We study how correlations in the random fitness assignment may affect the structure of fitness landscapes, in three classes of fitness models. The first is a phenotype space in which individuals are characterized by a large number n of continuously varying traits. In a simple model of random fitness assignment, viable phenotypes are likely to form a giant connected cluster percolating throughout the phenotype space provided the viability probability is larger than 1/2(n). The second model explicitly describes genotype-to-phenotype and phenotype-to-fitness maps, allows for neutrality at both phenotype and fitness levels, and results in a fitness landscape with tunable correlation length. Here, phenotypic neutrality and correlation between fitnesses can reduce the percolation threshold, and correlations at the point of phase transition between local and global are most conducive to the formation of the giant cluster. In the third class of models, particular combinations of alleles or values of phenotypic characters are "incompatible" in the sense that the resulting genotypes or phenotypes have zero fitness. This setting can be viewed as a generalization of the canonical Bateson-Dobzhansky-Muller model of speciation and is related to K-SAT problems, prominent in computer science. We analyze the conditions for the existence of viable genotypes, their number, as well as the structure and the number of connected clusters of viable genotypes. We show that analysis based on expected values can easily lead to wrong conclusions, especially when fitness correlations are strong. We focus on pairwise incompatibilities between diallelic loci, but we also address multiple alleles, complex incompatibilities, and continuous phenotype spaces. In the case of diallelic loci, the number of clusters is stochastically bounded and each cluster contains a very large sub-cube. Finally, we demonstrate that the discrete NK model shares some signature properties of models with high correlations.
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http://dx.doi.org/10.1016/j.jtbi.2007.07.009 | DOI Listing |
Mol Biol Evol
January 2025
Institut de Biologie, École Normale Supérieure, CNRS UMR 8197, Inserm U1024, PSL Research University, Paris, F-75005, France.
Modifiers of recombination rates have been described but the selective pressures acting on them and their effect on adaptation to novel environments remain unclear. We performed experimental evolution in the nematode Caenorhabditis elegans using alternative rec-1 alleles modifying the position of meiotic crossovers along chromosomes without detectable direct fitness effects. We show that adaptation to a novel environment is impaired by the allele that decreases recombination rates in the genomic regions containing fitness variation.
View Article and Find Full Text PDFPLoS Genet
December 2024
Laboratory of Genetics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Advances in DNA sequencing technology and computation now enable genome-wide scans for natural selection to be conducted on unprecedented scales. By examining patterns of sequence variation among individuals, biologists are identifying genes and variants that affect fitness. Despite this progress, most population genetic methods for characterizing selection assume that variants mutate in a simple manner and at a low rate.
View Article and Find Full Text PDFPLoS Comput Biol
January 2025
Microsoft Research, Cambridge, Massachusetts, United States of America.
Machine learning sequence-function models for proteins could enable significant advances in protein engineering, especially when paired with state-of-the-art methods to select new sequences for property optimization and/or model improvement. Such methods (Bayesian optimization and active learning) require calibrated estimations of model uncertainty. While studies have benchmarked a variety of deep learning uncertainty quantification (UQ) methods on standard and molecular machine-learning datasets, it is not clear if these results extend to protein datasets.
View Article and Find Full Text PDFNat Genet
January 2025
Institute of Molecular Oncology, Philipps-University, Marburg, Germany.
The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Department of Physics and Astronomy, University of California, Los Angeles, CA 90095.
The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence-function maps and constrain the availability of adaptive paths. While theoretical intuition is often built on global statistics of large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood of a reference genotype.
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