Steinberg Barrett, Ostermeier Marc
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
Sci Adv. 2016 Jan 22;2(1):e1500921. doi: 10.1126/sciadv.1500921. eCollection 2016 Jan.
In the basic fitness landscape metaphor for molecular evolution, evolutionary pathways are presumed to follow uphill steps of increasing fitness. How evolution can cross fitness valleys is an open question. One possibility is that environmental changes alter the fitness landscape such that low-fitness sequences reside on a hill in alternate environments. We experimentally test this hypothesis on the antibiotic resistance gene TEM-15 β-lactamase by comparing four evolutionary strategies shaped by environmental changes. The strategy that included initial steps of selecting for low antibiotic resistance (negative selection) produced superior alleles compared with the other three strategies. We comprehensively examined possible evolutionary pathways leading to one such high-fitness allele and found that an initially deleterious mutation is key to the allele's evolutionary history. This mutation is an initial gateway to an otherwise relatively inaccessible area of sequence space and participates in higher-order, positive epistasis with a number of neutral to slightly beneficial mutations. The ability of negative selection and environmental changes to provide access to novel fitness peaks has important implications for natural evolutionary mechanisms and applied directed evolution.
在分子进化的基本适应度景观隐喻中，进化路径被假定为遵循适应度增加的上坡步骤。进化如何跨越适应度低谷是一个悬而未决的问题。一种可能性是环境变化改变了适应度景观，使得低适应度序列在交替环境中位于一座山上。我们通过比较由环境变化塑造的四种进化策略，对抗生素抗性基因TEM-15β-内酰胺酶进行了实验验证这一假设。与其他三种策略相比，包括选择低抗生素抗性的初始步骤（负选择）的策略产生了更优的等位基因。我们全面研究了导致一个这样的高适应度等位基因的可能进化路径，发现一个最初有害的突变是该等位基因进化历史的关键。这个突变是进入序列空间中原本相对难以到达区域的初始通道，并与许多中性到轻微有益的突变参与高阶正上位性。负选择和环境变化提供进入新适应度峰值的能力对自然进化机制和应用定向进化具有重要意义。
