小柯机器人

美国哈佛医学院Joseph Loscalzo研究小组揭示了疾病突变对蛋白质相互作用的综合影响。2021年2月8日，《自然—遗传学》杂志在线发表了这项成果。

研究人员表明，与疾病相关的种系变体相比，从项目1000 Genomes和ExAC的健康参与者中鉴定出的变体在编码蛋白质-蛋白质相互作用（PPI）接口的序列中显著富集。与10,861个肿瘤外显子组中的非接口相比，PPI接口中的体细胞错义突变也显著富集。研究人员在全癌分析中通过计算确定了470种可能的oncoPPI，并证明oncoPPI与患者生存率和耐药性/敏感性高度相关。

研究人员使用系统性二元相互作用实验性地验证了13 oncoPPI的网络效应，并且还证明了其中的两个对肿瘤细胞生长的功能影响。

总而言之，这种人类相互作用组网络框架为区分具有PPI干扰突变的等位基因提供了一个有力的工具，从而可促进基于病理生物学机制和基因型的疗法发现。 

据介绍，基因组学和相互作用组学的技术和计算进展使人们能够确定疾病突变如何扰乱人类细胞内的PPI网络。

附：英文原文

Title: Comprehensive characterization of protein–protein interactions perturbed by disease mutations

Author: Feixiong Cheng, Junfei Zhao, Yang Wang, Weiqiang Lu, Zehui Liu, Yadi Zhou, William R. Martin, Ruisheng Wang, Jin Huang, Tong Hao, Hong Yue, Jing Ma, Yuan Hou, Jessica A. Castrillon, Jiansong Fang, Justin D. Lathia, Ruth A. Keri, Felice C. Lightstone, Elliott Marshall Antman, Raul Rabadan, David E. Hill, Charis Eng, Marc Vidal, Joseph Loscalzo

Issue&Volume: 2021-02-08

Abstract: Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861tumor exomes. We computationally identified 470putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery.

DOI: 10.1038/s41588-020-00774-y

Source: https://www.nature.com/articles/s41588-020-00774-y

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex