Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles

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.

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression

“…This phenomenon has previously been hypothesized to maintain genetic risk variants in the population. 25,28 We note several limitations to our study: many GWASs and eQTL studies are underpowered to detect most traitassociated loci at current sample sizes, and the selection of eQTL tissues could have been even broader in terms of tissues and developmental time points. These factors will most likely improve in the future, but we remark that they will have affected which genes were identified to show association with the individual traits and, similarly, which genes were found to show associations with multiple traits.…”

“…25 For instance, mutations leading to decreased function of CFTR are associated with both cystic fibrosis and azoospermia. 26 We term this an example of agonistic pleiotropy because the effects of decreased gene function in both traits are detrimental.…”

“…In other cases, the effect can be antagonistic: a change in function might be beneficial to one trait and detrimental to another. 25 With this in mind and to illustrate how our data can be used to elucidate the biology of various traits, we explored shared associations in three different approaches: (1) exploring which gene associations were shared between related and unrelated traits, (2) analyzing correlations of changes in expression between traits, and (3) evaluating instances of genes associated with many traits.…”

Pleiotropic Effects of Lipid Genes on Plasma Glucose, HbA1c, and HOMA-IR Levels

“…The positive metabolic relationship but opposite genetic effect may explain the low power seen in studies trying to detect the genetic association of lipid loci with glucose traits. Further studies investigating the potential evolutionary implications (37,38) and underlying functional mechanisms using a system-based approach are warranted. …”

Fibrosis: ultimate and proximate causes

“…The concept of antagonistic pleiotropy was proposed by Williams in 1957 to explain senescence and aging (40); however, this concept may even more aptly apply to a number of complex, age-related diseases (41,42). If a particular gene mediates beneficial effects in early life but exerts detrimental effects after reproductive age, there will be evolutionary pressure to conserve that gene despite its potential disease-causing effects with aging.…”