Random Field Model Reveals Structure of the Protein Recombinational Landscape

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. Mutation and recombination are the primary sources of genetic variation in evolving populations. The relative benefit of these two diversification mechanisms and how they complement each other has been a long-standing question in evolutionary biology. While it is clear what types of genetic diversity these two mechanisms can create, a significant challenge is relating these sequence changes to changes in fitness. The fitness landscape, which describes this mapping from genotype to phenotype, is extraordinarily complex and defined over an incomprehensibly large space of sequences. Here, we develop a model of the landscape that relies not on the details of this mapping, but rather on the statistical relationships between sequences. By studying the expected values of landscape properties, we can gain insights into the structure of the landscape that are independent of the details of how genotype dictates phenotype. We use this random field model to understand how recombination explores a functionally enriched and diverse subset of protein sequence space.