Lindeboom Rik G H, Supek Fran, Lehner Ben
EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Nat Genet. 2016 Oct;48(10):1112-8. doi: 10.1038/ng.3664. Epub 2016 Sep 12.
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs. We also show that dosage compensation may sometimes mask the effects of NMD. Applying the NMD model identifies signatures of both positive and negative selection on NMD-triggering mutations in human tumors and provides a classification for tumor-suppressor genes.
提前终止密码子（PTC）导致了很大一部分人类遗传性疾病。含有PTC的转录本可通过一种称为无义介导的mRNA降解（NMD）的mRNA监测途径被降解。然而，NMD的效率各不相同；当PTC位于最后一个外显子连接复合体（EJC）下游时，其效率较低。我们使用来自9769个人类肿瘤的匹配外显子组和转录组数据，系统地阐明了人类细胞中NMD靶向的规则。一个整合了超越经典EJC模型的多个规则的模型解释了数千个PTC中NMD效率的约四分之三的非随机变异。我们还表明，剂量补偿有时可能掩盖NMD的作用。应用NMD模型可识别出人类肿瘤中NMD触发突变的正选择和负选择特征，并为肿瘤抑制基因提供一种分类。
