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Masel, J. & Bergman, A. The evolution of the evolvability properties of the yeast prion [PSI+]. Evolution 57, 1498-1512
Abstract
Saccharomyces cerevisiae's ability to form the prion [PSI+] may increase the rate of evolvability, defined as the rate of appearance of heritable and potentially adaptive phenotypic variants. The increase in evolvability occurs when the appearance of the prion causes read-through translation and reveals hidden variation in untranslated regions. Eventually the portion of the phenotypic variation that is adaptive loses its dependence on the revealing mechanism. The mechanism is reversible, so the restoration of normal translation termination conceals the revealed deleterious variation, leaving the yeast without a permanent handicap. Given that the ability to form [PSI+] is known to be fixed and conserved in yeast, we construct a mathematical model to calculate whether this ability is more likely to have become fixed due to chance alone or due to its evolvability characteristics. We find that evolvability is a more likely explanation, as long as environmental change makes partial read-through of stop codons adaptive at a frequency of at least once every million years.
... The N-terminus of the protein is well conserved (S5 File), indicating that the lack of PLDs is not due to genome mis-annotation. Such sporadicity may be linked to the potent nature of prion propagation, meaning that prion-forming proteins may be tolerated or remain useful for short evolutionary timespans of several millions of years, since their propagation may arise so rarely in wild bacterial populations, but thereafter the prion domains could be subsequently purged from the proteins if they lose their utility or become detrimental to fitness [60]. Alternatively, the intrinsically disordered region may have a different function that allows more variation over a wide amino-acid compositional range, including a 'prion-like' composition. ...
... These results motivate several hypotheses. Prion propagation may arise rarely enough in wild bacterial populations that prion-like domains are maintained in specific clades of organisms for millions of years [60]. They may occasionally be beneficial, but then may also occasionally become detrimental to fitness, and so be subsequently purged. ...
Prions in eukaryotes have been linked to diseases, evolutionary capacitance, large-scale genetic control and long-term memory formation. In bacteria, constructed prion-forming proteins have been described, such as the prion-forming protein recently described for Clostridium botulinum transcription terminator Rho. Here, I analyzed the evolution of the Rho prion-forming domain across bacteria, and discovered that its conservation is sporadic both in the Clostridium genus and in bacteria generally. Nonetheless, it has an apparent evolutionary reach into eight or more different bacterial phyla. Motivated by these results, I investigated whether this pattern of wide-ranging evolutionary sporadicity is typical of bacterial prion-like domains. A measure of coverage of a domain (C) within its evolutionary range was derived, which is effectively a weighted fraction of the number of species in which the domain is found. I observe that occurrence across multiple phyla is not uncommon for bacterial prion-like protein domain families, but that they tend to sample of a low fraction of species within their evolutionary range, like Rho. The Rho prion-like domain family is one of the top three most widely distributed prion-like protein domain families in terms of number of phyla. There are >60 prion-like protein domain families that have at least the evolutionary coverage of Rho, and are found in multiple phyla. The implications of these findings for evolution and for experimental investigations into prion-forming proteins are discussed.
... The models just described are speculative, but point to areas in which empirical and theoretical studies may be worthwhile. The same is true of models of the evolution of epigenetic strategies, and of the genetics of epigenetics (Lachmann and Jablonka, 1996; Masel and Bergman, 2003). Of more immediate practical importance is the extension of the classical quantitative genetic models to include epigenetic inheritance, since these enable rough estimates to be made of the contribution of heritable epigenetic variation to total phenotypic variance (Tal et al., 2010). ...
... [8][9][10] Furthermore, the conserved 11 ability to adopt a prion conformation and associated new phenotype, [4][5][6] and the responsiveness of the [PSI + ] system to environmental stresses [12][13][14][15] supports the hypothesis that the [PSI + ] prion is an evolutionary capacitor that facilitates adaptation of yeast to fluctuating environments and might impact the evolution of new traits. 8,9,16,17 Such a function may not be limited to the [PSI + ] prion, but could apply to other yeast prions. 4,5,18 As for their mammalian counterparts, yeast prions can exist in different yet stable prion strains or variants. ...
The yeast prion phenomenon is very widespread and mounting evidence suggests that it has an impact on cellular regulatory mechanisms related to phenotypic responses to changing environments. Studying the aggregation patterns of prion amyloids during different stages of the prion life cycle is a first key step to understand major principles of how and where cells generate, organize and turn-over prion aggregates. The induction of the [PSI (+) ] state involves the actin cytoskeleton and quality control compartments such as the Insoluble Protein Deposit (IPOD). An initially unstable transitional induction state can be visualized by overexpression of the prion determinant and displays characteristic large ring- and ribbon-shaped aggregates consisting of poorly fragmented bundles of very long prion fibrils. In the mature prion state, the aggregation pattern is characterized by highly fragmented, shorter prion fibrils that form aggregates, which can be visualized through tagging with fluorescent proteins. The number of aggregates formed varies, ranging from a single large aggregate at the IPOD to multiple smaller ones, depending on several parameters discussed. Aggregate units below the resolution of light microscopy that are detectable by fluorescence correlation spectroscopy are in equilibrium with larger aggregates in this stage and can mediate faithful inheritance of the prion state. Loss of the prion state is often characterized by reduced fragmentation of prion fibrils and fewer, larger aggregates.
... 39,40 This domain is not required for the termination activity of eRF3; its conservation in distantly related to budding yeast species, such as Candida albicans, Pichia methalonica and Saccharomyces cerevisiae, 39,[41][42][43] thus suggesting that it fulfils another physiological role. 44 The [PSI + ] prion may act as a possible evolutionary capacitor based on its positive effect on evolvability 45 and the fact that its induction/loss frequencies respond to environmental stresses. 35,46 Nucleotides upstream and downstream from the stop codon have a profound impact on termination efficiency. ...
The [PSI (+) ] determinant in Saccharomyces cerevisiae is the prion protein corresponding to the eRF3 translation termination factor. Numerous infectious proteins have been described in yeast, in comparison of the unique PrP protein in higher eukaryotes. The presence of the PrP prion is associated with mammalian diseases. Whether fungal prions are beneficial or deleterious are still under discussions. The review focuses on [PSI (+) ] -induced phenotypes and the resulting physiological consequences to shed light on the cellular changes occurring in a [PSI (+) ] cell and its possible role in nature. To date, only two genes directly regulated at the translational level by [PSI (+) ] have been identified. Yet, through all the published works, obtaining a consensus for the described [PSI (+) ] phenotypes appeared a tricky task. They are highly dependent on the prion variant and the genetic background of the strain. The [PSI (+) ] prion might generate diverse modifications not only at the translational, but also at the transcriptional levels, and the phenotypic heterogeneity is the result of these complex combinations of the genotypic expression.
