背景:确定体细胞突变的影响需要了解基因获得突变的功能关系;但是,功能相关基因的突变是如何相互影响的,这在很大程度上是未知的。
方法:我们采用非同义对同义或dNdS比率来评估基因对的进化依赖性(ED),假设一个基因对的一个基因中的突变会影响其伴侣基因中突变作为突变背景的进化适应性。我们使用PanCancer和肿瘤类型特异性突变谱来推断基因对的ED,并评估了它们在基因依赖性和药物敏感性方面的生物学相关性。
结果:我们建议基因对的dNdS比率及其衍生的cdNS(环境依赖性dNdS)评分作为ED区分基因对的测量,无论是协同(SYN)还是拮抗(ANT)。突变背景可以诱导配对基因中突变的进化适应性发生实质性变化,例如,IDH1和IDH2突变背景导致ATRXindel和IDH1错义突变的dNdS比率大幅增加和减少,对应于SYN和ANT与cdNS评分的正负关系,分别。基因沉默或敲除对细胞活力(遗传依赖性)的影响通常取决于ED,这表明ED可以指导合成致死性候选基因的选择,如TCF7L2-KRAS突变。使用基于细胞系的药物敏感性数据,靶向药物对细胞系的影响通常与具有靶基因的ED基因的突变有关,告知靶向抑制剂的药物致敏或耐药突变,例如,PRSS1和CTCF突变作为肺腺癌和黑色素瘤的EGFR和BRAF抑制剂的耐药突变,分别。
结论:我们建议通过dNdS比率评估基因对的ED可以促进我们对具有潜在生物学和临床意义的基因功能关系的理解。
BACKGROUND: Determining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other.
METHODS: We employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity.
RESULTS: We propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively.
CONCLUSIONS: We propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications.