Evolution by natural selection (adaptive evolution) is one of the major generalizations in biology. It also hasimportant ramifications for medicine, agriculture, and biotechnology. Unfortunately, many outcomes ofnatural selection have been to our detriment. The most obvious ones are apparent in medicine - theevolution of drug-resistant bacteria and viruses, to the point that some infections are now untreatable. Yet,whatever problems arise from natural selection of pests and parasites, we need not remain as helplessvictims to its effects: understanding evolution offers potential solutions. Our ability to predict adaptiveevolution is still in its infancy. Yet it is now apparent that many opportunities exist for improving thatunderstanding, aided by molecular biology. This proposal integrates theoretical and experimental methodsto explore properties of adaptive evolution. Although population genetic theory has long given us afoundation for describing adaptive and non-adaptive evolution, that theory is concerned with predicting thecourse of gene frequency evolution after the beneficial effects and other properties of those genes arespecified. Here we ask whether there are general, statistical properties about the numbers and effects ofbeneficial mutations. While it might seem that the characteristics of beneficial mutations will varyidiosyncratically from system to system, recent work by Orr using statistical theory suggests that there mayindeed be generalities that transcend the biological details of a system. Exploring the nature of thesegeneralities leads to the following objectives: Aim 1: Characterize the properties of the first step in anadaptive walk. Aim 2: Investigate the relationship between first step beneficial mutations and subsequentsteps in an adaptive walk. Each aspect of the proposed research integrates mathematical models andstatistical methods with experimental evolution of bacteriophages and total genome sequencing. If theabove mentioned generalities hold, they will have broad implications for our general understanding ofmolecular evolution. This theory may also suggest useful approaches to predict the trajectory of evolution inorganisms of medical importance. Such information could be extremely useful at early stages of drugdevelopment, as well as in designing treatments that are more resilient to evolution in the target species.