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1.
Wang GZ  Liu J  Wang W  Zhang HY  Lercher MJ 《PloS one》2011,6(3):e17650

Background

Many single-gene knockouts result in increased phenotypic (e.g., morphological) variability among the mutant''s offspring. This has been interpreted as an intrinsic ability of genes to buffer genetic and environmental variation. A phenotypic capacitor is a gene that appears to mask phenotypic variation: when knocked out, the offspring shows more variability than the wild type. Theory predicts that this phenotypic potential should be correlated with a gene''s knockout fitness and its number of negative genetic interactions. Based on experimentally measured phenotypic capacity, it was suggested that knockout fitness was unimportant, but that phenotypic capacitors tend to be hubs in genetic and physical interaction networks.

Methodology/Principal Findings

We re-analyse the available experimental data in a combined model, which includes knockout fitness and network parameters as well as expression level and protein length as predictors of phenotypic potential. Contrary to previous conclusions, we find that the strongest predictor is in fact haploid knockout fitness (responsible for 9% of the variation in phenotypic potential), with an additional contribution from the genetic interaction network (5%); once these two factors are taken into account, protein-protein interactions do not make any additional contribution to the variation in phenotypic potential.

Conclusions/Significance

We conclude that phenotypic potential is not a mysterious “emergent” property of cellular networks. Instead, it is very simply determined by the overall fitness reduction of the organism (which in its compromised state can no longer compensate for multiple factors that contribute to phenotypic variation), and by the number (and presumably nature) of genetic interactions of the knocked-out gene. In this light, Hsp90, the prototypical phenotypic capacitor, may not be representative: typical phenotypic capacitors are not direct “buffers” of variation, but are simply genes encoding central cellular functions.  相似文献   

2.
The heat shock protein Hsp90 has been the focus of many studies since it was suggested that it acts to mediate the buffering of phenotypic variation. Hsp90-mediated buffering may result in the accumulation of cryptic genetic variation that, when released either as a consequence of environmental or genetic stress, increases the evolvability of a population. Recent studies using laboratory-induced mutations of Hsp90 and/or chemical inhibition to disrupt Hsp90 function confirm that Hsp90 can buffer cryptic genetic variation. We have previously identified a naturally occurring variant in the charged linker region of the Hsp90 gene, and now examine whether this variant is associated with altered levels of trait variability. The variant is associated with the release of cryptic genetic variation for canalized morphological (bristle) traits, but not for uncanalized morphological (wing and bristle) traits, and the effect on canalized traits depends on culture temperature. This suggests that natural genetic variation in Hsp90 may mediate the evolution of canalized morphological traits even if it does not influence the expression of variation for uncanalized traits.  相似文献   

3.
Genetic capacitors moderate expression of heritable variation and provide a novel mechanism for rapid evolution. The prototypic genetic capacitor, Hsp90, interfaces stress responses, developmental networks, trait thresholds and expression of wide-ranging morphological changes in Drosophila and other organisms. The Hsp90 capacitor hypothesis, that stress-sensitive storage and release of genetic variation through Hsp90 facilitates adaptive evolution in unpredictable environments, has been challenged by the belief that Hsp90-buffered variation is unconditionally deleterious. Here we review recent results supporting the Hsp90 capacitor hypothesis, highlighting the heritability, selectability, and potential evolvability of Hsp90-buffered traits. Despite a surprising bias toward morphological novelty and typically invariable quantitative traits, Hsp90-buffered changes are remarkably modular, and can be selected to high frequency independent of the expected negative side-effects or obvious correlated changes in other, unselected traits. Recent dissection of cryptic signal transduction variation involved in one Hsp90-buffered trait reveals potentially dozens of normally silent polymorphisms embedded in cell cycle, differentiation and growth control networks. Reduced function of Hsp90 substrates during environmental stress would destabilize robust developmental processes, relieve developmental constraints and plausibly enables genetic network remodeling by abundant cryptic alleles. We speculate that morphological transitions controlled by Hsp90 may fuel the incredible evolutionary lability of metazoan life-cycles.  相似文献   

