Burke, M. K. | Search bioRxiv

bioRxiv2025

Age-specific genomic and transcriptomic variation reveals limited evidence for cis-regulatory interactions modulating aging in Saccharomyces cerevisiae

AO_SCPLOWBSTRACTC_SCPLOWThe budding yeast Saccharomyces cerevisiae is a well-established model for studying the genetic basis of complex traits, and it is a powerful system for investigating mechanisms of aging. Here, we examine the genomic and transcriptomic factors contributing to increased replicative age in recombinant yeast populations harboring standing genetic variation. Using Fluorescence-Activated Cell Sorting (FACS), we isolated young and aged cohort pairs across twelve biological replicates and sequenced their progeny to assess patterns of differentiation at the nucleotide and transcription levels. Most differentiated alleles were located in coding regions, including significant variants within 132 unique genes. Transcriptomic analysis revealed 60 differentially expressed genes in aged populations, including 18 genes with increased expression in aged cohorts, and 42 genes with decreased expression. Although only two genes (RFA3 and WSC4) were implicated in both genomic and transcriptomic analyses, functional overlap associated with protein homeostasis, DNA repair, and cell cycle regulation was evident across datasets. Notably, we found no strong evidence that differentially expressed genes were more likely to occur in close proximity to significant gene variants. This suggests that late-life survival is not predominantly governed by local cis-regulatory interactions (e.g. variants within or near coding regions). These findings underscore the power of integrating genomic and transcriptomic data to elucidate the genetics of complex traits such as aging, demonstrating how multi-omics approaches can reveal functional relationships that may be overlooked by single-layer analyses. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWWhile many individual genes contributing to aging and lifespan have been identified, our understanding of the polygenic interactions and regulatory processes that contribute to phenotypic variation in these traits is much more limited. Using a recombinant population of yeast, we identify novel links between genetic variation and the phenotype of replicative age. Additionally, we find little evidence for local cis-regulatory interactions, suggesting that downstream regulation or trans-regulatory processes may serve more dominant roles in modulating aging. These results reveal new insights into the role of polygenicity in the evolution and regulation of age-associated phenotypes.

genomics↗

bioRxiv2022

Strength of selection potentiates distinct adaptive responses in an evolution experiment with outcrossing yeast

Experimental evolution studies with sexually-reproducing populations consistently find that adaptation is highly polygenic and fueled by standing genetic variation. However, studies vary substantially with respect to other evolutionary dynamics. Resolving these discrepancies is a crucial next step as we move toward extrapolating findings from laboratory systems to natural populations. Differences in experimental parameters between studies can perhaps answer these questions, and here we assess how one such parameter - selection intensity - influences outcomes. We subject populations of outcrossing Saccharomyces cerevisiae to zero, moderate, and high ethanol stress for [~]200 generations and ask: 1) does stronger selection lead to greater changes in allele frequencies at adaptive sites; and 2) do targets of selection vary with intensity? With respects to sites with large effects, we find some evidence for positive correlations between selection intensity and allele frequency change. While we observe shared genomic responses across treatments, we also identify treatment-specific responses. Combined with evidence of phenotypic trade-offs between treatments, our findings support the hypothesis that selection intensity influences evolutionary outcomes due to pleiotropic and epistatic interactions. We conclude that it should be a major consideration when attempting to generalize inferences across studies; in other words, we argue that different intensities of selection effectively create distinct environments and genotype-by-environment interactions. Lastly, our results demonstrate the importance of clearly-defined controls in experimental evolution. Despite working with a presumably lab-adapted model system, without this element we would not have been able to distinguish genomic responses to ethanol stress from those associated with laboratory conditions.

evolutionary biology↗