Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation

Jakobson, C.; Aguilar-Rodriguez, J.; Jarosz, D. F.

doi:10.1101/2023.10.30.564848

Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.10.30.564848

Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation

Jakobson, C.·Aguilar-Rodriguez, J.·Jarosz, D. F.

View original source ↗Export metadata ↓

Abstract

The essential, stress-responsive protein chaperone Hsp90 impacts adaptation from microbes to humans. Yet the molecular mechanisms involved remain unclear and are often presumed to be driven by variation in opening reading frames. Here, we identify over 1,000 natural genotype-to-phenotype associations governed by Hsp90 at single-nucleotide resolution in Saccharomyces cerevisiae. Strikingly, cis-regulatory variants contributed to the chaperones effect on heredity more strongly than coding variation. Most of these mutations nonetheless impacted clients of Hsp90 or targets of its direct binding partners. The chaperones influence was especially potent on evolutionarily young genes, highlighting its influence on variation central to novelty. Synthetic reconstructions and genome editing revealed that Hsp90 may regulate the relationship between activity and phenotype for many dosage-sensitive genes. The unexpected role of the chaperone in buffering the effects of regulatory variants and releasing their consequences under stress suggests a mechanism for its widespread effects on evolution and development.

Explore related subjects

evolutionary biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Jakobson, C., Aguilar-Rodriguez, J., Jarosz, D. F.. 2023-11-02. Hsp90 shapes adaptation by controlling the fitness consequences of regulatory variation. https://doi.org/10.1101/2023.10.30.564848

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Isoform inflation and annotation heterogeneity can confound Kunitz-repertoire comparisons in blood-feeding animals: a gene-level reappraisal

Hematophagy has arisen independently many times across Metazoa, and recurrent anticoagulant protein families in blood-feeders are often read as convergent recruitment - the Kunitz/BPTI domain a paradigm case, with the leech an oft-cited low-Kunitz exception. We re-examine this at the gene level and ask whether a confirmatory cross-phylum test of this blood-feeding/anticoagulant association is feasible with public genomes. Applying an auditable gene-level protocol (one longest-isoform representative per gene; conservation-checked protein to gene mapping) to eight metazoan lineages, we find no consistent, universal elevation of whole-genome gene-level Kunitz-repertoire size in these blood-feeders (blood-feeder median 18 genes vs non-blood-feeder median 39; a descriptive comparison of non-independent taxa, not a formal test). Protein-entry counts inflate gene-level Kunitz counts by up to ~4.6x (mosquito 23 to 5), and neither this inflation nor proteome-wide isoform density (1.0-2.7x) tracks diet, so protein-entry comparisons are an unreliable basis for repertoire claims. Separately, deterministic bookkeeping under a fixed topology and a no-reversal rule counts 12 independent blood-feeding origins (11 if the ancestral lamprey is treated as parasitic with two losses); a non-exhaustive screen of annotated public genomes yielded only one candidate blood/non-blood pair (bedbug), and, under the pre-registered simulation scenario, only a cross-origin heterogeneity endpoint is attainable within a realistic origin ceiling, and only under strong heterogeneity (among-origin SD >= 3-4). An exploratory, feasibility-grade secretome-composition estimate did not meet the pre-registered criterion. We offer a gene-level, annotation-aware re-analysis, a caution about isoform/annotation bias in cross-phylum comparisons, and an account of what current data can and cannot support.

evolutionary biology↗

bioRxiv2026

Denisovan introgression left differential selection regimes in Humans and Neanderthals on the SLC30A9 gene

Signals of positive selection around the SLC30A9 gene have been reported in human populations outside Africa. Selection likely acted on a highly differentiated single-nucleotide polymorphism, rs1047626, leading to a non-synonymous substitution in the encoded zinc transporter. Because of the striking similarity between the putatively selected SLC30A9 haplotype observed in several current human populations and the Denisovan individual, previous work has proposed adaptive introgression. Yet alternative explanations, including ancient human variation, and the precise archaic source -Neanderthal or Denisovan- remained unresolved. Considering the potentially complex evolution of SLC30A9, we applied Approximate Bayesian Computation (ABC) algorithms coupled to machine learning to investigate the most plausible evolutionary origin of this substitution. After modelling different evolutionary scenarios with forward-in-time simulations, our results highlight that the most probable scenario is a Denisovan origin of the rs1047626 polymorphism. However, the allele likely introgressed into Neanderthals first and was then passed into non-African modern humans. Moreover, the derived allele frequency for rs1047626 across several African populations is consistent with back-to-Africa migrations. Finally, our ABC analyses indicate strong positive selection in East Asian populations and other out-of-Africa populations, whereas in Neanderthal populations, the selection coefficient was probably neutral or slightly deleterious.

evolutionary biology↗

bioRxiv2026

Distinct associative learning abilities for colour and odour in the flower-feeding Drosophila elegans and the fruit-feeding Drosophila melanogaster

Animal behaviour is both innately constrained and shaped by learning. This mosaic organization has evolved in response to species-specific ecological demands and may differ between sensory modalities. Flower-visiting animals are a particularly useful system for investigating the relationship between sensory ecology and learning because they rely on multiple floral cues, particularly odour and colour, to locate food sources. However, it remains largely unexplored whether specialization on floral resources entails divergence in learning abilities across sensory modalities. Drosophila elegans is a flower-feeding species that depends heavily on floral resources throughout its life; adults spend much of their time on flowers and larvae develop on fallen flower leaves. Here, we compared odour-reward and colour-reward associative learning between the flower-feeding D. elegans and the fruit-feeding D. melanogaster. We found that, under conditions of equilibrated motivation, odour- and colour-preference, and using the same sugar reward, D. elegans exhibited poorer odour-reward learning performance but better colour-reward learning performance than D. melanogaster. These results suggest that the modality-specific eligibility of sensory information to enter into associations, known as the 'Garcia-effect' in experimental psychology, can evolve oppositely between species. This highlights the relationship between ecological specialization and mnemonic processing, and shows that biological 'intelligence' is not general.

evolutionary biology↗