... Prion propagation in yeast requires the involvement of chaperon proteins . Moreover , prions in yeast are associated with greater adaptability in yeast because they increase protein variation – a factor that may prove advantageous in variable environments and eventually be genetically assimilated ( True and Lindquist , 2000 ; Pál 2001 ; Masel and Bergman 2003 ) . It is these abilities to interact with biological processes at different levels of organization that presumably explain evolutionarily the prion ' s powers of persistence . ...
We address three fundamental questions: What does it mean for an entity to be living? What is the role of inter-organismic collaboration in evolution? What is a biological individual? Our central argument is that life arises when lineage-forming entities collaborate in metabolism. By conceiving of metabolism as a collaborative process performed by functional wholes, which are associations of a variety of lineage-forming entities, we avoid the standard tension between reproduction and metabolism in discussions of life – a tension particularly evident in discussions of whether viruses are alive. Our perspective assumes no sharp distinction between life and non-life, and does not equate life exclusively with cellular or organismal status. We reach this conclusion through an analysis of the capabilities of a spectrum of biological entities, in which we include the pivotal case of viruses as well as prions, plasmids, organelles, intracellular and extracellular symbionts, unicellular and multicellular life-forms. The usual criterion for classifying many of the entities of our continuum as non-living is autonomy. This emphasis on autonomy is problematic, however, because even paradigmatic biological individuals, such as large animals, are dependent on symbiotic associations with many other organisms. These composite individuals constitute the metabolic wholes on which selection acts. Finally, our account treats cooperation and competition not as polar opposites but as points on a continuum of collaboration. We suggest that competitive relations are a transitional state, with multi-lineage metabolic wholes eventually outcompeting selfish competitors, and that this process sometimes leads to the emergence of new types or levels of wholes. Our view of life as a continuum of variably structured collaborative systems leaves open the possibility that a variety of forms of organized matter – from chemical systems to ecosystems – might be usefully understood as living entities.
... To resolve whether this evolvability is an adaptation, however, we need more theoretical and practical understanding of the molecular basis and the short-and long-term costs of epigenomic plasticity and a quantitative measure of the extent to which this plasticity aids evolution (such as those being calculated for the benefits of recombination (Agrawal et al., 2005)), plus observational evidence such as the long-term maintenance of a gene with no other function than increasing evolvability. Relevant theoretical calculations of this nature have been attempted with regards to the evolutionary capacitance theory of the maintenance of psi prion of yeast which, assuming large population sizes, low mutation rates and a low cost of maintenance, must provide a new adaptive change every million years to survive mutational degeneration (Masel and Bergman, 2003). Similar work on the more complex plasticity of animals and plants would be extremely valuable. ...
Epigenetics has progressed rapidly from an obscure quirk of heredity into a data-heavy 'omic' science. Our understanding of the molecular mechanisms of epigenomic regulation, and the extent of its importance in nature, are far from complete, but in spite of such drawbacks, population-level studies are extremely valuable: epigenomic regulation is involved in several processes central to evolutionary biology including phenotypic plasticity, evolvability and the mediation of intragenomic conflicts. The first studies of epigenomic variation within populations suggest high levels of phenotypically relevant variation, with the patterns of epigenetic regulation varying between individuals and genome regions as well as with environment. Epigenetic mechanisms appear to function primarily as genome defences, but result in the maintenance of plasticity together with a degree of buffering of developmental programmes; periodic breakdown of epigenetic buffering could potentially cause variation in rates of phenotypic evolution.
... The first feature allows the biological system to keep its structure or function despite mutations altering functionality of its parts [158] [159] [160]. The latter refers to heritable phenotypic variations it can produce due to occurrence of mutations [161] [162] [163] [164] [165] [166] [167] [168] [169] [170]. On the one hand, organelle genomes are very evolvable and flexible when the rate of mutation fixation is considered, especially in the case of plant organellar genomes. ...
As a legacy of their endosymbiotic eubacterial origin, mitochondria possess a residual genome, encoding only a few proteins and dependent on a variety of factors encoded by the nuclear genome for its maintenance and expression. As a facultative anaerobe with well understood genetics and molecular biology, Saccharomyces cerevisiae is the model system of choice for studying nucleo-mitochondrial genetic interactions. Maintenance of the mitochondrial genome is controlled by a set of nuclear-coded factors forming intricately interconnected circuits responsible for replication, recombination, repair and transmission to buds. Expression of the yeast mitochondrial genome is regulated mostly at the post-transcriptional level, and involves many general and gene-specific factors regulating splicing, RNA processing and stability and translation. A very interesting aspect of the yeast mitochondrial system is the relationship between genome maintenance and gene expression. Deletions of genes involved in many different aspects of mitochondrial gene expression, notably translation, result in an irreversible loss of functional mtDNA. The mitochondrial genetic system viewed from the systems biology perspective is therefore very fragile and lacks robustness compared to the remaining systems of the cell. This lack of robustness could be a legacy of the reductive evolution of the mitochondrial genome, but explanations involving selective advantages of increased evolvability have also been postulated.
... We assumed that reversible and irreversible switches are equally able to meet the challenge of environmental change in the short term. A previous model by Masel and Bergman (2003) addressed the presence of irreversible mimics indirectly by defining environmental change as that leading to extinction unless reversible switching occurred. This implicitly assumes that if both reversible and irreversible mimic phenotypes appear in the population, then the mimics always lose in direct competition even in the short-term. ...
Reversible phenotypic switching can be caused by a number of different mechanisms including epigenetic inheritance systems and DNA-based contingency loci. Previous work has shown that reversible switching systems may be favored by natural selection. Many switches can be characterized as "on/off" where the "off" state constitutes a temporary and reversible loss of function. Loss-of-function phenotypes corresponding to the "off" state can be produced in many different ways, all yielding identical fitness in the short term. In the long term, however, a switch-induced loss of function can be reversed, whereas many loss-of-function mutations, especially deletions, cannot. We refer to these loss-of-function mutations as "irreversible mimics" of the reversible switch. Here, we develop a model in which a reversible switch evolves in the presence of both irreversible mimics and metapopulation structure. We calculate that when the rate of appearance of irreversible mimics exceeds the migration rate, the evolved reversible switching rate will exceed the bet-hedging rate predicted by panmictic models.