4.
ABSTRACT

Genetic capacitors moderate expression of heritable variation and provide a novel mechanism for rapid evolution. The prototypic genetic capacitor, Hsp90, interfaces stress responses, developmental networks, trait thresholds and expression of wide-ranging morphological changes in Drosophila and other organisms. The Hsp90 capacitor hypothesis, that stress-sensitive storage and release of genetic variation through Hsp90 facilitates adaptive evolution in unpredictable environments, has been challenged by the belief that Hsp90-buffered variation is unconditionally deleterious. Here we review recent results supporting the Hsp90 capacitor hypothesis, highlighting the heritability, selectability, and potential evolvability of Hsp90-buffered traits. Despite a surprising bias toward morphological novelty and typically invariable quantitative traits, Hsp90-buffered changes are remarkably modular, and can be selected to high frequency independent of the expected negative side-effects or obvious correlated changes in other, unselected traits. Recent dissection of cryptic signal transduction variation involved in one Hsp90-buffered trait reveals potentially dozens of normally silent polymorphisms embedded in cell cycle, differentiation and growth control networks. Reduced function of Hsp90 substrates during environmental stress would destabilize robust developmental processes, relieve developmental constraints and plausibly enables genetic network remodeling by abundant cryptic alleles. We speculate that morphological transitions controlled by Hsp90 may fuel the incredible evolutionary lability of metazoan life-cycles.  相似文献   

5.
The protein-folding chaperone Hsp90 has been proposed to buffer the phenotypic effects of mutations. The potential for Hsp90 and other putative buffers to increase robustness to mutation has had major impact on disease models, quantitative genetics, and evolutionary theory. But Hsp90 sometimes contradicts expectations for a buffer by potentiating rapid phenotypic changes that would otherwise not occur. Here, we quantify Hsp90’s ability to buffer or potentiate (i.e., diminish or enhance) the effects of genetic variation on single-cell morphological features in budding yeast. We corroborate reports that Hsp90 tends to buffer the effects of standing genetic variation in natural populations. However, we demonstrate that Hsp90 tends to have the opposite effect on genetic variation that has experienced reduced selection pressure. Specifically, Hsp90 tends to enhance, rather than diminish, the effects of spontaneous mutations and recombinations. This result implies that Hsp90 does not make phenotypes more robust to the effects of genetic perturbation. Instead, natural selection preferentially allows buffered alleles to persist and thereby creates the false impression that Hsp90 confers greater robustness.  相似文献   

6.
Cryptic genetic variation (CGV) is defined as the genetic variation that has little effect on phenotypic variation under a normal condition, but contributes to heritable variation under environmental or genetic perturbations. Genetic buffering systems that suppress the expression of CGV and store it in a population are called genetic capacitors, and the opposite systems are called genetic potentiators. One of the best‐known candidates for a genetic capacitor and potentiator is the molecular chaperone protein, HSP90, and one of its characteristics is that it affects the genetic variation in various morphological traits. However, it remains unclear whether the wide‐ranging effects of HSP90 on a broad range of traits are a general feature of genetic capacitors and potentiators. In the current study, I searched for novel genetic capacitors and potentiators for quantitative bristle traits of Drosophila melanogaster and then investigated the trait specificity of their genetic buffering effect. Three bristle traits of D. melanogaster were used as the target traits, and the genomic regions with genetic buffering effects were screened using the 61 genomic deficiencies examined previously for genetic buffering effects in wing shape. As a result, four and six deficiencies with significant effects on increasing and decreasing the broad‐sense heritability of the bristle traits were identified, respectively. Of the 18 deficiencies with significant effects detected in the current study and/or by the previous study, 14 showed trait‐specific effects, and four affected the genetic buffering of both bristle traits and wing shape. This suggests that most genetic capacitors and potentiators exert trait‐specific effects, but that general capacitors and potentiators with effects on multiple traits also exist.  相似文献   

7.
Evolutionary change, whether in populations of organisms or malignant tumor cells, is contingent on the availability of inherited variation for natural selection to act upon. It is becoming clear that the Hsp90 chaperone, which normally functions to buffer client proteins against the effects of genetic variation, plays a central role in this process. Severe environmental stress can overwhelm the chaperone's buffering capacity, causing previously cryptic genetic variation to be expressed. Recent studies now indicate that in addition to exposing existing variation, Hsp90 can induce novel epigenetic and genetic changes. We discuss key findings that suggest a rich set of pathways by which Hsp90 can mediate the influences of the environment on the genome.  相似文献   

8.

Background

In the laboratory, the Drosophila melanogaster heat shock protein Hsp90 can buffer the phenotypic effects of genetic variation. Laboratory experiments either manipulate Hsp90 activity pharmacologically, or they induce mutations with strong effects in the gene Hsp83, the single-copy fly gene encoding Hsp90. It is unknown whether observations from such laboratory experiments are relevant in the wild.

