Abstract
Genotype-to-phenotype maps and the related fitness landscapes that include epistatic interactions are difficult to measure because of their high dimensional structure. Here we construct such a map using the recently collected corpora of high-throughput sequence data from the 75 base pairs long mutagenized E. coli lac promoter region, where each sequence is associated with its phenotype, the induced transcriptional activity measured by a fluorescent reporter. We find that the additive (non-epistatic) contributions of individual mutations account for about two-thirds of the explainable phenotype variance, while pairwise epistasis explains about 7% of the variance for the full mutagenized sequence and about 15% for the subsequence associated with protein binding sites. Surprisingly, there is no evidence for third order epistatic contributions, and our inferred fitness landscape is essentially single peaked, with a small amount of antagonistic epistasis. There is a significant selective pressure on the wild type, which we deduce to be multi-objective optimal for gene expression in environments with different nutrient sources. We identify transcription factor (CRP) and RNA polymerase binding sites in the promotor region and their interactions without difficult optimization steps. In particular, we observe evidence for previously unexplored genetic regulatory mechanisms, possibly kinetic in nature. We conclude with a cautionary note that inferred properties of fitness landscapes may be severely influenced by biases in the sequence data.
Highlights
Many aspects of evolution, such as selection, recombination, and speciation, depend on the relationships between genotype, phenotype, and fitness
A major difficulty that has precluded mapping of large fitness landscape, is epistasis, which is the dependence of fitness effects of a mutation on the presence of other mutations
Millions of interactions between gene pairs have been measured from genetic knockout experiments [14,15,16,17,18,19]. That is those involving more than two loci at a time, have been investigated for small fitness landscapes [3]
Summary
Many aspects of evolution, such as selection, recombination, and speciation, depend on the relationships between genotype, phenotype, and fitness. These relationships often involve complex and collective effects [1], which are difficult to untangle. One approach is to measure the fitness of many different genotypes, and build a fitness landscape, a high dimensional map from genotype/phenotype to reproductive fitness. This concept was first introduced by Sewell Wright in 1932 [2]. Epistasis makes the inference of landscapes combinatorially complex. That is those involving more than two loci at a time, have been investigated for small fitness landscapes [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