... A predominantly deleterious role for [PSI 1 ] would raise the question as to why the ability to form [PSI 1 ] has not been eliminated by natural selection, but instead been conserved over long periods of yeast evolution (Chernoff et al. 2000; Kushnirov et al. 2000a; Santoso et al. 2000; Nakayashiki et al. 2001). Consider a modifier locus called prf [prion-forming (Masel and Bergman 2003)] with allele prf 1 permitting [PSI 1 ] formation and allele prf 0 preventing it. When [PSI 1 ] is deleterious, then prf 1 lineages are also at a disadvantage , as they repeatedly give rise to [PSI 1 ] progeny: this is known as indirect selection. ...
The [PSI(+)] prion causes widespread readthrough translation and is rare in natural populations of Saccharomyces, despite the fact that sex is expected to cause it to spread. Using the recently estimated rate of Saccharomyces outcrossing, we calculate the strength of selection necessary to maintain [PSI(+)] at levels low enough to be compatible with data. Using the best available parameter estimates, we find selection against [PSI(+)] to be significant. Inference regarding selection on modifiers of [PSI(+)] appearance depends on obtaining more precise and accurate estimates of the product of yeast effective population size N(e) and the spontaneous rate of [PSI(+)] appearance m. The ability to form [PSI(+)] has persisted in yeast over a long period of evolutionary time, despite a diversity of modifiers that could abolish it. If mN(e) < 1, this may be explained by insufficiently strong selection. If mN(e) > 1, then selection should favor the spread of [PSI(+)] resistance modifiers. In this case, rare conditions where [PSI(+)] is adaptive may permit its persistence in the face of negative selection.
Organisms rely on mutations to fuel adaptive evolution. However, many mutations impose a negative effect on fitness. Cells may have therefore evolved mechanisms that affect the phenotypic effects of mutations, thus conferring mutational robustness. Specifically, so-called buffer genes are hypothesized to interact directly or indirectly with genetic variation and reduce its effect on fitness. Environmental or genetic perturbations can change the interaction between buffer genes and genetic variation, thereby unmasking the genetic variation’s phenotypic effects and thus providing a source of variation for natural selection to act on. This review provides an overview of our understanding of mutational robustness and buffer genes, with the chaperone gene HSP90 as a key example. It discusses whether buffer genes merely affect standing variation or also interact with de novo mutations, how mutational robustness could influence evolution, and whether mutational robustness might be an evolved trait or rather a mere side-effect of complex genetic interactions.
De novo protein-coding innovations sometimes emerge from ancestrally non-coding DNA, despite the expectation that translating random sequences is overwhelmingly likely to be deleterious. The "pre-adapting selection" hypothesis claims that emergence is facilitated by prior, low-level translation of non-coding sequences via molecular errors. It predicts that selection on polypeptides translated only in error is strong enough to matter, and is strongest when erroneous expression is high. To test this hypothesis, we examined non-coding sequences located downstream of stop codons (i.e. those potentially translated by readthrough errors) in Saccharomyces cerevisiae genes. We identified a class of "fragile" proteins under strong selection to reduce readthrough, which are unlikely substrates for co-option. Among the remainder, sequences showing evidence of readthrough translation, as assessed by ribosome profiling, encoded C-terminal extensions with higher intrinsic structural disorder, supporting the pre-adapting selection hypothesis. The cryptic sequences beyond the stop codon, rather than spillover effects from the regular C-termini, are primarily responsible for the higher disorder. Results are robust to controlling for the fact that stronger selection also reduces the length of C-terminal extensions. These findings indicate that selection acts on 3' UTRs in S. cerevisiae to purge potentially deleterious variants of cryptic polypeptides, acting more strongly in genes that experience more readthrough errors.
Background
Variation in the non-coding regions of Y-chromosomes have been shown to influence gene regulation throughout the genome in some systems; a phenomenon termed Y-linked regulatory variation (YRV). This type of sex-specific genetic variance could have important implications for the evolution of male and female traits. If YRV contributes to the additive genetic variation of an autosomally coded trait shared between the sexes (e.g. body size), then selection could facilitate sexually dimorphic evolution via the Y-chromosome. In contrast, if YRV is entirely non-additive (i.e. interacts epistatically with other chromosomes), then Y-chromosomes could constrain trait evolution in both sexes whenever they are selected for the same trait value. The ability for this phenomenon to influence such fundamental evolutionary dynamics remains unexplored.
Results
Here we address the evolutionary contribution of Y-linked variance by selecting for improved male geotaxis in populations possessing multiple Y-chromosomes (i.e. possessed Y-linked additive and/or epistatic variation) or a single Y-chromosome variant (i.e. possessed no Y-linked variation). We found that males from populations possessing Y-linked variation did not significantly respond to selection; however, males from populations with no Y-linked variation did respond. These patterns suggest the presence of a large quantity of Y-linked epistatic variance in the multi-Y population that dramatically slowed its response.
Conclusions
Our results imply that YRV is unlikely to facilitate the evolution of sexually dimorphic traits (at least for the trait examined here), but can interfere with the rate of trait evolution in both males and females. This result could have real biological implications as it suggests that YRV can affect how quickly a population responds to new selective pressures (e.g. invasive species, novel pathogens, or climate change). Considering that YRV influences hundreds of genes and is likely typical of other independently-evolved hemizygous chromosomes, YRV-like phenomena may represent common and significant costs to hemizygous sex determination.
Evolution can favor organisms that are more adaptable, provided that genetic variation in adaptability exists. Here, we quantify this variation among 230 offspring of a cross between diverged yeast strains. We measure the adaptability of each offspring genotype, defined as its average rate of adaptation in a specific environmental condition, and analyze the heritability, predictability, and genetic basis of this trait. We find that initial genotype strongly affects adaptability and can alter the genetic basis of future evolution. Initial genotype also affects the pleiotropic consequences of adaptation for fitness in a different environment. This genetic variation in adaptability and pleiotropy is largely determined by initial fitness, according to a rule of declining adaptability with increasing initial fitness, but several individual QTLs also have a significant idiosyncratic role. Our results demonstrate that both adaptability and pleiotropy are complex traits, with extensive heritable differences arising from naturally occurring variation.
