A mutação e o excepcionalismo humano: nossa futura carga genética

segunda-feira, março 07, 2016

Mutation and Human Exceptionalism: Our Future Genetic Load

Michael Lynch

GENETICS March 7, 2016 vol. 202 no. 3 869-875; DOI: 10.1534/genetics.115.180471

Although the human germline mutation rate is higher than that in any other well-studied species, the rate is not exceptional once the effective genome size and effective population size are taken into consideration. Human somatic mutation rates are substantially elevated above those in the germline, but this is also seen in other species. What is exceptional about humans is the recent detachment from the challenges of the natural environment and the ability to modify phenotypic traits in ways that mitigate the fitness effects of mutations, e.g., precision and personalized medicine. This results in a relaxation of selection against mildly deleterious mutations, including those magnifying the mutation rate itself. The long-term consequence of such effects is an expected genetic deterioration in the baseline human condition, potentially measurable on the timescale of a few generations in westernized societies, and because the brain is a particularly large mutational target, this is of particular concern. Ultimately, the price will have to be covered by further investment in various forms of medical intervention. Resolving the uncertainties of the magnitude and timescale of these effects will require the establishment of stable, standardized, multigenerational measurement procedures for various human traits.
MUTATION, the production of heritable changes in DNA, is one of the most fundamental concepts in genetics. Yet, a broad phylogenetic understanding of the rate and molecular spectrum of mutations and the mechanisms driving the evolution of these key parameters has only recently begun to emerge (Baer et al. 2007Lynch 20102011). Of special concern is the rate at which mutations are arising in our own lineage and their long-term consequences. In terms of cognitive abilities and proclivity for dominating the global ecosystem, humans are clearly exceptional. But how exceptional are we with respect to the genetic machinery that is the key to long-term genome stability and evolutionary flexibility? And in light of our unusual behavioral features, what are the long-term genetic consequences of being a modern human? Will the miracles of molecular biology and modern medicine reduce the incidence and/or effects of genetic afflictions to negligible levels, or might such applications have the opposite effect?
Two issues are of central relevance here. First, few other species willingly expose themselves to environmental mutagens to the extent that humans do. Presumably, there is some room for reducing the human mutation rate by minimizing negative environmental effects,e.g., through reductions in exposure to smoke from tobacco and other sources, harmful food additives, radon gas, UV irradiation, etc. What, however, is the lower bound to the achievable mutation rate at both the germline and somatic levels? And do factors that influence the somatic mutation rate also have germline effects and vice versa?
Second, owing to the remarkable advances in living conditions and medicine over the past century, and many more likely to come, humans uniquely modify the environment in ways that minimize the consequences of acquired genetic afflictions. Today’s ethical imperative for maximizing individual reproductive potential and longevity independent of genetic background raises significant questions about the future of the human gene pool. Specifically, what are the long-term consequences of the accumulation of mutations whose phenotypic consequences can be transiently minimized through medical intervention and/or a sheltering environment?
It is fitting to review both of these issues in the year 2016, as this would have been the 100th birthday of James Crow, who played a central role in the Genetics Society of America and had a long-standing interest in human mutation (Crow 1993199720002006). Many of the issues addressed below were raised by Crow prior to the genomics revolution and can now be evaluated in a more quantitative way.