Abstract
BackgroundMany serious diseases have a genetic basis which, from an evolutionary point of view, should have been selected against, resulting in very low frequencies. The remarkable sustained prevalence of a number of disease-associated alleles is therefore surprising. We believe that antagonistic pleiotropy, when multiple effects of a gene have opposing effects on fitness (e.g., sickle cell disease), may be more widespread than typically considered. We hypothesize that, rather than being an exception to the rule of genetic disorders, antagonistic pleiotropy may be common.MethodsWe surveyed the medical literature in order to determine whether sufficient evidence exists to reassess the nature of antagonistic pleiotropy; from being considered an unusual scenario to one that is anticipated. We also used a simple population genetic model to examine the feasibility of antagonistic pleiotropy to act as a mechanism to maintain polymorphism for serious genetic disorders even if the benefits are subtle.ResultsWe identified a number of examples of antagonistic pleiotropy where the deleterious effect, the beneficial effect, and the exact molecular cause have been demonstrated. We also identified putative cases in which there is circumstantial evidence or a strong reason to expect antagonistic pleiotropy in a genetic disorder. The population genetic model demonstrates that alleles with severe deleterious health effects can be maintained at medically relevant frequencies with only minor beneficial pleiotropic effects.ConclusionWe believe that our identification of several cases of antagonistic pleiotropy, despite the lack of research on this question and the varied natures of the types of these disorders, speaks to both the underappreciated nature of this phenomenon and its potentially fundamental importance. If antagonistic pleiotropy is as common as our research suggests, this may explain why so many serious diseases, even apparently environmentally caused ones, have a genetic component. Furthermore, acceptance of a genome full of antagonistically pleiotropic genetic interactions poses important implications for clinical treatment and disease prevention research, especially genetically based therapies.
Highlights
Many serious diseases have a genetic basis which, from an evolutionary point of view, should have been selected against, resulting in very low frequencies
Genetic drift and mutation selection balance can explain the presence of segregating allelic variation for deleterious traits, many genetic disorders are present at frequencies higher than we would expect from a historical process by which mutations arise and are eliminated by selection over time
Huntington’s disease and Increased Fecundity Huntington’s disease (HD) is a rare, autosomal dominant neurodegenerative disorder in which symptoms typically manifest at an age that is post-reproductive, in the range of 30-45 years of age [12]
Summary
Many serious diseases have a genetic basis which, from an evolutionary point of view, should have been selected against, resulting in very low frequencies. A simple thought experiment where we consider that the human genome has approximately 23,000 genes (with multiple genes involved in the formation of each aspect of our phenotype) encoding a phenotype with more than 23,000 aspects demonstrates that many genes must have multiple functions This being the case, allelic variants that arise due to mutation may change the performances of that gene’s functions differently such that sometimes these changes result in opposing effects on fitness - i.e., some mutations can improve the performance of one aspect of a gene’s function while simultaneously making another worse. Consideration of the implications of such antagonistically pleiotropic effects has largely been the purview of studies of senescence
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