The yeast Sup35 protein is a subunit of the translation termination factor, and its conversion to the [PSI ⁺] prion state leads to more translational read-through. Although extensive studies have been done on [PSI ⁺], changes at the proteomic level have not been performed exhaustively. We therefore used a SILAC-based quantitative mass spectrometry approach and identified 4187 proteins from both [psi ⁻] and [PSI ⁺] strains. Surprisingly, there was very little difference between the two proteomes under standard growth conditions. We found however that several [PSI ⁺] strains harbored an additional chromosome, such as chromosome I. Albeit, we found no evidence to support that [PSI ⁺] induces chromosomal instability (CIN). Instead we hypothesized that the selective pressure applied during the establishment of [PSI ⁺]-containing strains could lead to a supernumerary chromosome due to the presence of the ade1-14 selective marker for translational read-through. We therefore verified that there was no prevalence of disomy among newly generated [PSI ⁺] strains in absence of strong selection pressure. We also noticed that low amounts of adenine in media could lead to higher levels of mitochondrial DNA in [PSI ⁺] in ade1-14 cells. Our study has important significance for the establishment and manipulation of yeast strains with the Sup35 prion.
Phenotypic mutations are amino acid changes caused by mistranslation. How phenotypic mutations affect the adaptive evolution of new protein functions is unknown. Here we evolve the antibiotic resistance protein TEM-1 towards resistance on the antibiotic cefotaxime in an Escherichia coli strain with a high mistranslation rate. TEM-1 populations evolved in such strains endow host cells with a general growth advantage, not only on cefotaxime but also on several other antibiotics that ancestral TEM-1 had been unable to deactivate. High-throughput sequencing of TEM-1 populations shows that this advantage is associated with a lower incidence of weakly deleterious genotypic mutations. Our observations show that mistranslation is not just a source of noise that delays adaptive evolution. It could even facilitate adaptive evolution by exacerbating the effects of deleterious mutations and leading to their more efficient purging. The ubiquity of mistranslation and its effects render mistranslation an important factor in adaptive protein evolution.
Since the late 1970s, the field of evolutionary biology has undergone empirical and theoretical developments that have threaten the pillars of evolutionary theory. Some evolutionary biologists have recently argued that evolutionary biology is not experiencing a paradigm shift, but an expansion of the modern synthesis. Philosophers of biology focusing on scientific practices seem to agree with this pluralistic interpretation and have argued that evolutionary theory should rather be seen as an organized network of multiple problem agendas with diverse disciplinary contributors. In this paper, I apply a computational analysis to study the dynamics and conceptual structure of one of the main emerging problem agendas in evolutionary biology: evolvability. I have used CiteSpace, an application for visualizing and analyzing trends and patterns in scientific literature that applies cocitation analysis to identify scientific specialities. I analyze the main clusters of the evolvability cocitation network with the aim to identify the main research lines and the interdisciplinary relationships that structure this research front. I then compare these results with the existing classifications of evolvability concepts, and identify four main conceptual tensions within the definitions of evolvability. Finally, I argue that there is a lot of usefulness in the inconsistency in which the term evolvability is used in biological research. I claim that evolvability research has set up "trading zones" in biology that make possible interdisciplinary exchanges.
Key challenges faced by all cells include how to spatiotemporally organize complex biochemistry and how to respond to environmental fluctuations. The budding yeast Saccharomyces cerevisiae harnesses alternative protein folding mediated by yeast prion domains (PrDs) for rapid evolution of new traits in response to environmental stress. Increasingly, it is appreciated that low complexity domains similar in amino acid composition to yeast PrDs (prion-like domains; PrLDs) found in metazoa have a prominent role in subcellular cytoplasmic organization, especially in relation to RNA homeostasis. In this review, we highlight recent advances in our understanding of the role of prions in enabling rapid adaptation to environmental stress in yeast. We also present the complete list of human proteins with PrLDs and discuss the prevalence of the PrLD in nucleic-acid binding proteins that are often connected to neurodegenerative disease, including: ataxin 1, ataxin 2, FUS, TDP-43, TAF15, EWSR1, hnRNPA1, and hnRNPA2. Recent paradigm-shifting advances establish that PrLDs undergo phase transitions to liquid states, which contribute to the structure and biophysics of diverse membraneless organelles. This structural functionality of PrLDs, however, simultaneously increases their propensity for deleterious protein-misfolding events that drive neurodegenerative disease. We suggest that even these PrLD-misfolding events are not irreversible and can be mitigated by natural or engineered protein disaggregases, which could have important therapeutic applications.
Errors in protein synthesis, so-called phenotypic mutations, are orders-of-magnitude more frequent than genetic mutations. Here, we provide direct evidence that alternative protein forms and phenotypic variability derived from translational errors paved the path to genetic, evolutionary adaptations via gene duplication. We explored the evolutionary origins of Saccharomyces cerevisiae IDP3 - an NADP-dependent isocitrate dehydrogenase mediating fatty acids ß-oxidation in the peroxisome. Following the yeast whole genome duplication, IDP3 diverged from a cytosolic ancestral gene by acquisition of a C-terminal peroxisomal targeting signal. We discovered that the pre-duplicated cytosolic IDPs are partially localized to the peroxisome owing to +1 translational frameshifts that bypass the stop codon and unveil cryptic peroxisomal targeting signals within the 3'-UTR. Exploring putative cryptic signals in all 3'-UTRs of yeast genomes, we found that other enzymes related to NADPH production such as pyruvate carboxylase 1 (PYC1) might be prone to peroxisomal localization via cryptic signals. Using laboratory evolution we found that these translational frameshifts are rapidly imprinted via genetic single base deletions occurring within the very same gene location. Further, as exemplified here, the sequences that promote translational frameshifts are also more prone to genetic deletions. Thus, genotypes conferring higher phenotypic variability not only meet immediate challenges by unveiling cryptic 3'-UTR sequences, but also boost the potential for future genetic adaptations.
