当前位置: X-MOL 学术Proc. Natl. Acad. Sci. U.S.A. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity [Biophysics and Computational Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2021-01-26 , DOI: 10.1073/pnas.2010612118
Robert Rauscher 1 , Giovana B Bampi 1 , Marta Guevara-Ferrer 1 , Leonardo A Santos 1 , Disha Joshi 2, 3 , David Mark 1 , Lisa J Strug 4, 5 , Johanna M Rommens 4 , Manfred Ballmann 6 , Eric J Sorscher 2, 3 , Kathryn E Oliver 2, 3 , Zoya Ignatova 7
Affiliation  

Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)—the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease–causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain–domain interactions that are otherwise perturbed by each individual mutation.



中文翻译:

致病错义突变和沉默多态性之间的阳性上位性对 mRNA 翻译速度的影响 [生物物理学和计算生物学]

上位性是指突变对其他突变和一般遗传背景的依赖性。在人类疾病的背景下,上位性使疾病症状谱复杂化,并被认为是导致疾病结果变化的主要因素。突变之间的非加性关系和对潜在生理效应缺乏完整理解限制了我们预测表型结果的能力。在这里,我们报告了囊性纤维化跨膜电导调节因子 (CFTR) 基因内突变之间的阳性上位性,该基因负责囊性纤维化 (CF) 病理学。我们鉴定了一种同义单核苷酸多态性 (sSNP),它对 CFTR 氨基酸序列是不变的,但在受影响的密码子处反转翻译速度。顺式中的这个 sSNP对一些引起 CF 疾病的错义突变表现出积极的上位效应。单独地,这两种突变都会改变 CFTR 的结构和功能,但当它们结合起来时,它们会导致蛋白质表达和活性增强。当 sSNP 与错义突变结合存在时,观察到最强烈的效果,错义突变连同初级氨基酸的变化,也改变了受影响密码子的翻译速度。功能研究表明,核糖体速度的协同改变是潜在的机制。翻译速度的改变可能会增加建立关键域-域相互作用的时间窗口,否则这些相互作用会受到每个单独突变的干扰。

更新日期:2021-01-20
down
wechat
bug