Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region
Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region
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DOI：
10.1534/genetics.109.112458
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发表时间：
2010-05-01
期刊：
影响因子：
3.3
通讯作者：
Mosier, Donald E.
中科院分区：
文献类型：
--
作者：
da Silva, Jack;Coetzer, Mia;Mosier, Donald E.
适应度上位（Fitness上位），即不同位点等位基因之间的相互作用对适应度的影响，对适应性进化具有潜在的重要影响。我们研究了人类免疫缺陷病毒1型（HIV-1）外包膜糖蛋白（gp120）一个功能重要区域氨基酸之间的适应性上位性。在野生型遗传背景下，研究人员对7个突变进行了单独和组合设计，并测量了它们对病毒感染性的影响，这些突变被认为涉及第二保守到第三可变蛋白区（C2-V3）对使用替代宿主细胞趋化因子辅助受体（CXCR4）进入细胞的适应性。上位性是一种既普遍又复杂的相互作用，不仅涉及成对相互作用，还涉及高阶相互作用。相互作用也可能出奇地强，改变适应度超过9个数量级，这可以用一些几乎致命的单一突变来解释。观察到的上位性的结果是，在表达替代共受体的细胞上，野生型和具有最高适应度的突变体之间的许多最小长度突变轨迹是选择性地不可接近的。这些结果可能有助于解释在培养中使用替代共受体的病毒进化的困难，以及在自然感染中这种表型的延迟进化。了解氨基酸之间共同的、复杂的和强适应的相互作用是充分理解蛋白质进化的必要条件。
Fitness epistasis, the interaction among alleles at different loci in their effects on fitness, has potentially important consequences for adaptive evolution. We investigated fitness epistasis among amino acids of a functionally important region of the human immunodeficiency virus type 1 (HIV-1) exterior envelope glycoprotein (gp120). Seven mutations putatively involved in the adaptation of the second conserved to third variable protein region (C2-V3) to the use of an alternative host-cell chemokine coreceptor (CXCR4) for cell entry were engineered singly and in combinations on the wild-type genetic background and their effects on viral infectivity were measured. Epistasis was found to be common and complex, involving not only pairwise interactions, but also higher-order interactions. Interactions could also be surprisingly strong, changing fitness by more than 9 orders of magnitude, which is explained by some single mutations being practically lethal. A consequence of the observed epistasis is that many of the minimum-length mutational trajectories between the wild type and the mutant with highest fitness on cells expressing the alternative coreceptor are selectively inaccessible. These results may help explain the difficulty of evolving viruses that use the alternative coreceptor in culture and the delayed evolution of this phenotype in natural infection. Knowledge of common, complex, and strong fitness interactions among amino acids is necessary for a full understanding of protein evolution.