<p>by Eva Bons, Hélène Chabas, Hannelore MacDonald, Alejandro Escalera Ledermann, Sira Ösze, Jenny Dunstan, Nicolas Ochsner, Daniel C. Angst, Sebastian Bonhoeffer, Roland R. Regoes</p> The study of evolution in organisms with high mutation rates requires detailed data on the genomic composition of the population. Here we report on an innovative use of high-throughput sequencing technology combined with rapid experimental evolution that allowed us to follow the genetic diversification of four independent bacteriophage populations for 412 generations in extraordinary detail. One of our goals was to assess phylodynamic methods that use genetic information to infer key parameters of the population history. Because phylodynamic methods assume neutral evolution, we did not actively impose any selection pressures in our evolution experiment (in addition to those inherent in the bacterial cell environment). Tracing over 80′000 bacteriophage genomes, representing 884 distinct genotypes, we find that the patterns of viral diversification result in largely non-congruent genotype distributions, but also document multiple instances of parallel evolution. Unlike previous observations of parallelism in viral evolution, we do not just see the parallel evolution of mutations at single sites, but on the level of full-length genomes. Computer simulations that recapitulate our experiments in great detail show that this degree of parallelism is inconsistent with neutral evolution. We further show that the observed extent of parallel evolution biases phylodynamic analysis of migration rates, and wrongly estimates significant migration between the independent evolution lines. Our approach is applicable to many other viruses and paves the way to advanced population genetic investigations that aim to shed light on phenomena that relate to genetic linkage across the genome.