Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, 41944, Korea.
Department of Biomedical Sciences, Korea University Ansan Hospital, Ansan-si, Gyeonggi-do, 425-707, Korea.
Genome Res. 2017 Sep;27(9):1487-1500. doi: 10.1101/gr.211649.116. Epub 2017 Jun 8.
To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin () and angiogenin (), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases.
为了理解疾病机制，进行了大规模的人类 - 酵母遗传相互作用分析。在检测的 1305 个人类疾病基因中，有 20 个基因在酵母中表现出很强的毒性。通过将人类疾病基因大规模转化为具有独特条形码序列的 4653 个同质二倍体酵母缺失突变体库，随后进行多重条形码测序以鉴定酵母毒性修饰剂，从而鉴定出人类 - 酵母遗传相互作用。随后的网络分析集中在肌萎缩侧索硬化症（ALS）相关基因，如 OPTN（optineurin）和 ANG（angiogenin），表明这些 ALS 基因的酵母毒性修饰剂的人类同源物富含几种生物学过程，如细胞死亡、脂质代谢和分子运输。当在哺乳动物细胞和斑马鱼中验证了人类 OPTN 和 ANG 之间共同的酵母遗传相互作用伙伴时，MAP2K5 激酶作为 ALS 治疗的潜在药物靶点出现。本研究中鉴定的毒性修饰剂可能加深我们对 ALS 和其他毁灭性疾病的发病机制的理解。
