A framework for inferring fitness landscapes of patient-derived viruses using quasispecies theory A Letter Submitted to Genetics

1 Fitness is a central quantity in evolutionary models of viruses. However, it remains difficult to determine viral fitness experimentally, and existing in vitro assays can be poor predictors of in vivo fitness of viral populations within their hosts. Next-generation sequencing can nowadays provide snapshots of evolving virus populations, and these data 5 offer new opportunities for inferring viral fitness. Using the equilibrium distribution of the quasispecies model, an established model of intra-host viral evolution, we linked fitness parameters to the composition of the virus population, which can be estimated by next-generation sequencing. For inference, we developed a Bayesian Markov Chain Monte Carlo method to sample from the posterior distribution of fitness values. The sampler can 10 overcome situations where no maximum likelihood estimator exists, and it can adaptively learn the posterior distribution of highly correlated fitness landscapes without prior knowledge of their shape. We tested our approach on simulated data and applied it to clinical HIV-1 samples to estimate their fitness landscapes in vivo. The posterior fitness distributions allowed for differentiating viral haplotypes from each other, for determining neutral 15 haplotype networks, in which no haplotype is more or less credibly fit than any other, and for detecting epistasis in fitness landscapes. Our implemented approach, called QuasiFit, is available at http://www.cbg.ethz.ch/software/quasifit.