Results

We here study naturally occurring mutations in Hsp83, and their effects on fitness and phenotypic buffering in flies derived from wild populations. We examined more than 4500 flies from 42 Drosophila populations distributed world-wide for insertions or deletions of mobile DNA in or near the Hsp83 gene. The insertions we observed occur at low population frequencies, and reduce Hsp83 gene expression. In competition experiments, mutant flies performed much more poorly than wild-type flies. Mutant flies were also significantly less fecund and shorter-lived than wild-type flies, as well as less well buffered against cryptic deleterious variation, as we show through inbreeding experiments. Specifically, in Hsp83 mutant flies female fecundity dropped to much lower levels after inbreeding than in wild-type flies. At even slightly elevated temperatures, inbred mutant Hsp83 populations went extinct, whereas inbred wild-type populations persisted.

Conclusions

Our work shows that Hsp90, a regulator of the stress response and of signaling, helps buffer deleterious variation in fruit flies derived from wild population, and that its buffering role becomes even more important under heat stress.  相似文献   

9.
The molecular chaperone protein Hsp90 has been widely discussed as a candidate gene for developmental buffering. We used the methods of geometric morphometrics to analyze its effects on the variation among individuals and fluctuating asymmetry of wing shape in Drosophila melanogaster. Three different experimental approaches were used to reduce Hsp90 activity. In the first experiment, developing larvae were reared in food containing a specific inhibitor of Hsp90, geldanamycin, but neither individual variation nor fluctuating asymmetry was altered. Two further experiments generated lines of genetically identical flies carrying mutations of Hsp83, the gene encoding the Hsp90 protein, in heterozygous condition in nine different genetic backgrounds. The first of these, introducing entire chromosomes carrying either of two Hsp83 mutations, did not increase shape variation or asymmetry over a wild-type control in any of the nine genetic backgrounds. In contrast, the third experiment, in which one of these Hsp83 alleles was introgressed into the wild-type background that served as the control, induced an increase in both individual variation and fluctuating asymmetry within each of the nine genetic backgrounds. No effect of Hsp90 on the difference among lines was detected, pro,iding no evidence for cryptic genetic variation of wing shape. Overall, these results suggest that Hsp90 contributes to, but is not controlling, the buffering of phenotypic variation in wing shape.  相似文献   

10.
Phenotypic robustness, or canalization, has been extensively investigated both experimentally and theoretically. However, it remains unknown to what extent robustness varies between individuals, and whether factors buffering environmental variation also buffer genetic variation. Here we introduce a quantitative genetic approach to these issues, and apply this approach to data from three species. In mice, we find suggestive evidence that for hundreds of gene expression traits, robustness is polymorphic and can be genetically mapped to discrete genomic loci. Moreover, we find that the polymorphisms buffering genetic variation are distinct from those buffering environmental variation. In fact, these two classes have quite distinct mechanistic bases: environmental buffers of gene expression are predominantly sex-specific and trans-acting, whereas genetic buffers are not sex-specific and often cis-acting. Data from studies of morphological and life-history traits in plants and yeast support the distinction between polymorphisms buffering genetic and environmental variation, and further suggest that loci buffering different types of environmental variation do overlap with one another. These preliminary results suggest that naturally occurring polymorphisms affecting phenotypic robustness could be abundant, and that these polymorphisms may generally buffer either genetic or environmental variation, but not both.  相似文献   

11.
Cryptic genetic variation (CGV) or a standing genetic variation that is not ordinarily expressed as a phenotype is released when the robustness of organisms is impaired under environmental or genetic perturbations. Evolutionary capacitors modulate the amount of genetic variation exposed to natural selection and hidden cryptically; they have a fundamental effect on the evolvability of traits on evolutionary timescales. In this study, I have demonstrated the effects of multiple genomic regions of Drosophila melanogaster on CGV in wing shape. I examined the effects of 61 genomic deficiencies on quantitative and qualitative natural genetic variation in the wing shape of D. melanogaster. I have identified 10 genomic deficiencies that do not encompass a known candidate evolutionary capacitor, Hsp90, exposing natural CGV differently depending on the location of the deficiencies in the genome. Furthermore, five genomic deficiencies uncovered qualitative CGV in wing morphology. These findings suggest that CGV in wing shape of wild‐type D. melanogaster is regulated by multiple capacitors with divergent functions. Future analysis of genes encompassed by these genomic regions would help elucidate novel capacitor genes and better understand the general features of capacitors regarding natural genetic variation.  相似文献   

