Origin of Mutations Under Selection: The Adaptive Mutation Controversy

Growth under selection causes new genotypes to predominate in a population. It is difficult to determine whether selection stimulates formation of new mutations or merely allows faster growth of mutants that arise independent of selection. In the practice of microbial genetics, selection is used to detect and enumerate pre-existing mutants; stringent conditions prevent growth of the parent and allow only the pre-existing mutants to grow. Used in this way, selection detects rare mutations that cause large, easily observable phenotypic changes. In natural populations, selection is imposed on growing cells and can detect the more common mutations that cause small growth improvements. As slighly improved clones expand, they can acquire additional mutational improvements. Selected sequential clonal expansions have huge power to produce new genotypes and have been suggested to underlie tumor progression. We suggest that the adaptive mutation controversy has persisted because the distinction between these two uses of selection has not been appreciated.