Lack of a developmental perspective in evolutionary studies of stress has left researchers with several unresolved questions. First, how can organisms prepare for novel and extreme environmental change? The organismal ability to mount an appropriate reaction to a stressor requires recognition and evaluation of the extreme environment. How can this ability evolve in relation to stressors that are short and rare in relation to a species generation time? Stress occurs when changes in the external or internal environment are interpreted by an organism as a threat to its homeostasis. The ability of an organism to mount an appropriate response to potentially stressful environmental changes requires correct recognition of environmental change and the activation of a stress response. The costs and benefits of stress detection and stress response implementation and the costs and benefits of maintaining stress resistance strategies vary among environments and individuals, favoring multiple solutions of dealing with stress. Numerous studies have documented an increase in phenotypic and genotypic variance under stress, and it is suggested that this variance is a source of novel adaptations under changed environments. The Chapter outlines this perspective, with specific focus on the effect of stress during development in animals and suggests that these questions are resolved by considering the organization of developmental systems that enable accommodation and channeling of stress-induced variation without compromising organismal functionality; the significance of phenotypic and genetic assimilation of neurological, physiological, morphological, and behavioral responses to stressors; as well as multiple inheritance systems that transfer the wide array or developmental resources and conditions between the generations enabling long-term persistence and evolution of stress-induced adaptations.
Handbook of Systems Biology, 2012 251-264. 10.1016/B978-0-12-385944-0.00013-7
Biologists have long observed that physiological and developmental processes are insensitive, or robust, to many genetic and environmental perturbations. A complete understanding of the evolutionary causes and consequences of this robustness is lacking. Recent progress has been made in uncovering the regulatory mechanisms that underlie environmental robustness in particular. Less is known about robustness to the effects of mutations, and indeed the evolution of mutational robustness remains a controversial topic. The controversy has spread to related topics, in particular the evolutionary relevance of cryptic genetic variation. This review aims to synthesize current understanding of robustness mechanisms and to cut through the controversy by shedding light on what is and is not known about mutational robustness. Some studies have confused mutational robustness with non-additive interactions between mutations (epistasis). We conclude that a profitable way forward is to focus investigations (and rhetoric) less on mutational robustness and more on epistasis.
Biological systems are resistant to genetic changes; a property known as mutational robustness, the origin of which remains an open question. In recent years, researchers have explored emergent properties of biological systems and mechanisms of genetic redundancy to reveal how mutational robustness emerges and persists. Several mechanisms have been proposed to explain the origin of mutational robustness, including molecular chaperones and gene duplication. The latter has received much attention, but its role in robustness remains controversial. Here, I examine recent findings linking genetic redundancy through gene duplication and mutational robustness. Experimental evolution and genome resequencing have made it possible to test the role of gene duplication in tolerating mutations at both the coding and regulatory levels. This evidence as well as previous findings on regulatory reprogramming of duplicates support the role of gene duplication in the origin of robustness.
Copyright © 2015 Elsevier Ltd. All rights reserved.
It has long been known that temporally unstable environments are likely to promote the evolution of plastic adaptations, whilst it is equally clear that such adaptations are precisely those that characterize successful colonizers. These two established findings, however, are rarely related within a single framework. This article bridges this gap via the development of a very simple evolutionary algorithm that tracks both directional selection and the evolution of plasticity under various synthetic climatic regimes. The output of the model allows for the construction of a dispersal index that provides a measure of population-level dispersal potential under each particular climatic regime. The output thus establishes both the timing and extent of selection for plasticity and the consequences of that plasticity for the timing of probable dispersal events in the context of climatic instability. Results suggest that periods of low climatic instability abruptly following extended periods of higher climatic instability are particularly conducive to dispersal, leading to the formulation of the Accumulated Plasticity Hypothesis. These results, and the hypothesis they support, are discussed in relation to the varied manifestations of plasticity in biological systems and their relevance to human evolution.
Biological systems are known to be both robust and evolvable to internal and external perturbations, but what causes these apparently contradictory properties? We used Boolean network modeling and attractor landscape analysis to investigate the evolvability and robustness of the human signaling network. Our results show that the human signaling network can be divided into an evolvable core where perturbations change the attractor landscape in state space, and a robust neighbor where perturbations have no effect on the attractor landscape. Using chemical inhibition and overexpression of nodes, we validated that perturbations affect the evolvable core more strongly than the robust neighbor. We also found that the evolvable core has a distinct network structure, which is enriched in feedback loops, and features a higher degree of scale-freeness and longer path lengths connecting the nodes. In addition, the genes with high evolvability scores are associated with evolvability-related properties such as rapid evolvability, low species broadness, and immunity whereas the genes with high robustness scores are associated with robustness-related properties such as slow evolvability, high species broadness, and oncogenes. Intriguingly, US Food and Drug Administration-approved drug targets have high evolvability scores whereas experimental drug targets have high robustness scores.
This volume collects essays written by John Dupré during his time as Director of the ESRC centre for Genomics in Society, and reflects his interest in the implications of emerging ideas in biology for philosophy. Particular interests include: epigenetics and related areas of molecular biology that have eroded the exceptional status of the gene, and presented the genome as fully interactive with the rest of the cell; developmental systems theory which, especially in the light of epigenetics, provides a space for a vision of evolution that takes full account of the fundamental importance of developmental processes; and microbiology, the elephant in the room of contemporary philosophy of biology. The emphasis on the importance of microbes is perhaps the most distinctive theme of the essays, and one that is shown to subvert such basic biological assumptions as the organization of biological kinds on a branching Tree of Life, and the simple traditional conception of the biological organism. These topics are understood in the context of a view of science, partly taken from earlier work, but developed further in some of the present essays, as realistically grounded in the natural order, but at the same time pluralistic and inextricably integrated within a social and normative context. Topics to which these philosophical and scientific ideas are addressed include the nature of the organism, the limits of neo-Darwinian evolutionary theory, the significance of genomics, the biological status of human races, and the evolutionary and developmental plasticity of human nature.
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
I n vivo amyloid formation is a widespread phenomenon in eukaryotes. Self-perpetuating amyloids provide a basis for the infectious or heritable protein isoforms (prions). At least for some proteins, amyloid-forming potential is conserved in evolution despite divergence of the amino acid (aa) sequences. In some cases, prion formation certainly represents a pathological process leading to a disease. However, there are several scenarios in which prions and other amyloids or amyloid-like aggregates are either shown or suspected to perform positive biological functions. Proven examples include self/nonself recognition, stress defense and scaffolding of other (functional) polymers. Role of prion-like phenomena in memory has been hypothesized. As an additional mechanism of heritable change, prion formation may in principle contribute to heritable variability at the population level. Moreover, it is possible that amyloid-based prions represent by-products of the transient feedback regulatory circuits, as normal cellular function of at least some prion proteins is decreased in the prion state.
