Evolutionary footprint of epistasis

Abstract

Variation of an inherited trait across a population cannot be explained by additive contributions of relevant genes, due to epigenetic effects and biochemical interactions (epistasis). Detecting epistasis in genomic data still represents a significant challenge that requires a better understanding of epistasis from the mechanistic point of view. Using a standard Wright-Fisher model of bi-allelic asexual population, we study how compensatory epistasis affects the process of adaptation. The main result is a universal relationship between four haplotype frequencies of a single site pair in a genome, which depends only on the epistasis strength of the pair defined regarding Darwinian fitness. We demonstrate the existence, at any time point, of a quasi-equilibrium between epistasis and disorder (entropy) caused by random genetic drift and mutation. We verify the accuracy of these analytic results by Monte-Carlo simulation over a broad range of parameters, including the topology of the interacting network. Thus, epistasis assists the evolutionary transit through evolutionary hurdles leaving marks at the level of haplotype disequilibrium. The method allows determining selection coefficient for each site and the epistasis strength of each pair from a sequence set. The resulting ability to detect clusters of deleterious mutation close to full compensation is essential for biomedical applications. These findings help to understand the role of epistasis in multiple compensatory mutations in viral resistance to antivirals and immune response.

Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome

“…Epistatic interactions have been doc umented between variants in different genes [49] as well as variants within the same gene [50] and are believed to be widespread properties of biological networks [51,52] . Although the genomic consequences of additive deleteri ous variants which multiplicatively (across loci) affect fitness are extensively studied, pairwise interactions amongst variants might be a non-negligible force governing molecular evolution.…”

“…Although the genomic consequences of additive deleteri ous variants which multiplicatively (across loci) affect fitness are extensively studied, pairwise interactions amongst variants might be a non-negligible force governing molecular evolution. Current methods to identify plausible pairwise interactions between SNPs rely on classic population genetic summary statistics of linkage disequilibrium or other summaries of pairwise association frequencies [51,53,54] . Although we detect differences in LD summary statistics in the human genome amongst variants of different annotations, our simulations suggest this difference can be explained by interference without the need to invoke epistasis ( Fig 7 ).…”

Epistasis detectably alters correlations between genomic sites in a narrow parameter window

“…The total population stays constant with the use of the broken-stick algorithm. To include natural selection, we calculate fitness (average progeny number) e W of sequence K i as given by [50] …”

An evolution-based high-fidelity method of epistasis measurement: theory and application to influenza

“…This situation will be referred below as "quasiequilibrium". The time required for the system to arrive there is ≫ 1/ (PEDRUZZI et al 2018). In quasi-equilibrium, the entropy ( ) (degree of disorder) is at its current maximum and represents a function of fitness ( ), which slowly changes in time during the process of adaptation:…”

“…where depends on and, hence, on time, but is the same for all loci (PEDRUZZI et al 2018). This simple derivation neglects interaction of the site pair with the other sites of the genome.…”