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.
Most descriptions of mutation have emphasized its negative consequences, and randomness with respect to biological function. This book seeks to balance the discussion by emphasizing mechanisms that both diversify the genome and increase the probability that a genome's descendants will survive. This chapter provides a framework for, and overview of, the diverse contributions to this book; these contributions will be stimulating companions, well into the 21st Century, as we work to comprehend the information contained in genomic databases. Genomes that encode "better" amino acid sequences are at a selective advantage. Genomes that generate diversity also are at an advantage to the extent that they can navigate efficiently through the space of possible sequence changes. Biochemical systems that tend to increase the ratio of useful to destructive genetic change may harness preexisting information (horizontal gene transfer, DNA translocation and/or DNA duplication), focus the location, timing, and extent of genetic change, adjust the dynamic range of a gene's activity, and/or sample regulatory connections between sites distributed across the genome. Rejecting entirely random genetic variation as the substrate of genome evolution is not a refutation, but rather provides a deeper understanding, of the theory of natural selection of Darwin and Wallace. The fittest molecular strategies survive, along with descendants of the genomes that encode them.
Biological diversity reflects an underlying molecular diversity. The molecules found in nature may be regarded as solutions to challenges that have been confronted and overcome during molecular evolution. As our understanding ofthese solutions deepens, the efficiency with which we can discover and/or design new treatments for human disease grows. Nature assists our drug discovery efforts in a variety ofways. Some compounds synthesized by microorganisms and
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