Strong selection significantly increases epistatic interactions in the long-term evolution of a protein

Epistatic interactions between residues determine a protein’s adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient) condition that detects epistasis ...残基间的上位性相互作用（epistatic interactions）决定了蛋白质的适应性，并塑造其进化轨迹。当蛋白质所处环境发生改变时，其会受到强烈的选择压力，以在新的适应度景观（fitness landscape）中寻得适应峰值。已有研究证实，强烈的选择压力会增强上位性相互作用，同时提升适应度景观的崎岖程度；但目前针对蛋白质长期进化过程中，选择压力下上位性相互作用的变化规律，学界仍所知有限。本研究依托近十年间从接受抗逆转录病毒治疗与未接受治疗的患者体内采集的蛋白酶（protease）序列，针对人类免疫缺陷病毒1型（HIV-1）的蛋白酶展开上位性进化分析，以期阐明上位性相互作用的变化模式，及其对蛋白质长期可进化性的影响。本研究采用一种基于信息论的上位性代理指标，用于量化位点间的共变异程度，并证实正信息是检测上位性相互作用的必要（但非充分）条件……