Systematic discovery of nonobvious human disease models through orthologous phenotypes
Systematic discovery of nonobvious human disease models through orthologous phenotypes
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DOI：
10.1073/pnas.0910200107
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发表时间：
2010-04-06
影响因子：
11.1
通讯作者：
Marcotte, Edward M.
中科院分区：
文献类型：
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作者：
McGary, Kriston L.;Park, Tae Joo;Marcotte, Edward M.
生物学家长期以来一直使用模型生物来研究人类疾病，特别是当模型与疾病非常相似时。我们提出了一种方法，基于来自人类、小鼠、酵母、蠕虫和植物的重叠组直系同源基因（212,542 个基因-表型关联），定量和系统地识别不同物种中突变表型之间的非明显等价性。这些直系同源表型或酚类可预测与疾病相关的独特基因。我们的方法提出了针对血管生成缺陷的酵母模型、针对乳腺癌的蠕虫模型、针对自闭症的小鼠模型以及针对与瓦登堡综合征相关的神经嵴缺陷的植物模型等。使用这些模型，我们表明 SOX13 调节血管生成，而 SEC23IP 可能是 Waardenburg 基因。物候学揭示了功能连贯、进化保守的基因网络（许多早于动植物分歧），能够识别候选疾病基因。
Biologists have long used model organisms to study human diseases, particularly when the model bears a close resemblance to the disease. We present a method that quantitatively and systematically identifies nonobvious equivalences between mutant phenotypes in different species, based on overlapping sets of orthologous genes from human, mouse, yeast, worm, and plant (212,542 gene-phenotype associations). These orthologous phenotypes, or phenologs, predict unique genes associated with diseases. Our method suggests a yeast model for angiogenesis defects, a worm model for breast cancer, mouse models of autism, and a plant model for the neural crest defects associated with Waardenburg syndrome, among others. Using these models, we show that SOX13 regulates angiogenesis, and that SEC23IP is a likely Waardenburg gene. Phenologs reveal functionally coherent, evolutionarily conserved gene networks-many predating the plant-animal divergence-capable of identifying candidate disease genes.