Strong Selection Significantly Increases Epistatic Interactions in the Long-Term Evolution of a Protein

Epistatic interactions between residues determine a protein's adaptability and shape its evolutionary trajectory. When a protein experiences a changed environment, it is under strong selection to find a peak in the new fitness landscape. It has been shown that strong selection increases epistatic interactions as well as the ruggedness of the fitness landscape, but little is known about how the epistatic interactions change under selection in the long-term evolution of a protein. Here we analyze the evolution of epistasis in the protease of the human immunodeficiency virus type 1 (HIV-1) using protease sequences collected for almost a decade from both treated and untreated patients, to understand how epistasis changes and how those changes impact the long-term evolvability of a protein. We use an information-theoretic proxy for epistasis that quantifies the co-variation between sites, and show that positive information is a necessary (but not sufficient) condition that detects epistasis in most cases. We analyze the "fossils" of the evolutionary trajectories of the protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for evolution after 9 years of adapting to a drug environment that itself is constantly changing.Comment: 25 pages, 9 figures, plus Supplementary Material including Supplementary Text S1-S7, Supplementary Tables S1-S2, and Supplementary Figures S1-2. Version that appears in PLoS Genetic

Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms

Evolvability signatures of generative encodings: beyond standard performance benchmarks

Evolutionary robotics is a promising approach to autonomously synthesize machines with abilities that resemble those of animals, but the field suffers from a lack of strong foundations. In particular, evolutionary systems are currently assessed solely by the fitness score their evolved artifacts can achieve for a specific task, whereas such fitness-based comparisons provide limited insights about how the same system would evaluate on different tasks, and its adaptive capabilities to respond to changes in fitness (e.g., from damages to the machine, or in new situations). To counter these limitations, we introduce the concept of "evolvability signatures", which picture the post-mutation statistical distribution of both behavior diversity (how different are the robot behaviors after a mutation?) and fitness values (how different is the fitness after a mutation?). We tested the relevance of this concept by evolving controllers for hexapod robot locomotion using five different genotype-to-phenotype mappings (direct encoding, generative encoding of open-loop and closed-loop central pattern generators, generative encoding of neural networks, and single-unit pattern generators (SUPG)). We observed a predictive relationship between the evolvability signature of each encoding and the number of generations required by hexapods to adapt from incurred damages. Our study also reveals that, across the five investigated encodings, the SUPG scheme achieved the best evolvability signature, and was always foremost in recovering an effective gait following robot damages. Overall, our evolvability signatures neatly complement existing task-performance benchmarks, and pave the way for stronger foundations for research in evolutionary robotics.Comment: 24 pages with 12 figures in the main text, and 4 supplementary figures. Accepted at Information Sciences journal (in press). Supplemental videos are available online at, see http://goo.gl/uyY1R