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The genomic landscape and evolutionary resolution of antagonistic pleiotropy in yeast.

ABSTRACT: Antagonistic pleiotropy (AP), or genetic tradeoff, is an important concept that is frequently invoked in theories of aging, cancer, genetic disease, and other common phenomena. However, the prevalence of AP, which genes are subject to AP, and to what extent and how AP may be resolved remain unclear. By measuring the fitness difference between the wild-type and null alleles of ~5,000 nonessential genes in yeast, we found that in any given environment, yeast expresses hundreds of genes that harm rather than benefit the organism, demonstrating widespread AP. Nonetheless, under sufficient selection, AP is often resolvable through regulatory evolution, primarily by trans-acting changes, although in one case we also detected a cis-acting change and localized its causal mutation. However, AP is resolved more slowly in smaller populations, predicting more unresolved AP in multicellular organisms than in yeast. These findings provide an empirical foundation for AP-dependent theories and have broad biomedical and evolutionary implications.

SUBMITTER: Qian W

PROVIDER: S-EPMC3513580 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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The genomic landscape and evolutionary resolution of antagonistic pleiotropy in yeast.

Qian Wenfeng W Ma Di D Xiao Che C Wang Zhi Z Zhang Jianzhi J

Cell reports 20121025 5

Antagonistic pleiotropy (AP), or genetic tradeoff, is an important concept that is frequently invoked in theories of aging, cancer, genetic disease, and other common phenomena. However, the prevalence of AP, which genes are subject to AP, and to what extent and how AP may be resolved remain unclear. By measuring the fitness difference between the wild-type and null alleles of ~5,000 nonessential genes in yeast, we found that in any given environment, yeast expresses hundreds of genes that harm r ...[more]

PMID: 23103169

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Project description:Lewy body diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as ?-synuclein (?S) and amyloid-? (A?) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.

Project description:Queens of eusocial species live extraordinarily long compared to their workers. So far, it has been argued that these lifespan divergences are readily explained by the classical evolutionary theory of ageing. As workers predominantly perform risky tasks, such as foraging and nest defense, and queens stay in the well-protected nests, selection against harmful genetic mutations expressed in old age should be weaker in workers than in queens due to caste differences in extrinsic mortality risk, and thus, lead to the evolution of longer queen and shorter worker lifespans. However, these arguments have not been supported by formal models. Here, we present a model for the evolution of caste-specific ageing in social insects, based on Williams' antagonistic pleiotropy theory of ageing. In individual-based simulations, we assume that mutations with antagonistic fitness effects can act within castes, that is, mutations in early life are accompanied by an antagonistic effect acting in later life, or between castes, where antagonistic effects emerge due to caste antagonism or indirect genetic effects between castes. In monogynous social insect species with sterile workers, large lifespan divergences between castes evolved under all different scenarios of antagonistic effects, but regardless of the degree of caste-specific extrinsic mortality. Mutations with antagonistic fitness effects within castes reduced lifespans of both castes, while mutations with between-caste antagonistic effects decreased worker lifespans more than queen lifespans, and consequently increased lifespan divergences. Our results challenge the central explanatory role of extrinsic mortality for caste-specific ageing in eusocial organisms and suggest that antagonistic pleiotropy affects castes differently due to reproductive monopolization by queens, hence, reproductive division of labor. Finally, these findings provide new insights into the evolution of tissue-specific ageing in multicellular organisms in general.

Dataset Information

The genomic landscape and evolutionary resolution of antagonistic pleiotropy in yeast.

Publications

The genomic landscape and evolutionary resolution of antagonistic pleiotropy in yeast.

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