Human disease locus discovery and mapping to molecular pathways through phylogenetic profiling
Human disease locus discovery and mapping to molecular pathways through phylogenetic profiling
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DOI：
10.1038/msb.2013.50
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发表时间：
2013-10-01
影响因子：
9.9
通讯作者：
Ruvkun, Gary
中科院分区：
文献类型：
--
作者：
Tabach, Yuval;Golan, Tamar;Ruvkun, Gary
在不同的基因组中具有共同的存在和不存在谱的基因往往在相同的途径中起作用。通过将所有人类基因映射到约1000个基因簇中，这些基因簇在真核生物发生学中具有相似的保守模式，我们确定了与特定疾病相关的基因组具有相似的系统发育谱。通过关注那些人类系统发育基因簇，这些基因簇与数千个人类基因组中的一些基因明显重叠，这些基因组由它们的共表达或对通路或其他分子属性的注释定义，我们揭示了连接分子通路和人类疾病的进化图。系统发育簇中富集特定已知疾病基因或分子途径的其他基因鉴定在那些相同病症和途径中起作用的候选基因。聚焦于与小眼症相关转录因子（MITF）共进化的蛋白质，我们鉴定了无毛Notch途径抑制因子（RBP-Jk/SuH）转录因子，并表明RBP-Jk作为MITF辅因子发挥功能。
Genes with common profiles of the presence and absence in disparate genomes tend to function in the same pathway. By mapping all human genes into about 1000 clusters of genes with similar patterns of conservation across eukaryotic phylogeny, we determined that sets of genes associated with particular diseases have similar phylogenetic profiles. By focusing on those human phylogenetic gene clusters that significantly overlap some of the thousands of human gene sets defined by their coexpression or annotation to pathways or other molecular attributes, we reveal the evolutionary map that connects molecular pathways and human diseases. The other genes in the phylogenetic clusters enriched for particular known disease genes or molecular pathways identify candidate genes for roles in those same disorders and pathways. Focusing on proteins coevolved with the microphthalmia-associated transcription factor (MITF), we identified the Notch pathway suppressor of hairless (RBP-Jk/SuH) transcription factor, and showed that RBP-Jk functions as an MITF cofactor.