Biology subjects

Claus O. Wilke

Publications and source records attributed to Claus O. Wilke.

4 recordsLinked to original sources

bioRxiv2016

Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein

Proteins evolve through two primary mechanisms: substitution, where mutations alter a proteins amino-acid sequence, and insertions and deletions (indels), where amino acids are either added to or removed from the sequence. Protein structure has been shown to influence the rate at which substitutions accumulate across sites in proteins, but whether structure similarly constrains the occurrence of indels has not been rigorously studied. Here, we investigate the extent to which structural properties known to covary with protein evolutionary rates might also predict protein tolerance to indels. Specifically, we analyze a publicly available dataset of single-amino-acid deletion mutations in enhanced green fluorescent protein (eGFP) to assess how well the functional effect of deletions can be predicted from protein structure. We find that weighted contact number (WCN), which measures how densely packed a residue is within the proteins three-dimensional structure, provides the best single predictor for whether eGFP will tolerate a given deletion. We additionally find that using protein design to explicitly model deletions results in improved predictions of functional status when combined with other structural predictors. Our work suggests that structure plays fundamental role in constraining deletions at sites in proteins, and further that similar biophysical constraints influence both substitutions and deletions. This study therefore provides a solid foundation for future work to examine how protein structure influences tolerance of more complex indel events, such as insertions or large deletions.

Bioinformatics↗

bioRxiv2014

Increased evolutionary rate in the 2014 West African Ebola outbreak is due to transient polymorphism and not positive selection

Gire et al. (Science 345:1369-1372, 2014) analyzed 81 complete genomes sampled from the 2014 Zaire ebolavirus (EBOV) outbreak and reported \"rapid accumulation of [...] genetic variation\" and a substitution rate that was \"roughly twice as high within the 2014 outbreak as between outbreaks.\" These findings have received widespread attention, and many have perceived Gire et al. (2014)s results as implying rapid adaptation of EBOV to humans during the current outbreak. Here, we argue that, on the contrary, sequence divergence in EBOV is rather limited, and that the currently available data contain no robust signal of particularly rapid evolution or adaptation to humans. The doubled substitution rate can be attributed entirely to the application of a molecular-clock model to a population of sequences with minimal divergence and segregating polymorphisms. Our results highlight how subtle technical aspects of sophisticated evolutionary analysis methods may result in highly-publicized, misconstrued statements about an ongoing public health crisis.

Evolutionary Biology↗

bioRxiv2014

Relationship between protein thermodynamic constraints and variation of evolutionary rates among sites

Evolutionary-rate variation among sites within proteins depends on functional and biophysical properties that constrain protein evolution. It is generally accepted that proteins must be able to fold stably in order to function. However, the relationship between stability constraints and among-sites rate variation is not well understood. Here, we present a biophysical model that links the thermodynamic stability changes due to mutations at sites in proteins ({Delta}{Delta}G) to the rate at which mutations accumulate at those sites over evolutionary time. We find that such a "stability model" generally performs well, displaying correlations between predicted and empirically observed rates of up to 0.75 for some proteins. We further find that our model has comparable predictive power as does an alternative, recently proposed "stress model" that explains evolutionary-rate variation among sites in terms of the excess energy needed for mutants to adopt the correct active structure ({Delta}{Delta}G*). The two models make distinct predictions, though, and for some proteins the stability model outperforms the stress model and vice versa. We conclude that both stability and stress constrain site-specific sequence evolution in proteins.

Biophysics↗

bioRxiv2014

Predicting evolutionary site variability from structure in viral proteins: buriedness, packing, flexibility, and design

Several recent works have shown that protein structure can predict site-specific evolutionary sequence variation. In particular, sites that are buried and/or have many contacts with other sites in a structure have been shown to evolve more slowly, on average, than surface sites with few contacts. Here, we present a comprehensive study of the extent to which numerous structural properties can predict sequence variation. The quantities we considered include buriedness (as measured by relative solvent accessibility), packing density (as measured by contact number), structural flexibility (as measured by B factors, root-mean-square fluctuations, and variation in dihedral angles), and variability in designed structures. We obtained structural flexibility measures both from molecular dynamics simulations performed on 9 non-homologous viral protein structures and from variation in homologous variants of those proteins, where available. We obtained measures of variability in designed structures from flexible-backbone design in the Rosetta software. We found that most of the structural properties correlate with site variation in the majority of structures, though the correlations are generally weak (correlation coefficients of 0.1 to 0.4). Moreover, we found that buriedness and packing density were better predictors of evolutionary variation than was structural flexibility. Finally, variability in designed structures was a weaker predictor of evolutionary variability than was buriedness or packing density, but it was comparable in its predictive power to the best structural flexibility measures. We conclude that simple measures of buriedness and packing density are better predictors of evolutionary variation than are more complicated predictors obtained from dynamic simulations, ensembles of homologous structures, or computational protein design.

Evolutionary Biology↗