rDNA array length is a major determinant of replicative lifespan in budding yeast

Hotz, Manuel; Thayer, Nathaniel H.; Hendrickson, David G.; Schinski, Elizabeth L.; Xu, Jun; Gottschling, Daniel E.

doi:10.1073/pnas.2119593119

Cited by 29 publications

(25 citation statements)

References 57 publications

(116 reference statements)

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“…Our results show that the bottleneck effect is very mild because it delays by less than 1 the number of generations required to obtain the final 220 repeat number (Model A3, Fig 2B and 2C ). Then we analyzed the effect of limiting the number of replications that a mother yeast cell can make because the aging of the mother limits the number of allowed generations [ 15 , 32 ]. We found that no changes in predictions happen when this feature is taken into account (not shown).…”

Section: Resultsmentioning

confidence: 99%

“…The appearance of this kind of autoregulated circuits has obviously been driven by natural selection, but not to necessarily allow deterministic evolution. Such a circuit has most likely evolved because it allows the efficient regulation of physiological responses, such as the adaptation of the rDNA copy number to the yeast cell volume for optimal RNA pol I transcription and genome integrity [13][14][15][16]. The circuit can, however, be activated by unusual circumstances (e.g.…”

Section: Plos Onementioning

confidence: 99%

“…Its variation may contribute to the disease risk in several cancers and mental disorders [13]. In S. cerevisiae, the rDNA cluster varies between 40 and 350 copies, and is very dynamically rearranged [14,15]. In a previous study, we found that the rDNA repeat number evolves from 125 to about 220-250 copies along 160-180 generations in a freshly made ("early") cln3 yeast mutant [16].…”

Section: Introductionmentioning

confidence: 99%

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A feedback mechanism controls rDNA copy number evolution in yeast independently of natural selection

et al. 2022

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Ribosomal DNA (rDNA) is the genetic loci that encodes rRNA in eukaryotes. It is typically arranged as tandem repeats that vary in copy number within the same species. We have recently shown that rDNA repeats copy number in the yeast Saccharomyces cerevisiae is controlled by cell volume via a feedback circuit that senses cell volume by means of the concentration of the free upstream activator factor (UAF). The UAF strongly binds the rDNA gene promoter, but is also able to repress SIR2 deacetylase gene transcription that, in turn, represses rDNA amplification. In this way, the cells with a smaller DNA copy number than what is optimal evolve to increase that copy number until they reach a number that sequestrates free UAF and provokes SIR2 derepression that, in turn, blocks rDNA amplification. Here we propose a mathematical model to show that this evolutionary process can amplify rDNA repeats independently of the selective advantage of yeast cells having bigger or smaller rDNA copy numbers. We test several variants of this process and show that it can explain the observed experimental results independently of natural selection. These results predict that an autoregulated feedback circuit may, in some instances, drive to non Darwinian deterministic evolution for a limited time period.

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Section: Resultsmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A feedback mechanism controls rDNA copy number evolution in yeast independently of natural selection

et al. 2022

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“…Therefore, the link between mitochondrial dysfunction and senescence is supported across studies, but nucleolar changes are more variable across experimental systems and the importance and timing of rDNA instability remains to be clarified. A major contributor to these differences may be variation in rDNA copy number between strains, which changes during routine yeast transformation and influences both lifespan and rDNA recombination rate (Hotz et al, 2022; Kwan et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Dietary change without caloric restriction maintains a youthful profile in ageing yeast

Horkai

Houseley

2022

Preprint

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Caloric restriction increases lifespan and improves ageing health, but it is unknown whether these outcomes can be separated or achieved through less severe interventions. Here we show that an unrestricted galactose diet in early life minimises change during replicative ageing in budding yeast, irrespective of diet later in life. Lifespan and average mother cell division rate are comparable between glucose and galactose diets, but markers of senescence and the progressive dysregulation of gene expression observed on glucose are minimal on galactose, showing these to be associated rather than intrinsic aspects of the replicative ageing process. Respiration on galactose is critical for minimising hallmarks of ageing, and forced respiration during ageing on glucose by over-expression of the mitochondrial biogenesis factor Hap4 also has the same effect though only in a fraction of cells. This fraction maintains Hap4 activity to advanced age with low senescence and a youthful gene expression profile, whereas other cells in the same population lose Hap4 activity, undergo dramatic dysregulation of gene expression and accumulate fragments of chromosome XII (ChrXIIr), which are tightly associated with senescence. Our findings support the existence of two separable ageing trajectories in yeast. We propose that a complete shift to the healthy ageing mode can be achieved in wild-type cells through dietary change in early life without restriction.

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“…1a). Most eukaryotic genomes harbor dozens or hundreds of rDNA copies arranged in one or multiple loci 5 , and it is well established that rDNA copy numbers vary widely even among individuals of a single species, contributing to phenotypic diversity [6][7][8][9][10] . By contrast, but how much rDNA sequences vary within a genome remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Deep selection shapes the intragenomic diversity of rRNA genes

Sultanov

Hochwagen

2022

Preprint

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Ribosome biogenesis in eukaryotes is supported by hundreds of ribosomal RNA (rRNA) gene copies that are encoded in the ribosomal DNA (rDNA) and are thought to undergo frequent sequence homogenization by concerted evolution. Here, we present species-wide rDNA sequence analysis in Saccharomyces cerevisiae that challenges this model of evolution. We show that rDNA copies in yeast are far from homogeneous, both among and within isolates, and that rapid sequence homogenization is unlikely because many variants avoided fixation or elimination over evolutionary time. Instead, the diversity landscape across the rDNA shows clear functional stratification, suggesting that different copy-number thresholds for selection shape rDNA diversity. Notably, variants in the most highly conserved rDNA elements are sufficiently deleterious to exhibit signatures of purifying selection even when present in only 1% of rRNA gene copies. Our results portray a complex selection landscape that shapes rDNA diversity within a single species and reveal unexpectedly deep purifying selection of multi-copy genes.

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rDNA array length is a major determinant of replicative lifespan in budding yeast

Cited by 29 publications

References 57 publications

A feedback mechanism controls rDNA copy number evolution in yeast independently of natural selection

A feedback mechanism controls rDNA copy number evolution in yeast independently of natural selection

Dietary change without caloric restriction maintains a youthful profile in ageing yeast

Deep selection shapes the intragenomic diversity of rRNA genes

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