12.
The heat-shock protein 90 (Hsp90) is currently thought to buffer eukaryotic cells against perturbations caused by pre-existing cryptic genetic variation. A new study suggests that the buffering function of Hsp90 could instead be due to its repression of de novo transposon-mediated mutagenesis.  相似文献   

13.
Conrad Waddington published an influential model for evolution in his 1942 paper, Canalization of Development and Inheritance of Acquired Characters. In this classic, albeit controversial, paper, he proposed that an unknown mechanism exists that conceals phenotypic variation until the organism is stressed. Recent studies have proposed that the highly conserved chaperone Hsp90 could function as a "capacitor," or an "adaptively inducible canalizer," that masks silent phenotypic variation of either genetic or epigenetic origin. This review will discuss evidence for, and arguments against, the role of Hsp90 as a capacitor for morphological evolution, and as a key component of what we call "Waddington's widget."  相似文献   

14.
The term ‘phenotypic capacitance’ was introduced nearly 15 years ago to describe the strain‐specific effects of impairing Hsp90, a molecular chaperone, in the fly Drosophila melanogaster (Rutherford & Lindquist 1998 ). In one genetic background, Hsp90 depletion caused deformed eyes, whereas in other genetic backgrounds, the wings or abdomens or other aspects of morphology were affected. Hsp90 was therefore viewed as acting like a capacitor, allowing genetic differences to build up and to be released at a later time. In the years since, it has been debated whether capacitance is a laboratory curiosity or a major force in evolution. In this issue of Molecular Ecology, Takahashi ( 2013 ) presents evidence, from high‐resolution morphometric analysis of fly wings, that a large number of other capacitors exist in D. melanogaster, and that the variation they reveal can be quite subtle. His results advance our understanding of capacitance and contribute to a new view of its role in evolutionary adaptation.  相似文献   

15.
The mechanisms of biological evolution have always been, and still are, the subject of intense debate and modeling. One of the main problems is how the genetic variability is produced and maintained in order to make the organisms adaptable to environmental changes and therefore capable of evolving. In recent years, it has been reported that, in flies and plants, mutations in Hsp90 gene are capable to induce, with a low frequency, many different developmental abnormalities depending on the genetic backgrounds. This has suggested that the reduction of Hsp90 amount makes different development pathways more sensitive to hidden genetic variability. This suggestion revitalized a classical debate around the original Waddington hypothesis of canalization and genetic assimilation making Hsp90 the prototype of morphological capacitor. Other data have also suggested a different mechanism that revitalizes another classic debate about the response of genome to physiological and environmental stress put forward by Barbara McClintock. That data demonstrated that Hsp90 is involved in repression of transposon activity by playing a significant role in piwi-interacting RNA (piRNAs)-dependent RNA interference (RNAi) silencing. The important implication is that the fixed phenotypic abnormalities observed in Hsp90 mutants are probably related to de novo induced mutations by transposon activation. In this case, Hsp90 could be considered as a mutator. In the present theoretical paper, we discuss several possible implications about environmental stress, transposon, and evolution offering also a support to the concept of evolvability.  相似文献   

16.
Recently a heat shock protein (Hsp90) has been implicated as controlling the expression of cryptic genetic variation through buffering developmental processes. The release of variability in canalized characters following Hsp90 inhibition has been established in model species including Drosophila melanogaster and Arabidopsis thaliana , but has not yet been examined in species with limited distributions. To test if Hsp90 has a role in releasing phenotypic variation in rainforest Drosophila species, developing larvae from a large (> 1000 individuals) outbred population of Drosophila birchii were treated with the Hsp90 inhibitors geldanamycin and radicicol, and morphological traits, desiccation resistance, and life-history traits were measured. The means of all traits were influenced by inhibition. Although only the phenotypic variances of two canalized bristle traits were affected consistently, variability for two of the continuously varying traits (fecundity and development time) were also affected, albeit inconsistently. There was also no effect of Hsp90 inhibition on the developmental stability of the morphological traits as measured by fluctuating asymmetry. Hsp90 inhibition did not increase phenotypic variability in desiccation resistance, a trait previously shown to represent an evolutionary limit in this species. These results question the extent to which Hsp90 buffers variation for both quantitative and discrete traits, and highlight the need for further empirical studies to determine the involvement of Hsp90 in canalization and developmental stability. Nevertheless the results demonstrated increased variability in canalized traits, consistent with observations in model systems. © 2007 The Linnean Society of London, Biological Journal of the Linnean Society , 2007, 92 , 457–465.  相似文献   

