A Comprehensive, High-Resolution Map of a Gene's Fitness Landscape

被引:211
作者
Firnberg, Elad [1 ]
Labonte, Jason W. [1 ]
Gray, Jeffrey J. [1 ]
Ostermeier, Marc [1 ]
机构
[1] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA
基金
美国国家科学基金会;
关键词
protein evolution; fitness landscape; beta-lactamase; SINGLE-NUCLEOTIDE SUBSTITUTIONS; ACTIVITY TRADE-OFFS; ESCHERICHIA-COLI; BETA-LACTAMASES; INITIATION CODON; PROTEIN FUNCTION; ANTIBIOTIC-RESISTANCE; DARWINIAN EVOLUTION; ORGANISMAL FITNESS; SEQUENCE SPACE;
D O I
10.1093/molbev/msu081
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations are central to evolution, providing the genetic variation upon which selection acts. A mutation's effect on the suitability of a gene to perform a particular function (gene fitness) can be positive, negative, or neutral. Knowledge of the distribution of fitness effects (DFE) of mutations is fundamental for understanding evolutionary dynamics, molecular-level genetic variation, complex genetic disease, the accumulation of deleterious mutations, and the molecular clock. We present comprehensive DFEs for point and codon mutants of the Escherichia coli TEM-1 beta-lactamase gene and missense mutations in the TEM-1 protein. These DFEs provide insight into the inherent benefits of the genetic code's architecture, support for the hypothesis that mRNA stability dictates codon usage at the beginning of genes, an extensive framework for understanding protein mutational tolerance, and evidence that mutational effects on protein thermodynamic stability shape the DFE. Contrary to prevailing expectations, we find that deleterious effects of mutation primarily arise from a decrease in specific protein activity and not cellular protein levels.
引用
收藏
页码:1581 / 1592
页数:12
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