhyanglung and Baruwal), and two lowland breeds (Kage and Lampuchhre) using Illumina ovine 50KSNP Beadchip. Re-sequencing data of the candidate locus was analyzed to map the major variant and Nepalese sheep individuals were further screened for the variant
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