Tibetan sheep were introduced to the Qinghai Tibet plateau roughly 3,000 B.P., making this species a good model for investigating genetic mechanisms of high-altitude adaptation over a relatively short timescale. Here, we characterize genomic structural variants (SVs) that distinguish Tibetan sheep from closely related, low-altitude Hu sheep, and we examine associated changes in tissue-specific gene expression. We document differentiation between the two sheep breeds in frequencies of SVs associated with genes involved in cardiac function and circulation. In Tibetan sheep, we identified high-frequency SVs in a total of 462 genes, including EPAS1 , PAPSS2 , and PTPRD . Single-cell RNA-Seq data and luciferase reporter assays revealed that the SVs had cis -acting effects on the expression levels of these three genes in specific tissues and cell types. In Tibetan sheep, we identified a high-frequency chromosomal inversion that exhibited modified chromatin architectures relative to the noninverted allele that predominates in Hu sheep. The inversion harbors several genes with altered expression patterns related to heart protection, brown adipocyte proliferation, angiogenesis, and DNA repair. These findings indicate that SVs represent an important source of genetic variation in gene expression and may have contributed to high-altitude adaptation in Tibetan sheep.

中文翻译：

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基因组结构变异导致高海拔藏羊基因表达的进化变化


藏羊大约在距今 3000 年被引入青藏高原，使该物种成为在相对较短的时间内研究高海拔适应遗传机制的良好模型。在这里，我们描述了将藏羊与密切相关的低海拔湖羊区分开来的基因组结构变异（SV），并检查了组织特异性基因表达的相关变化。我们记录了两个绵羊品种在与心脏功能和循环相关的基因相关的 SV 频率方面的差异。在藏羊中，我们在总共 462 个基因中鉴定出了高频 SV，包括 EPAS1、PAPSS2 和 PTPRD。单细胞 RNA-Seq 数据和荧光素酶报告基因分析表明，SV 对特定组织和细胞类型中这三个基因的表达水平具有顺式作用。在藏羊中，我们发现了一种高频染色体倒位，与湖羊中占主导地位的非倒位等位基因相比，该染色体倒位表现出修饰的染色质结构。这种倒位包含一些与心脏保护、棕色脂肪细胞增殖、血管生成和 DNA 修复相关的表达模式改变的基因。这些发现表明，SVs是基因表达遗传变异的重要来源，可能有助于藏羊的高海拔适应。