The Biochemical Architecture of an Ancient Adaptive Landscape

Lunzer, Mark; Miller, Stephen; Felsheim, Roderick F.; Dean, Anthony M.

doi:10.1126/science.1115649

Cited by 225 publications

(293 citation statements)

References 23 publications

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“…Several reports have documented both inter- [4,5,56] and intralocus [27,57,58] sign epistasis in different model systems. These observations promoted the idea that genetic constraints could be prevalent and hence adaptation could proceed through very few mutational paths to optimal genotypes [8,11].…”

Section: Discussionmentioning

confidence: 99%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a b-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness.

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Section: Discussionmentioning

confidence: 99%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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“…In multi-peaked landscapes, evolutionary trajectories can become trapped on sub-optimal peaks, which may lead to (temporary) evolutionary stasis. While empirical information on the ruggedness of fitness landscapes remains scarce, significant progress has recently been made by systematically reconstructing neighboring genotypes that affect a specific molecular function, such as the resistance against an antibiotic (Burch and Chao 1999;Buckling et al 2003;Lunzer, Miller 2005;Bridgham, Carroll 2006;Miller et al 2006;Weinreich, Delaney 2006;Fernandez et al 2007), which has yielded some indications for the presence of multiple peaks (Korona, Nakatsu 1994;Poelwijk, Kiviet 2006;Poelwijk, Kiviet 2007;Salverda 2008). However, conclusively demonstrating that two adaptive peaks are distinct -and not interconnected by a ridge that circumvents the adaptive valley-remains difficult if not impossible, due to the high-dimensional nature of sequence space (Whitlock et al 1995).…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, the mutations must occur in a specific order for the paths to be selectively accessible. Sign-epistatic interactions between mutations have been observed empirically, by reconstructing neighboring genotypes and determining their fitness (Lunzer et al 2005;Bridgham et al 2006;Weinreich et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

Poelwijk¹,

Tănase‐Nicola²,

Kiviet³

et al. 2011

Journal of Theoretical Biology

202

260

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Having multiple peaks within fitness landscapes critically affects the course of evolution, but whether their presence imposes specific requirements at the level of genetic interactions remains unestablished. Here we show that to exhibit multiple fitness peaks, a biological system must contain reciprocal sign epistatic interactions, which are defined as genetic changes that are separately unfavorable but jointly advantageous. Using Morse theory, we argue that it is impossible to formulate a sufficient condition for multiple peaks in terms of local genetic interactions. These finding indicate that systems incapable of reciprocal sign epistasis will always possess a single fitness peak. However, reciprocal sign epistasis should be pervasive in nature as it is a logical consequence of specificity in molecular interactions. The results thus predict that specific molecular interactions may yield multiple fitness peaks, which can be tested experimentally. 2 1. Introduction.

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“…Epistsis may occur at the genotypic level in determining fitness while not being detectable at the level of phenotype, as shown by Lunzer et al (2005). In this paper we shall be concerned with the genotype-fitness relationship as well as the role of recombination.…”

Section: Introductionmentioning

confidence: 99%

“…In this paper we shall be concerned with the genotype-fitness relationship as well as the role of recombination. In Lunzer et al (2005), the locations of the variants were specified by amino-acids in a single enzyme; recombination was, therefore, not important in their chemostat competition experiments with E. coli.…”

Section: Introductionmentioning

confidence: 99%

On the evolution of epistasis III: The haploid case with mutation

Liberman

Feldman

2008

Theoretical Population Biology

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Whether interaction between genes is better represented by synergistic or antagonistic epistasis has been a focus of experimental research in bacterial population genetics. Our previous research on evolution of modifiers of epistasis in diploid systems has indicated that the strength of positive or negative epistasis should increase provided linkage disequilibrium is maintained. Here we study a modifier of epistasis in fitness between two loci in a haploid system. Epistasis is modified in the neighborhood of a mutation selection balance. We show that when linkage in the three-locus system is tight, an increase in the frequency of a modifier allele that induces either more negative or more positive epistasis is possible. Epistasis here can be measured on either an additive or multiplicative scale.

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The Biochemical Architecture of an Ancient Adaptive Landscape

Cited by 225 publications

References 23 publications

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Reciprocal sign epistasis is a necessary condition for multi-peaked fitness landscapes

On the evolution of epistasis III: The haploid case with mutation

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