The biological and medical importance of epigenetics is now taken for granted, but the significance of one aspect of it—epigenetic inheritance—is less widely recognized. New data suggest that not only is it ubiquitous, but both the generation and the transmission of epigenetic variations may be affected by developmental conditions. Population studies, formal models, and research on genomic and ecological stresses all suggest that epigenetic inheritance is important in both micro- and macroevolutionary change.Clinical Pharmacology & Therapeutics (2012); 92 6, 683-688. doi:10.1038/clpt.2012.158
The concept of a prion as an infectious self-propagating protein isoform was initially proposed to explain certain mammalian diseases. It is now clear that yeast also has heritable elements transmitted via protein. Indeed, the "protein only" model of prion transmission was first proven using a yeast prion. Typically, known prions are ordered cross-β aggregates (amyloids). Recently, there has been an explosion in the number of recognized prions in yeast. Yeast continues to lead the way in understanding cellular control of prion propagation, prion structure, mechanisms of de novo prion formation, specificity of prion transmission, and the biological roles of prions. This review summarizes what has been learned from yeast prions.
What factors shape the evolution of invasive populations? Recent theoretical and empirical studies suggest that an evolutionary history of disturbance might be an important factor. This perspective presents hypotheses regarding the impact of disturbance on the evolution of invasive populations, based on a synthesis of the existing literature. Disturbance might select for life-history traits that are favorable for colonizing novel habitats, such as rapid population growth and persistence. Theoretical results suggest that disturbance in the form of fluctuating environments might select for organismal flexibility, or alternatively, the evolution of evolvability. Rapidly fluctuating environments might favor organismal flexibility, such as broad tolerance or plasticity. Alternatively, longer fluctuations or environmental stress might lead to the evolution of evolvability by acting on features of the mutation matrix. Once genetic variance is generated via mutations, temporally fluctuating selection across generations might promote the accumulation and maintenance of genetic variation. Deeper insights into how disturbance in native habitats affects evolutionary and physiological responses of populations would give us greater capacity to predict the populations that are most likely to tolerate or adapt to novel environments during habitat invasions. Moreover, we would gain fundamental insights into the evolutionary origins of invasive populations.
Recent work has shown that genetic robustness can either facilitate or impede adaptation. But the impact of environmental robustness on adaptation remains unclear. Environmental robustness helps ensure that organisms consistently develop the same phenotype in the face of "environmental noise" during development. Under purifying selection, those genotypes that express the optimal phenotype most reliably will be selectively favored. The resulting reduction in genetic variation tends to slow adaptation when the population is faced with a novel target phenotype. However, environmental noise sometimes induces the expression of an alternative advantageous phenotype, which may speed adaptation by genetic assimilation. Here, we use a population-genetic model to explore how these two opposing effects of environmental noise influence the capacity of a population to adapt. We analyze how the rate of adaptation depends on the frequency of environmental noise, the degree of environmental robustness in the population, the distribution of environmental robustness across genotypes, the population size, and the strength of selection for a newly adaptive phenotype. Over a broad regime, we find that environmental noise can either facilitate or impede adaptation. Our analysis uncovers several surprising insights about the relationship between environmental noise and adaptation, and it provides a general framework for interpreting empirical studies of both genetic and environmental robustness.
Prions in the yeast Saccharomyces cerevisiae show a surprising degree of interdependence. Specifically, the rate of appearance of the [PSI+] prion, which is thought to be an important mechanism to respond to changing environmental conditions, is greatly increased by another prion, [RNQ+]. While the domains of the Rnq1 protein important for formation of the [RNQ+] prion have been defined, the specific residues required remain unknown. Furthermore, residues in Rnq1p that mediate the interaction between [PSI+] and [RNQ+] are unknown. To identify residues important for prion protein interactions, we created a mutant library of Rnq1p clones in the context of a chimera that serves as proxy for [RNQ+] aggregates. Several of the mutant Rnq1p proteins showed structural differences in the aggregates they formed, as revealed by semi-denaturing detergent agarose gel electrophoresis. Additionally, several of the mutants showed a striking defect in the ability to promote [PSI+] induction. These data indicate that the mutants formed strain variants of [RNQ+]. By dissecting the mutations in the isolated clones, we found five single mutations that caused [PSI+] induction defects, S223P, F184S, Q239R, N297S, and Q298R. These are the first specific mutations characterized in Rnq1p that alter [PSI+] induction. Additionally, we have identified a region important for the propagation of certain strain variants of [RNQ+]. Deletion of this region (amino acids 284–317) affected propagation of the high variant but not medium or low [RNQ+] strain variants. Furthermore, when the low [RNQ+] strain variant was propagated by Δ284–317, [PSI+] induction was greatly increased. These data suggest that this region is important in defining the structure of the [RNQ+] strain variants. These data are consistent with a model of [PSI+] induction caused by physical interactions between Rnq1p and Sup35p.
Prions are self-templating protein conformers that are naturally transmitted between individuals and promote phenotypic change. In yeast, prion-encoded phenotypes can be beneficial, neutral or deleterious depending upon genetic background and environmental conditions. A distinctive and portable 'prion domain' enriched in asparagine, glutamine, tyrosine and glycine residues unifies the majority of yeast prion proteins. Deletion of this domain precludes prionogenesis and appending this domain to reporter proteins can confer prionogenicity. An algorithm designed to detect prion domains has successfully identified 19 domains that can confer prion behavior. Scouring the human genome with this algorithm enriches a select group of RNA-binding proteins harboring a canonical RNA recognition motif (RRM) and a putative prion domain. Indeed, of 210 human RRM-bearing proteins, 29 have a putative prion domain, and 12 of these are in the top 60 prion candidates in the entire genome. Startlingly, these RNA-binding prion candidates are inexorably emerging, one by one, in the pathology and genetics of devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer's disease and Huntington's disease. For example, FUS and TDP-43, which rank 1st and 10th among RRM-bearing prion candidates, form cytoplasmic inclusions in the degenerating motor neurons of ALS patients and mutations in TDP-43 and FUS cause familial ALS. Recently, perturbed RNA-binding proteostasis of TAF15, which is the 2nd ranked RRM-bearing prion candidate, has been connected with ALS and FTLD-U. We strongly suspect that we have now merely reached the tip of the iceberg. We predict that additional RNA-binding prion candidates identified by our algorithm will soon surface as genetic modifiers or causes of diverse neurodegenerative conditions. Indeed, simple prion-like transfer mechanisms involving the prion domains of RNA-binding proteins could underlie the classical non-cell-autonomous emanation of neurodegenerative pathology from originating epicenters to neighboring portions of the nervous system. This article is part of a Special Issue entitled RNA-Binding Proteins.
