Our understanding of molecular evolution depends on our ability to identify adaptive substitutions and estimate their frequency in the genome. Numerous statistical tests of neutrality have been developed to detect adaptive evolution and application of these tests to genome sequence variation has provided strong evidence against the neutral theory of molecular evolution. Yet, our ability to detect positive selection and estimate its frequency in the genome may be unknowingly affected by deleterious mutations. First, the spread of an advantageous allele through a population may cause the fixation of linked deleterious mutations, leading to overestimates of the frequency of adaptive substitution. Second, deleterious mutations may interfere with the spread of an advantageous allele through a population, leading to altered patterns of linked neutral variation. The goal of the proposed research is to use computer simulations to investigate the conditions under which deleterious mutations significantly alter our ability to identify and estimate the frequency of adaptive evolution. PUBLIC HEALTH RELEVANCE: Adaptive substitutions play an important role in evolution and may impact human health through their influence on disease-causing mutations and microbial pathogenesis. Yet, our ability to identify adaptive substitutions may be significantly influenced by nearby deleterious mutations. The proposed research will characterize the effects of deleterious mutations on adaptive evolution and vice-versa.