Evolutionary feedback from the environment shapes mechanisms that generate genome variation.

Darwin recognized that 'a grand and almost untrodden field of inquiry will be opened, on the causes and laws of variation.' However, because the Modern Synthesis assumes that the intrinsic probability of any individual mutation is unrelated to that mutation's potential adaptive value, attention has been focused on selection rather than on the intrinsic generation of variation. Yet many examples illustrate that the term 'random' mutation, as widely understood, is inaccurate. The probabilities of distinct classes of variation are neither evenly distributed across a genome nor invariant over time, nor unrelated to their potential adaptive value. Because selection acts upon variation, multiple biochemical mechanisms can and have evolved that increase the relative probability of adaptive mutations. In effect, the generation of heritable variation is in a feedback loop with selection, such that those mechanisms that tend to generate variants that survive recurring challenges in the environment would be captured by this survival and thus inherited and accumulated within lineages of genomes. Moreover, because genome variation is affected by a wide range of biochemical processes, genome variation can be regulated. Biochemical mechanisms that sense stress, from lack of nutrients to DNA damage, can increase the probability of specific classes of variation. A deeper understanding of evolution involves attention to the evolution of, and environmental influences upon, the intrinsic variation generated in gametes, in other words upon the biochemical mechanisms that generate variation across generations. These concepts have profound implications for the types of questions that can and should be asked, as omics databases become more comprehensive, detection methods more sensitive, and computation and experimental analyses even more high throughput and thus capable of revealing the intrinsic generation of variation in individual gametes. These concepts also have profound implications for evolutionary theory, which, upon reflection it will be argued, predicts that selection would increase the probability of generating adaptive mutations, in other words, predicts that the ability to evolve itself evolves. [ABSTRACT FROM AUTHOR]