Rugged fitness landscapes minimize promiscuity in the evolution of transcriptional repressors.

Cell systems Pub Date : 2024-04-17 Epub Date: 2024-03-26 DOI:10.1016/j.cels.2024.03.002
Anthony T Meger, Matthew A Spence, Mahakaran Sandhu, Dana Matthews, Jackie Chen, Colin J Jackson, Srivatsan Raman
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Abstract

How a protein's function influences the shape of its fitness landscape, smooth or rugged, is a fundamental question in evolutionary biochemistry. Smooth landscapes arise when incremental mutational steps lead to a progressive change in function, as commonly seen in enzymes and binding proteins. On the other hand, rugged landscapes are poorly understood because of the inherent unpredictability of how sequence changes affect function. Here, we experimentally characterize the entire sequence phylogeny, comprising 1,158 extant and ancestral sequences, of the DNA-binding domain (DBD) of the LacI/GalR transcriptional repressor family. Our analysis revealed an extremely rugged landscape with rapid switching of specificity, even between adjacent nodes. Further, the ruggedness arises due to the necessity of the repressor to simultaneously evolve specificity for asymmetric operators and disfavors potentially adverse regulatory crosstalk. Our study provides fundamental insight into evolutionary, molecular, and biophysical rules of genetic regulation through the lens of fitness landscapes.

在转录抑制因子的进化过程中,崎岖的适应性景观将杂交性降到最低。
蛋白质的功能如何影响其适应性景观的形状(平滑或崎岖),这是生物化学进化中的一个基本问题。当增量突变步骤导致功能逐渐改变时,就会出现平滑的景观,这在酶和结合蛋白中很常见。另一方面,由于序列变化对功能的影响具有固有的不可预测性,人们对崎岖地貌的了解甚少。在这里,我们通过实验描述了 LacI/GalR 转录抑制因子家族 DNA 结合域 (DBD) 的整个序列系统发育,包括 1,158 个现存序列和祖先序列。我们的分析表明,即使在相邻的节点之间,特异性也会快速转换,从而形成一个极其崎岖不平的景观。此外,这种崎岖是由于抑制因子必须同时进化出对非对称操作者的特异性,并且不利于潜在的不利调控串扰。我们的研究通过适合度景观的视角,对遗传调控的进化、分子和生物物理规则提供了基本的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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