1] Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
Mol Syst Biol. 2013 Oct 1;9:692. doi: 10.1038/msb.2013.50.
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.
具有不同基因组中存在和缺失共同特征的基因往往在同一途径中发挥作用。通过将所有人类基因映射到大约 1000 个具有相似真核生物进化史保守模式的基因簇中，我们确定与特定疾病相关的基因集具有相似的系统发生谱。通过关注那些与特定疾病相关的人类系统发生基因簇，这些基因簇与通过共表达或注释到途径或其他分子属性定义的数千个人类基因集中的一些显著重叠，我们揭示了连接分子途径和人类疾病的进化图谱。在系统发生聚类中富集特定已知疾病基因或分子途径的其他基因，确定了在这些相同疾病和途径中起作用的候选基因。我们专注于与小眼相关转录因子 (MITF) 共同进化的蛋白质，鉴定出 Notch 途径抑制毛发生长的基因（RBP-Jk/SuH）转录因子，并表明 RBP-Jk 作为 MITF 的共因子发挥作用。
