Merging molecular mechanism and evolution: theory and computation at the interface of biophysics and evolutionary population genetics

Serohijos, Adrian W.R.; Shakhnovich, Eugene I.

doi:10.1016/j.sbi.2014.05.005

Cited by 95 publications

(90 citation statements)

References 80 publications

(111 reference statements)

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“…Studies of molecular evolution attributed CUB to both genetic drift (neutralist) (Kimura, 1968b, Kimura, 1968a) and natural selection (selectionist) mechanisms (Mayr, 1961, Mayr, 1967). Although the selectionist or neutralist theories are not exclusive of each other (Bilgin et al, 2013, Bulmer, 1991, Duret, 2002a, Duret et al, 2002, Lercher et al, 2002, Wagner, 2008), we lack a complete understanding of the relative contribution of these pathways with regard to the evolution of CUB (reviewed in: (Nei and Nozawa, 2011, Nei et al, 2010, Serohijos and Shakhnovich, 2014, Hershberg and Petrov, 2008). …”

Section: Historical Perspective and Terminologymentioning

confidence: 99%

Decoding mechanisms by which silent codon changes influence protein biogenesis and function

Bali

Bebök

2015

The International Journal of Biochemistry & Cell Biology

112

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Scope Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. Purpose This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. Physiological and medical relevance Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies.

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Section: Historical Perspective and Terminologymentioning

confidence: 99%

Decoding mechanisms by which silent codon changes influence protein biogenesis and function

Bali

Bebök

2015

The International Journal of Biochemistry & Cell Biology

112

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“…Therefore, in recent years, there has been a drive to integrate the fields of protein biophysics and molecular evolution in order to better understand protein evolution (Harms and Thornton 2013;Liberles et al 2012;Serohijos and Shakhnovich 2014;Soskine and Tawfik 2010). One technique that has proved particularly useful in this pursuit is ancestral sequence reconstruction (ASR).…”

Section: Introductionmentioning

confidence: 99%

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

et al. 2015

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Ancestral sequence reconstruction has been widely used to study historical enzyme evolution, both from biochemical and cellular perspectives. Two properties of reconstructed ancestral proteins/enzymes are commonly reported-high thermostability and high catalytic activity-compared with their contemporaries. Increased protein stability is associated with lower aggregation rates, higher soluble protein abundance and a greater capacity to evolve, and therefore, these proteins could be considered ''superior'' to their contemporary counterparts. In this study, we investigate the relationship between the favourable in vitro biochemical properties of reconstructed ancestral enzymes and the organismal fitness they confer in vivo. We have previously reconstructed several ancestors of the enzyme LeuB, which is essential for leucine biosynthesis. Our initial fitness experiments revealed that overexpression of ANC4, a reconstructed LeuB that exhibits high stability and activity, was only able to partially rescue the growth of a DleuB strain, and that a strain complemented with this enzyme was outcompeted by strains carrying one of its descendants. When we expanded our study to include five reconstructed LeuBs and one contemporary, we found that neither in vitro protein stability nor the catalytic rate was correlated with fitness. Instead, fitness showed a strong, negative correlation with estimated evolutionary age (based on phylogenetic relationships). Our findings suggest that, for reconstructed ancestral enzymes, superior in vitro properties do not translate into organismal fitness in vivo. The molecular basis of the relationship between fitness and the inferred age of ancestral LeuB enzymes is unknown, but may be related to the reconstruction process. We also hypothesise that the ancestral enzymes may be incompatible with the other, contemporary enzymes of the metabolic network.

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“…Developing models of fitness landscapes based on the physics of proteins and other biomolecules has emerged as a powerful approach for understanding molecular evolution [14,16,[31][32][33].…”

Section: Discussionmentioning

confidence: 99%

Scaling properties of evolutionary paths in a biophysical model of protein adaptation

Manhart

Morozov

2015

Phys. Biol.

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Abstract. The enormous size and complexity of genotypic sequence space frequently requires consideration of coarse-grained sequences in empirical models. We develop scaling relations to quantify the effect of this coarse-graining on properties of fitness landscapes and evolutionary paths. We first consider evolution on a simple Mount Fuji fitness landscape, focusing on how the length and predictability of evolutionary paths scale with the coarse-grained sequence length and alphabet. We obtain simple scaling relations for both the weakand strong-selection limits, with a non-trivial crossover regime at intermediate selection strengths. We apply these results to evolution on a biophysical fitness landscape that describes how proteins evolve new binding interactions while maintaining their folding stability. We combine the scaling relations with numerical calculations for coarse-grained protein sequences to obtain quantitative properties of the model for realistic binding interfaces and a full amino acid alphabet. ‡ Current address:

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Merging molecular mechanism and evolution: theory and computation at the interface of biophysics and evolutionary population genetics

Cited by 95 publications

References 80 publications

Decoding mechanisms by which silent codon changes influence protein biogenesis and function

Decoding mechanisms by which silent codon changes influence protein biogenesis and function

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

Scaling properties of evolutionary paths in a biophysical model of protein adaptation

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