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.

In Darwinian evolution, feedback from natural selection leads to biased mutations.

Natural selection provides feedback through which information about the environment and its recurring challenges is captured, inherited, and accumulated within genomes in the form of variations that contribute to survival. The variation upon which natural selection acts is generally described as "random." Yet evidence has been mounting for decades, from such phenomena as mutation hotspots, horizontal gene transfer, and highly mutable repetitive sequences, that variation is far from the simplifying idealization of random processes as white (uniform in space and time and independent of the environment or context).  This paper focuses on what is known about the generation and control of mutational variation, emphasizing that it is not uniform across the genome or in time, not unstructured with respect to survival, and is neither memoryless nor independent of the (also far from white) environment. We suggest that, as opposed to frequentist methods, Bayesian analysis could capture the evolution of nonuniform probabilities of distinct classes of mutation, and argue not only that the locations, styles, and timing of real mutations are not correctly modeled as generated by a white noise random process, but that such a process would be inconsistent with evolutionary theory.

Overview of the creative genome: effects of genome structure and sequence on the generation of variation and evolution.

This overview of a special issue of Annals of the New York Academy of Sciences discusses uneven distribution of distinct types of variation across the genome, the dependence of specific types of variation upon distinct classes of DNA sequences and/or the induction of specific proteins, the circumstances in which distinct variation-generating systems are activated, and the implications of this work for our understanding of evolution and of cancer. Also discussed is the value of non text-based computational methods for analyzing information carried by DNA, early insights into organizational frameworks that affect genome behavior, and implications of this work for comparative genomics.

Natural selection and the emergence of a mutation phenotype: an update of the evolutionary synthesis considering mechanisms that affect genome variation.

Most descriptions of evolution assume that all mutations are completely random with respect to their potential effects on survival. However, much like other phenotypic variations that affect the survival of the descendants, intrinsic variations in the probability, type, and location of genetic change can feel the pressure of natural selection. From site-specific recombination to changes in polymerase fidelity and repair of DNA damage, an organism's gene products affect what genetic changes occur in its genome. Through the action of natural selection on these gene products, potentially favorable mutations can become more probable than random. With examples from variation in bacterial surface proteins to the vertebrate immune response, it is clear that a great deal of genetic change is better than "random" with respect to its potential effect on survival. Indeed, some potentially useful mutations are so probable that they can be viewed as being encoded implicitly in the genome. An updated evolutionary theory includes emergence, under selective pressure, of genomic information that affects the probability of different classes of mutation, with consequences for genome survival.

El descubrimiento de medicamentos y la diversidad biológica: colaboraciones y riesgo en el descubrimiento de nuevos productos / Drug discovery and biodiversity: collaborations and risks in the discovery of new pharmaceuticals

II. El nexo entre la biodiversidad y la biotecnología en farmacología y agricultura

Drug discovery and biodiversity: collaborations and risks in the discovery of new pharmaceuticals

II. The nexus between biodiversity and biotechnology in pharmaceuticals and agriculrure