Hyperlipidemia-associated gene variations and expression patterns revealed by whole-genome and transcriptome sequencing of rabbit models.
Hyperlipidemia-associated gene variations and expression patterns revealed by whole-genome and transcriptome sequencing of rabbit models.
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兔模型全基因组和转录组测序揭示高脂血症相关基因变异和表达模式
DOI：
10.1038/srep26942
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发表时间：
2016-06-01
影响因子：
4.6
通讯作者：
Li Y
中科院分区：
文献类型：
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作者：
Wang Z;Zhang J;Li H;Li J;Niimi M;Ding G;Chen H;Xu J;Zhang H;Xu Z;Dai Y;Gui T;Li S;Liu Z;Wu S;Cao M;Zhou L;Lu X;Wang J;Yang J;Fu Y;Yang D;Song J;Zhu T;Li S;Ning B;Wang Z;Koike T;Shiomi M;Liu E;Chen L;Fan J;Chen YE;Li Y
兔（穴兔）是研究人类疾病（如高胆固醇血症和动脉粥样硬化）的重要实验动物。尽管如此，实验兔的基因信息和RNA表达谱仍较为缺乏。在此，我们对三种最常用的实验兔品种——新西兰白兔（NZW）、日本白兔（JW）和渡边遗传性高脂血症兔（WHHL）的全基因组变异进行了特征分析。尽管WHHL兔的遗传多样性相对较低，但由于种群规模较小，它们积累了大量高频有害突变。除了低密度脂蛋白受体（LDLR）缺陷外，一些有害突变还与WHHL兔的病理生理学有关。此外，我们对WHHL兔和喂食高胆固醇饮食（Chol）的NZW兔的不同器官进行了转录组测序。我们发现，尽管这两种兔模型表现出不同类型的高胆固醇血症，但它们在主动脉中的基因表达谱基本相似。相比之下，喂食高胆固醇饮食的兔（而非WHHL兔）在肝脏中表现出明显的炎症反应和异常的脂质代谢。这些结果为利用兔模型确定高胆固醇血症和动脉粥样硬化的治疗靶点提供了有价值的见解。
The rabbit (Oryctolagus cuniculus) is an important experimental animal for studying human diseases, such as hypercholesterolemia and atherosclerosis. Despite this, genetic information and RNA expression profiling of laboratory rabbits are lacking. Here, we characterized the whole-genome variants of three breeds of the most popular experimental rabbits, New Zealand White (NZW), Japanese White (JW) and Watanabe heritable hyperlipidemic (WHHL) rabbits. Although the genetic diversity of WHHL rabbits was relatively low, they accumulated a large proportion of high-frequency deleterious mutations due to the small population size. Some of the deleterious mutations were associated with the pathophysiology of WHHL rabbits in addition to theLDLRdeficiency. Furthermore, we conducted transcriptome sequencing of different organs of both WHHL and cholesterol-rich diet (Chol)-fed NZW rabbits. We found that gene expression profiles of the two rabbit models were essentially similar in the aorta, even though they exhibited different types of hypercholesterolemia. In contrast, Chol-fed rabbits, but not WHHL rabbits, exhibited pronounced inflammatory responses and abnormal lipid metabolism in the liver. These results provide valuable insights into identifying therapeutic targets of hypercholesterolemia and atherosclerosis with rabbit models.