An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape
An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape
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DOI：
10.1371/journal.pgen.1008079
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发表时间：
2019-04-01
期刊：
影响因子：
4.5
通讯作者：
Kondrashov, Fyodor A.
中科院分区：
文献类型：
--
作者：
Pokusaeva, Victoria O.;Usmanova, Dinara R.;Kondrashov, Fyodor A.
描述适应度景观（代表大量基因型的适应度）是理解如何解释遗传信息以创建功能生物体的关键。在这里，我们确定了 His3 适应度景观中与进化相关的部分，His3 是组氨酸合成途径中一种酶的编码基因，重点关注在现有物种的直系同源位点发现的氨基酸状态组合。在酵母 His3 直系同源物中，只有 15% 的氨基酸始终是中性的，而其余 85% 的氨基酸对健康的影响取决于遗传背景。此外，在 67% 的位点，氨基酸替换处于符号上位性，在不同的遗传背景中既有强烈的积极影响，也有强烈的消极影响。 46% 的位点处于倒数上位状态。氨基酸替换的适应度影响仅受少数遗传背景的影响，但涉及多个位点的相互作用，形成了一个崎岖的适应度景观，其中高度适应的基因型之间的许多最短路径是不可接近的。 作者摘要 对蛋白质进化的直观理解表明，除了适应性替换之外，氨基酸状态应该在来自不同物种的相同基因之间自由交换。然而，这一说法的正确程度尚未在对照实验中得到检验。在这里，我们证明氨基酸状态是否可以在直向同源物之间交换取决于同一蛋白质中的其他氨基酸状态。此外，我们表明氨基酸状态的相互作用模式是多维的。假设氨基酸替换以几种独立的方式影响蛋白质，大大提高了我们预测自然界中未观察到的蛋白质序列中氨基酸状态影响的能力。
Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible.Author summary An intuitive understanding of protein evolution dictates that, with the exception of adaptive substitutions, amino acid states should be freely exchangeable between the same gene from different species. However, the extent to which this assertion holds true has not been tested in a controlled experiment. Here, we show that whether an amino acid state can be exchanged between orthologues depends on other amino acid states in the same protein. Furthermore, we show that the mode of interaction of amino acid states is multidimensional. Assuming that amino acid replacements influence the protein in several independent ways substantially improves our ability to predict the effect of an amino acid state in a protein sequence that has not been observed in nature.