Antagonistic pleiotropy and mutation accumulation influence human senescence and disease

Rodríguez, Juan Antonio; Marigorta, Urko M.; Hughes, David A.; Spataro, Nino; Bosch, Elena; Navarro, Arcadi

doi:10.1038/s41559-016-0055

Cited by 88 publications

(68 citation statements)

References 38 publications

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“…The antagonistic pleiotropy and mutation accumulation theories of ageing both involve mutations as the cause of senescence and are not mutually exclusive (e.g., Rodriguez et al. ). Recent studies did provide some support for the mutation accumulation (e.g., Durham et al.…”

Section: State‐of‐art Of Our Current Knowledge In Relation To the Ninmentioning

confidence: 99%

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The Williams' legacy: A critical reappraisal of his nine predictions about the evolution of senescence

2017

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Williams' evolutionary theory of senescence based on antagonistic pleiotropy has become a landmark in evolutionary biology, and more recently in biogerontology and evolutionary medicine. In his original article, Williams launched a set of nine "testable deductions" from his theory. Although some of these predictions have been repeatedly discussed, most have been overlooked and no systematic evaluation of the whole set of Williams' original predictions has been performed. For the sixtieth anniversary of the publication of the Williams' article, we provide an updated evaluation of all these predictions. We present the pros and cons of each prediction based on recent accumulation of both theoretical and empirical studies performed in the laboratory and in the wild. From our viewpoint, six predictions are mostly supported by our current knowledge at least under some conditions (although Williams' theory cannot thoroughly explain why for some of them). Three predictions, all involving the timing of senescence, are not supported. Our critical review of Williams' predictions highlights the importance of William's contribution and clearly demonstrates that, 60 years after its publication, his article does not show any sign of senescence.

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Section: State‐of‐art Of Our Current Knowledge In Relation To the Ninmentioning

confidence: 99%

“…2014 on Drosophila and Rodriguez et al. on humans based on genome‐wide analyses, see Flatt and Schmidt and Arbuthnott et al. for a broader discussion) and the antagonistic pleiotropy (as reviewed below).…”

Section: State‐of‐art Of Our Current Knowledge In Relation To the Ninmentioning

confidence: 99%

The Williams' legacy: A critical reappraisal of his nine predictions about the evolution of senescence

2017

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“…The MA hypothesis predicts that burden of slightly deleterious germline substitutions will increase with age due to the declining force of negative selection 3 . Our approach differs from earlier attempts to test this hypothesis [6][7][8][9][10][11]13,14 in two respects. First, instead of relying on intra-species variation to estimate mutational load, we used inter-species divergence, which may be statistically more powerful as it involves a larger number of substitutions.…”

Section: Discussionmentioning

confidence: 98%

“…In an indirect test of the expectation for inbreeding depression, outbreeding was reported to reduce age-related increase in mortality in hermaphroditic snails 13 , again in line with MA. Finally, Rodríguez et al 14 studied >2,500 human genetic variants linked to 120 genetic diseases and reported that variants associated with late-onset disease segregate at higher frequencies than those associated with early-onset disease, a third prediction under MA 14 .…”

Section: Introductionmentioning

confidence: 99%

Mutation accumulation differentially impacts ageing in mammalian tissues

Turan¹,

Parvizi²,

Dönertaş

et al. 2018

Preprint

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Medawar's mutation accumulation (MA) hypothesis explains ageing by the declining force of natural selection with age: slightly deleterious germline mutations that are functional in old age are not effectively eliminated by selection and therefore lead to ageing-related phenotypes. Although widely cited, empirical support for the MA hypothesis, particularly molecular evidence, has remained limited. Here we test one of its predictions, that genes relatively highly expressed in old adults vs. young adults should be under weaker purifying selection than those relatively highly expressed in young adults. To do so, we combine 23 RNA-sequencing and 35 microarray gene expression datasets (including 9 tissues from 5 mammalian species) with protein and regulatory sequence conservation estimates across mammals. We identify age-related decrease in transcriptome conservation (ADICT) in four tissues, brain, liver, lung, and artery, but not in other tissues, most notably muscle and heart. ADICT is driven both by decreased expression of highly conserved genes and up-regulation of poorly conserved genes during ageing, in line with the MA hypothesis. Lowly conserved and up-regulated genes in ADICT-associated tissues have overlapping functional properties, particularly involving apoptosis and inflammation, with no evidence for a history of positive selection. Our results suggest that tissues vary in how evolution has shaped their ageing patterns. We find that in some tissues, genes up-regulated during ageing, possibly in response to accumulating cellular and histological damage, are under weaker purifying selection than other genes. We propose that accumulation of slightly deleterious substitutions in these genes may underlie their suboptimal regulation and activity during ageing, shaping senescent phenotypes such as inflammaging.

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“…Considering that, several evolutionary theories of aging have been proposed and demonstrated to some extent, e.g. mutation accumulation (MA) and antagonistic pleiotropy (AP) 50 , 51 . Theoretical and experimental models for MA further support inbreeding effects for late-onset diseases 52 , 53 .…”

Section: Discussionmentioning

confidence: 99%

Autosomal Recessive Alzheimer’s disease (arAD): homozygosity mapping of genomic regions containing arAD loci

Moreno‐Grau

Fernández

Rojas

et al. 2020

Preprint

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Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of recent inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD). However, the search for recessive variants has been poorly assessed to date. To investigate homozygosity in AD, we performed a fine-scale ROH analysis including 21,100 individuals from 10 cohorts of European ancestry (11,919 AD cases and 9,181 controls). We detected an increase of homozygosity in AD cases compared to controls [β FROH (CI95%) = 0.051 (0.023 -0.078); P = 3.25 x 10 -4 ]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 x 10 -16 ). The top associated ROH with AD risk (β (CI95%) = 1.09 (0.48 -1.48), p value = 9.03x 10 -4 ) was detected upstream the HS3ST1 locus (chr4: 11,189,305,456), previously related to AD. Next, to construct a homozygosity map of AD cases, we selected ROHs shared by inbred AD cases extracted from an outbred population. We used whole-exome sequencing data from 1,449 individuals from the Knight-ADRC-NIA-LOAD (KANL) cohort to identify potential recessive variants in candidate ROHs. We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

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Antagonistic pleiotropy and mutation accumulation influence human senescence and disease

Cited by 88 publications

References 38 publications

The Williams' legacy: A critical reappraisal of his nine predictions about the evolution of senescence

The Williams' legacy: A critical reappraisal of his nine predictions about the evolution of senescence

Mutation accumulation differentially impacts ageing in mammalian tissues

Autosomal Recessive Alzheimer’s disease (arAD): homozygosity mapping of genomic regions containing arAD loci

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