Mutation-Driven Evolution

Masatoshi Nei has been one of the major figures in evolutionary genetics since the latter third of the 20th century. He has personally contributed enormously to what we know today and remembers with awe-inspiring detail what others have said. When such an oracle speaks, we should listen carefully.Nei challenges the widely if often reflexively held view that natural selection is the fine-tuning process that accounts for the traits of organisms. This classical Darwinian view holds that there is always enough standing genomic variation that, when the environment changes, a species can adapt to it. However, through the years prominent geneticists, including Nei, have argued that mutation rather than selection is the driver of evolution. The reasoning is basically that at any given time the complex integration of genomic mechanisms has been molded by eons of adaptive selection and cannot be changed much without being harmful. Major phenotypic change can arise only after the occurrence of rare “constraint-breaking” mutations that escape the established mold.Nei expresses his view by tracing the history of ideas on selection and mutation as new knowledge of genes and their mechanisms has accumulated. Comparative sequence analysis clearly shows that the amino acid code of most genes is constrained relative to less clearly functional parts of the genome. Because developmental processes involve many interacting genes, a mutation of large effect is most likely to disrupt the system—for example, to cause serious disease. But genomic data have also shown that more substantial mutations, such as redundancy generated by gene duplication, that can enable new function to evolve do occasionally arise.Contrary to widespread assumptions, species are not as a rule narrowly adaptive but can make choices on where or how to live. Yet, environmental or behavioral niches can remain empty until appropriate variation has arisen to enable an organism to fill them. The evolutionary theory of population genetics is too vaguely schematic in relation to the details of actual cases of complex traits to be very useful in this regard. Selection is usually so slow, subtle, and changeable as environments change that, if we make selection our explanatory axiom, it enables facile retrospective stories to be constructed. Instead, Nei argues that the experimental and molecular evidence suggest the importance of rare constraint-breaking mutations, which he illustrates with historic and recent examples of such mutations that have effected major behavioral and physical changes.Although he generally treats the issues as a dichotomy, Nei also notes that reality is more nuanced and that life is a mix of these various factors. Thus, what one judges to be “most important” is subjective. For example, he notes that organisms can seek and find niches that they like and aggregate there, while gradually diverging from their more conventional fellows until mutual sterility—and hence speciation—occurs. This is organismal selection, and no competitive Darwinian selection need be involved.Nei feels compelled to define evolution as the process of increased organismal complexity, as manifest for example in an increasing number of cell types. This seems unnecessary, harkening to earlier and I think obsolete progressivism. Bacteria, yeast, and algae are, after all, still with us, whatever their constraint-breaking adaptations might have been.This is not a long book, but it is well supplied with historical, theoretical, quantitative, and molecular details, including methods and concepts that bear on the issues. The final chapter is a cogent and clear summary of stand-alone quality, and you can start there and branch back for details to chapters of your own interest.Why should human geneticists read this book? These issues have everything to do with genomic causation because how humans work as organisms depends on genotype-to-phenotype relationships. Selection is based on Detectance—Pr[Genotype | Phenotype], analogous to genome-wide mapping—because what the environment can’t sense it can’t screen, whereas causation and predictive genomic medicine are based on Predictance—Pr[Phenotype | Genotype]. If we use naive caricatures of how genetic variation affects phenotypes or how stringently nature screens them for fitness, we apply uncritically deterministic models of genome function. If genomic mechanisms are complex and creepingly slow to change, and if major highly penetrant but viable effects are rare, then one would expect mapping and prediction both to generally be weak—as is the widespread current experience.In this capstone book to his distinguished career, Nei provides a clear call to reset a balanced view of the factors in genetic causation and evolution. The issues are of oracular depth, and Nei’s pronouncements sometimes of Delphic subtlety. He presents his case, and readers can debate the issues to determine where they might lead to a fundamentally improved understanding and where they are mainly semantic. This book provides a legacy of one of the major scientists of our age, and in it Nei has constructed the present on which the future of our understanding can be built.