17.
The Hsp90 protein encoded by the Hsp83 gene is required for the development of many traits in Drosophila. Hsp83 is also thought to play a role in the expression of phenotypic and genetic variability for subsequent selection and evolutionary change. Here we examine the impact of different E(sev) and Su(Raf) Hsp83 mutants on means and phenotypic variances of invariant and variable bristle traits. One of the mutants influenced the normally invariant thoracic bristle number, while none affected invariant scutellar bristle number. E(sev) alleles consistently influenced variable bristle traits while there were fewer effects of the Su(Raf) alleles. For the variable traits, none of the Hsp83 alleles had any effect on phenotypic variance, environmental variance, or developmental stability of the bristle traits. When alleles were combined in trans-heterozygotes, there were both cumulative and complementary effects on thoracic and variable bristle trait numbers, depending on the allelic combination. Overall, the results suggest that Hsp83 mutants do not have detectable effects on the phenotypic or environmental variance of bristle traits and that complementation of E(sev) and Su(Raf) Hsp83 mutants can extend to thoracic bristles as well as previously reported effects on viability. Some allelic combinations lead to more severe effects on variable bristle trait means than do single Hsp83 mutations.  相似文献   

18.
The shell colour of many pulmonate land snail species is highly diverse. Besides a genetic basis, environmentally triggered epigenetic mechanisms including stress proteins as evolutionary capacitors are thought to influence such phenotypic diversity. In this study, we investigated the relationship of stress protein (Hsp70) levels with temperature stress tolerance, population structure and phenotypic diversity within and among different populations of a xerophilic Mediterranean snail species (Xeropicta derbentina). Hsp70 levels varied considerably among populations, and were significantly associated with shell colour diversity: individuals in populations exhibiting low diversity expressed higher Hsp70 levels both constitutively and under heat stress than those of phenotypically diverse populations. In contrast, population structure (cytochrome c oxidase subunit I gene) did not correlate with phenotypic diversity. However, genetic parameters (both within and among population differences) were able to explain variation in Hsp70 induction at elevated but non-pathologic temperatures. Our observation that (1) population structure had a high explanatory potential for Hsp70 induction and that (2) Hsp70 levels, in turn, correlated with phenotypic diversity while (3) population structure and phenotypic diversity failed to correlate provides empirical evidence for Hsp70 to act as a mediator between genotypic variation and phenotype and thus for chaperone-driven evolutionary capacitance in natural populations.  相似文献   

19.
Seasonal variation in heat shock proteins Hsp70 and Hsp90 expression was studied in the leaves of two naturally growing Iris pumila populations, one inhabiting an open dune site, and the other the understorey of a Pinus silvestris stand. The Hsps were quantified by an immunoblotting procedure. The level of the Hsps was found to vary significantly both across seasons and between habitats. The mean Hsp70 concentration was significantly greater at the open area than in the woodland understorey, reaching its maximum in the summer, especially in plants experiencing full sunlight. Two Hsp90 isoforms, referred to as Hsp90a (86 kDa) and Hsp90b (84 kDa), were detected. At both habitats, the level of Hsp90a was highest in autumn, that of Hsp90b in spring, whereas both of them reached a nadir in summer. Throughout the growing season, the relative abundance of Hsp90b was higher in plants growing under vegetation canopy in comparison to those inhabiting the open dune site. An inverse relationship between the phenotypic variation in specific leaf area and the level of Hsp90b over seasons at both habitats was observed, suggesting the role of this protein in buffering phenotypic variation in the wild.  相似文献   

20.
DNA sequence variation is abundant in wild populations. While molecular biologists use genetically homogeneous strains of model organisms to avoid this variation, evolutionary biologists embrace genetic variation as the material of evolution since heritable differences in fitness drive evolutionary change. Yet, the relationship between the phenotypic variation affecting fitness and the genotypic variation producing it is complex. Genetic buffering mechanisms modify this relationship by concealing the effects of genetic and environmental variation on phenotype. Genetic buffering allows the build-up and storage of genetic variation in phenotypically normal populations. When buffering breaks down, thresholds governing the expression of previously silent variation are crossed. At these thresholds, phenotypic differences suddenly appear and are available for selection. Thus, buffering mechanisms modulate evolution and regulate a balance between evolutionary stasis and change. Recent work provides a glimpse of the molecular details governing some types of genetic buffering.  相似文献   

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