Abstract
We are interested in how intragenic recombination contributes to the evolution of proteins and how this mechanism complements and enhances the diversity generated by random mutation. Experiments have revealed that proteins are highly tolerant to recombination with homologous sequences (mutation by recombination is conservative); more surprisingly, they have also shown that homologous sequence fragments make largely additive contributions to biophysical properties such as stability. Here, we develop a random field model to describe the statistical features of the subset of protein space accessible by recombination, which we refer to as the recombinational landscape. This model shows quantitative agreement with experimental results compiled from eight libraries of proteins that were generated by recombining gene fragments from homologous proteins. The model reveals a recombinational landscape that is highly enriched in functional sequences, with properties dominated by a large-scale additive structure. It also quantifies the relative contributions of parent sequence identity, crossover locations, and protein fold to the tolerance of proteins to recombination. Intragenic recombination explores a unique subset of sequence space that promotes rapid molecular diversification and functional adaptation.
Highlights
The ubiquity of sex and recombination suggests a significant role in evolution, yet their benefit is still debated [1,2]
We have developed techniques for the design, construction, and characterization of libraries of chimeric proteins generated by sitedirected recombination of homologous sequences [9,10,11,12]
A probabilistic contact potential was used to specify the mean energy of individual chimeric proteins and how the energy of any sequence is expected to co-vary with others, defining a multivariate probability distribution over all sequences accessible by recombination
Summary
The ubiquity of sex and recombination suggests a significant role in evolution, yet their benefit is still debated [1,2]. Random mutations frequently result in a non-parental amino acid and cause deleterious novel interactions with all contacting residues This simplified model recapitulates the exponential decline in functional sequences that was observed upon random mutagenesis of b-lactamase (Figure 2A) and in other mutational studies [13,14,15]. With the random field model, both parental and novel contacts contribute to the distribution of sequence energies within a recombination library and to the fraction of functional sequences. To better understand the variation in the fraction of functional sequences in the different recombination libraries, we sampled random libraries, calculated E1⁄2fF , and estimated the contribution from protein fold, specific breakpoints, and parent sequence identity. We define the landscape’s additivity A as the fraction of the total variance that is explained by additive effects
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