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

Abstract

Linkage effects in a multi-locus population strongly influence its evolution. The models based on the traveling wave approach enable us to predict the average speed of evolution and the statistics of phylogeny. However, predicting statistically the evolution of specific sites and pairs of sites in the multi-locus context remains a mathematical challenge. In particular, the effects of epistasis, the interaction of gene regions contributing to phenotype, is difficult to predict theoretically and detect experimentally in sequence data. A large number of false-positive interactions arises from stochastic linkage effects and indirect interactions, which mask true epistatic interactions. Here we develop a proof-of-principle method to filter out false-positive interactions. We start by demonstrating that the averaging of haplotype frequencies over multiple independent populations is necessary but not sufficient for epistatic detection, because it still leaves high numbers of false-positive interactions. To compensate for the residual stochastic noise, we develop a three-way haplotype method isolating true interactions. The fidelity of the method is confirmed analytically and on simulated genetic sequences evolved with a known epistatic network. The method is then applied to a large sequence database of neurominidase protein of influenza A H1N1 obtained from various geographic locations to infer the epistatic network responsible for the difference between the pre-pandemic virus and the pandemic strain of 2009. These results present a simple and reliable technique to measure epistatic interactions of any sign from sequence data.

Long-range linkage effects in adapting sexual populations

“…Alternative theories of the emergence of VOCs 45 include reverse zoonosis, the evolution within immunocompromised patients 46 , 47 and the evolution in population pockets not covered by the genetic surveillance. Still another possibility is the fitness valley effect, a cascade emergence of compensating mutations following a primary mutation, an effect previously inferred for HIV and influenza 12 , 48 and studied theoretically 49 .…”

“…New mutations are neglected, which is shown to be correct in the short-term in the presence of pre-existing genetic variation, both in simulation and experimentally 31 , 32 . Epistasis is absent; for epistatic analysis, see 12 and references therein.…”

Evolutionary implications of SARS-CoV-2 vaccination for the future design of vaccination strategies

“…The method was applied to related species for proteins of various organisms 119 – 123 and, recently, to SARS-CoV-2 using different species of coronavirus 124 . A recent method developed for the multi-locus regime that does not neglect genetic linkage and hence can be applied to genome sequence data from either different species or to the same species, also permits to predict fitness effects of mutations and their interactions 125 , 126 . The availability of these and related methods makes us confident that soon we will have accurate and regularly updated fitness maps of SARS-CoV-2, enabling the prediction of its potential genetic trajectories to the extent made possible by current methods.…”

“…Alternative theories of the emergence of VOCs 19 include reverse zoonosis, evolution within immunocompromised patients with chronic infection 136 – 138 , and evolution in subpopulations not covered by genetic surveillance. To all these diverse hypotheses, we can add the fitness valley effect, a cascade emergence of compensating mutations following a primary mutation inferred for HIV and influenza 126 , 139 . Primary mutations in HIV are caused by the early immune response in CTL epitopes.…”

“…About half of the epitopes do not undergo antigenic escape and are left to limit virus replication 58 , 140 . The effect could be investigated using methods developed to measure interactions between mutations at different genomic locations 119 , 123 , 124 , 126 , 141 , 142 .…”