The self-templating conformations of yeast prion proteins act as epigenetic elements of inheritance. Yeast prions might provide a mechanism for generating heritable phenotypic diversity that promotes survival in fluctuating environments and the evolution of new traits. However, this hypothesis is highly controversial. Prions that create new traits have not been found in wild strains, leading to the perception that they are rare 'diseases' of laboratory cultivation. Here we biochemically test approximately 700 wild strains of Saccharomyces for [PSI(+)] or [MOT3(+)], and find these prions in many. They conferred diverse phenotypes that were frequently beneficial under selective conditions. Simple meiotic re-assortment of the variation harboured within a strain readily fixed one such trait, making it robust and prion-independent. Finally, we genetically screened for unknown prion elements. Fully one-third of wild strains harboured them. These, too, created diverse, often beneficial phenotypes. Thus, prions broadly govern heritable traits in nature, in a manner that could profoundly expand adaptive opportunities.
The formation of fibrillar amyloid is most often associated with protein conformational disorders such as prion diseases, Alzheimer disease and Huntington disease. Interestingly, however, an increasing number of studies suggest that amyloid structures can sometimes play a functional role in normal biology. Several proteins form self-propagating amyloids called prions in the budding yeast Saccharomyces cerevisiae. These unique elements operate by creating a reversible, epigenetic change in phenotype. While the function of the non-prion conformation of the Rnq1 protein is unclear, the prion form, [RNQ+], acts to facilitate the de novo formation of other prions to influence cellular phenotypes. The [RNQ+] prion itself does not adversely affect the growth of yeast, but the overexpression of Rnq1p can form toxic aggregated structures that are not necessarily prions. The [RNQ+] prion is also involved in dictating the aggregation and toxicity of polyglutamine proteins ectopically expressed in yeast. Thus, the [RNQ+] prion provides a tractable model that has the potential to reveal significant insight into the factors that dictate how amyloid structures are initiated and propagated in both physiological and pathological contexts.
Biological messiness relates to infidelity, heterogeneity, stochastic noise and variation--both genetic and phenotypic--at all levels, from single proteins to organisms. Messiness comes from the complexity and evolutionary history of biological systems and from the high cost of accuracy. For better or for worse, messiness is inherent to biology. It also provides the raw material for physiological and evolutionary adaptations to new challenges.
Why isn't random variation always deleterious? Are there factors that sometimes make adaptation easier? Biological systems are extraordinarily robust to perturbation by mutations, recombination and the environment. It has been proposed that this robustness might make them more evolvable. Robustness to mutation allows genetic variation to accumulate in a cryptic state. Switching mechanisms known as evolutionary capacitors mean that the amount of heritable phenotypic variation available can be correlated to the degree of stress and hence to the novelty of the environment and remaining potential for adaptation. There have been two somewhat separate literatures relating robustness to evolvability. One has focused on molecular phenotypes and new mutations, the other on morphology and cryptic genetic variation. Here, we review both literatures, and show that the true distinction is whether recombination rates are high or low. In both cases, the evidence supports the claim that robustness promotes evolvability.
Drug resistance is a refractory barrier in the battle against many fatal diseases caused by rapidly evolving agents, including HIV, apicomplexans and specific cancers. Emerging evidence suggests that drug resistance might extend to lethal prion disorders and related neurodegenerative amyloidoses. Prions are self-replicating protein conformers, usually 'cross-beta' amyloid polymers, which are naturally transmitted between individuals and promote phenotypic change. Prion conformers are catalytic templates that specifically convert other copies of the same protein to the prion form. Once in motion, this chain reaction of conformational replication can deplete all non-prion copies of a protein. Typically, prions exist as ensembles of multiple structurally distinct, self-replicating forms or 'strains'. Each strain confers a distinct phenotype and replicates at different rates depending on the environment. As replicators, prions are units of selection. Thus, natural selection inescapably enriches or depletes various prion strains from populations depending on their conformational fitness (ability to self-replicate) in the prevailing environment. The most successful prions confer advantages to their host as with numerous yeast prions. Here, I review recent evidence that drug-like small molecules can antagonize some prion strains but simultaneously select for drug-resistant prions composed of mammalian PrP or the yeast prion protein, Sup35. For Sup35, the drug-resistant strain configures original intermolecular amyloid contacts that are not ordinarily detected. Importantly, a synergistic small-molecule cocktail counters prion diversity by eliminating multiple Sup35 prion strains. Collectively, these advances illuminate the plasticity of prionogenesis and suggest that synergistic combinatorial therapies might circumvent this pathological vicissitude.
