Genomic structural variation contributes to evolved changes in gene expression in high-altitude Tibetan sheep

Area of Science:

• Genomics
• Evolutionary Biology
• Physiology

Background:

• Tibetan sheep, introduced to high altitudes ~3,000 years ago, serve as a model for studying rapid adaptation.
• Understanding the genetic basis of high-altitude adaptation is crucial for evolutionary and physiological research.

Purpose of the Study:

• To characterize genomic structural variants (SVs) differentiating Tibetan sheep from low-altitude Hu sheep.
• To investigate how these SVs affect tissue-specific gene expression in Tibetan sheep.
• To identify genetic mechanisms underlying high-altitude adaptation in Tibetan sheep.

Main Methods:

• Comparative genomics to identify structural variants (SVs) between Tibetan and Hu sheep.
• Analysis of tissue-specific gene expression using single-cell RNA-Sequencing (scRNA-Seq).
• Luciferase reporter assays to confirm cis-acting effects of SVs on gene expression.

Main Results:

• Significant differentiation in SV frequencies between breeds, particularly in genes related to cardiac function and circulation.
• High-frequency SVs identified in 462 genes in Tibetan sheep, including key adaptation genes like EPAS1, PAPSS2, and PTPRD.
• A high-frequency chromosomal inversion in Tibetan sheep alters chromatin structure and affects expression of genes involved in heart protection, brown adipogenesis, angiogenesis, and DNA repair.

Conclusions:

• Genomic structural variants (SVs) are a significant source of genetic variation influencing gene expression.
• SVs likely played a crucial role in the rapid high-altitude adaptation of Tibetan sheep.
• Specific SVs identified provide insights into the genetic architecture of adaptation to extreme environments.