Comprehensive fitness maps of Hsp90 show widespread environmental dependence
Abstract
Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard conditions and under five stress conditions. To our knowledge these are the largest determined comprehensive fitness maps of point mutants. The growth of many variants differed between conditions, indicating that environment can have a large impact on Hsp90 evolution. Multiple variants provided growth advantages under individual conditions, however these variants tended to exhibit growth defects in other environments. The diversity of Hsp90 sequences observed in extant eukaryotes preferentially contains variants that supported robust growth under all tested conditions. Rather than favoring substitutions in individual conditions, the long-term selective pressure on Hsp90 may have been that of fluctuating environments, leading to robustness under a variety of conditions.
Data availability
Next generation sequencing data has been deposited to the NCBI short read archive (Project # PRJNA593726). Tabulated raw counts of all variants in all conditions are included in the manuscript in Figure 1 - source data 1 and Figure 2 - source data 2. Source data files have been provided for Figure 1, 2, 3, 4, 5 and 6.
-
Comprehensive fitness maps of Hsp90 show widespread environmental dependenceNCBI Short Read Archive, PRJNA593726.
Article and author information
Author details
Funding
National Institutes of Health (R01-GM112844)
- Julia M Flynn
- Ammeret Rossouw
- Pamela Cote-Hammarlof
- David Mavor
- Carl Hollins
- Daniel NA Bolon
National Institutes of Health (F32-GM119205)
- Julia M Flynn
Fundação para a Ciência e a Tecnologia (JPIAMR/0001/2016)
- Inês Fragata
EMBO Installation Grant (IG4152)
- Claudia Bank
ERC Starting Grant (804569-FIT2GO)
- Claudia Bank
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Flynn et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,148
- views
-
- 363
- downloads
-
- 58
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Evolutionary Biology
- Immunology and Inflammation
The incessant arms race between viruses and hosts has led to numerous evolutionary innovations that shape life’s evolution. During this process, the interactions between viral receptors and viruses have garnered significant interest since viral receptors are cell surface proteins exploited by viruses to initiate infection. Our study sheds light on the arms race between the MDA5 receptor and 5’ppp-RNA virus in a lower vertebrate fish, Miichthys miiuy. Firstly, the frequent and independent loss events of RIG-I in vertebrates prompted us to search for alternative immune substitutes, with homology-dependent genetic compensation response (HDGCR) being the main pathway. Our further analysis suggested that MDA5 of M. miiuy and Gallus gallus, the homolog of RIG-I, can replace RIG-I in recognizing 5’ppp-RNA virus, which may lead to redundancy of RIG-I and loss from the species genome during evolution. Secondly, as an adversarial strategy, 5’ppp-RNA SCRV can utilize the m6A methylation mechanism to degrade MDA5 and weaken its antiviral immune ability, thus promoting its own replication and immune evasion. In summary, our study provides a snapshot into the interaction and coevolution between vertebrate and virus, offering valuable perspectives on the ecological and evolutionary factors that contribute to the diversity of the immune system.
-
- Evolutionary Biology
- Neuroscience
The cerebral cortex displays a bewildering diversity of shapes and sizes across and within species. Despite this diversity, we present a universal multi-scale description of primate cortices. We show that all cortical shapes can be described as a set of nested folds of different sizes. As neighbouring folds are gradually merged, the cortices of 11 primate species follow a common scale-free morphometric trajectory, that also overlaps with over 70 other mammalian species. Our results indicate that all cerebral cortices are approximations of the same archetypal fractal shape with a fractal dimension of df = 2.5. Importantly, this new understanding enables a more precise quantification of brain morphology as a function of scale. To demonstrate the importance of this new understanding, we show a scale-dependent effect of ageing on brain morphology. We observe a more than fourfold increase in effect size (from two standard deviations to eight standard deviations) at a spatial scale of approximately 2 mm compared to standard morphological analyses. Our new understanding may, therefore, generate superior biomarkers for a range of conditions in the future.