PT - JOURNAL ARTICLE AU - Kelly, John K AU - Hughes, Kim TI - An examination of the evolve-and-resequence method using <em>Drosophila simulans</em> AID - 10.1101/337188 DP - 2018 Jan 01 TA - bioRxiv PG - 337188 4099 - http://biorxiv.org/content/early/2018/06/03/337188.short 4100 - http://biorxiv.org/content/early/2018/06/03/337188.full AB - We develop a set of analytical and simulation tools for Evolve-and-Resequence (E&amp;R) experiments and apply them to a new study of rapid evolution in Drosophila simulans. Likelihood based test statistics combined with permutation suggest parallel evolution of about 120 polymorphisms across the genome. Whole genome simulations calibrated from several Drosophila genetic datasets indicate this response could be generated by as few as 20 loci under strong directional selection, with a corresponding hitch-hiking effect. While this resolves the “excessive significance” paradox typical of E&amp;R experiments, a rank-based correlation analysis of genomic windows that suggests that weaker selection might be acting at a much larger number of sites. Finally, the allele frequency spectrum at sites that experience strong selection in the novel laboratory environment suggests that loci responding to selection may be balanced polymorphisms in nature.