Epigenetically inherited aggregates of the yeast prion [PSI+] cause genomewide readthrough translation that sometimes increases evolvability in certain harsh environments. The effects of natural selection on modifiers of [PSI+] appearance have been the subject of much debate. It seems likely that [PSI+] would be at least mildly deleterious in most environments, but this may be counteracted by its evolvability properties on rare occasions. Indirect selection on modifiers of [PSI+] is predicted to depend primarily on the spontaneous [PSI+] appearance rate, but this critical parameter has not previously been adequately measured. Here we measure this epimutation rate accurately and precisely as 5.8 x 10(-7) per generation, using a fluctuation test. We also determine that genetic "mimics" of [PSI+] account for up to 80% of all phenotypes involving general nonsense suppression. Using previously developed mathematical models, we can now infer that even in the absence of opportunities for adaptation, modifiers of [PSI+] are only weakly deleterious relative to genetic drift. If we assume that the spontaneous [PSI+] appearance rate is at its evolutionary optimum, then opportunities for adaptation are inferred to be rare, such that the [PSI+] system is favored only very weakly overall. But when we account for the observed increase in the [PSI+] appearance rate in response to stress, we infer much higher overall selection in favor of [PSI+] modifiers, suggesting that [PSI+]-forming ability may be a consequence of selection for evolvability.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008. Includes bibliographical references. Several well-characterized fungal proteins act as prions, proteins capable of multiple conformations, each with different activities, at least one of which is selfpropagating. We report a protein-based heritable element that confers resistance to glucosamine, [GAR⁺]. Genetically it resembles other yeast prions: it appears spontaneously at a rate higher than mutations and is transmissible by non-Mendelian, cytoplasmic inheritance. However, [GAR⁺] is in other ways profoundly different from known prions. [GAR⁺] propagation involves Pmal, the plasma membrane protein pump, and [GAR⁺] formation is induced by Stdl, a member of the Snf3/Rgt2 glucose signaling pathway. Also, [GAR⁺] does not appear to involve the formation of an amyloid template and the prion state represents only a fraction of the Pmal protein in the cell,· consistent with the prion form constituting a complex between Pmal and Stdl, a much lower abundance protein. [GAR⁺] propagation is subject to a strong species barrier, as substitution of PMAl from other Saccharomyces species blocks propagation to s.. cerevisiae PMAl. Direct competition between [gar-] and [GAR⁺] cells indicate that cells carrying [GAR⁺] have an advantage under certain environmental conditions. [GAR⁺] appears spontaneously in a yeast isolated from a variety of sources and can be induced by co-culturing yeast and a number of Staphylococcus species. Overall, [GAR⁺] expands the conceptual framework for self-propagating protein-based elements of inheritance to include non-amyloid, potentially multicomponent systems such as transmembrane proteins and signal transducers. by Jessica C. S. Brown. Ph.D.
Biological systems are robust to perturbation by mutations and environmental fluctuations. New data are shedding light on the biochemical and network-level mechanisms responsible for robustness. Robustness to mutation might have evolved as an adaptation to reduce the effect of mutations, as a congruent byproduct of adaptive robustness to environmental variation, or as an intrinsic property of biological systems selected for their primary functions. Whatever its mechanism or origin, robustness to mutation results in the accumulation of phenotypically cryptic genetic variation. Partial robustness can lead to pre-adaptation, and thereby might contribute to evolvability. The identification and characterization of phenotypic capacitors - which act as switches of the degree of robustness - are critical to understanding the mechanisms and consequences of robustness.
The [PSI(+)] prion may enhance evolvability by revealing previously cryptic genetic variation, but it is unclear whether such evolvability properties could be favored by natural selection. Sex inhibits the evolution of other putative evolvability mechanisms, such as mutator alleles. This paper explores whether sex also prevents natural selection from favoring modifier alleles that facilitate [PSI(+)] formation. Sex may permit the spread of "cheater" alleles that acquire the benefits of [PSI(+)] through mating without incurring the cost of producing [PSI(+)] at times when it is not adaptive. Using recent quantitative estimates of the frequency of sex in Saccharomyces paradoxus, we calculate that natural selection for evolvability can drive the evolution of the [PSI(+)] system, so long as yeast populations occasionally require complex adaptations involving synergistic epistasis between two loci. If adaptations are always simple and require substitution at only a single locus, then the [PSI(+)] system is not favored by natural selection. Obligate sex might inhibit the evolution of [PSI(+)]-like systems in other species.
The yeast [PSI+] prion is an epigenetic modifier of translation termination fidelity that causes nonsense suppression. The prion [PSI+] forms when the translation termination factor Sup35p adopts a self-propagating conformation. The presence of the [PSI+] prion modulates survivability in a variety of growth conditions. Nonsense suppression is essential for many [PSI+]-mediated phenotypes, but many do not appear to be due to read-through of a single stop codon, but instead are multigenic traits. We hypothesized that other global mechanisms act in concert with [PSI+] to influence [PSI+]-mediated phenotypes. We have identified one such global regulator, the Paf1 complex (Paf1C). Paf1C is conserved in eukaryotes and has been implicated in several aspects of transcriptional and posttranscriptional regulation. Mutations in Ctr9p and other Paf1C components reduced [PSI+]-mediated nonsense suppression. The CTR9 deletion also alters nonsense suppression afforded by other genetic mutations but not always to the same extent as the effects on [PSI+]-mediated read-through. Our data suggest that the Paf1 complex influences mRNA translatability but not solely through changes in transcript stability or abundance. Finally, we demonstrate that the CTR9 deletion alters several [PSI+]-dependent phenotypes. This provides one example of how [PSI+] and genetic modifiers can interact to uncover and regulate phenotypic variability.
In vivo amyloid formation is a widespread phenomenon in eukaryotes. Self-perpetuating amyloids provide a basis for the infectious or heritable protein isoforms (prions). At least for some proteins, amyloid-forming potential is conserved in evolution despite divergence of the amino acid (aa) sequences. In some cases, prion formation certainly represents a pathological process leading to a disease. However, there are several scenarios in which prions and other amyloids or amyloid-like aggregates are either shown or suspected to perform positive biological functions. Proven examples include self/nonself recognition, stress defense and scaffolding of other (functional) polymers. The role of prion-like phenomena in memory has been hypothesized. As an additional mechanism of heritable change, prion formation may in principle contribute to heritable variability at the population level. Moreover, it is possible that amyloid-based prions represent by-products of the transient feedback regulatory circuits, as normal cellular function of at least some prion proteins is decreased in the prion state.
Evolution depends on the manner in which genetic variation is translated into new phenotypes. There has been much debate about whether organisms might have specific mechanisms for "evolvability," which would generate heritable phenotypic variation with adaptive value and could act to enhance the rate of evolution. Capacitor systems, which allow the accumulation of cryptic genetic variation and release it under stressful conditions, might provide such a mechanism. In yeast, the prion [PSI(+)] exposes a large array of previously hidden genetic variation, and the phenotypes it thereby produces are advantageous roughly 25% of the time. The notion that [PSI(+)] is a mechanism for evolvability would be strengthened if the frequency of its appearance increased with stress. That is, a system that mediates even the haphazard appearance of new phenotypes, which have a reasonable chance of adaptive value would be beneficial if it were deployed at times when the organism is not well adapted to its environment. In an unbiased, high-throughput, genome-wide screen for factors that modify the frequency of [PSI(+)] induction, signal transducers and stress response genes were particularly prominent. Furthermore, prion induction increased by as much as 60-fold when cells were exposed to various stressful conditions, such as oxidative stress (H2O2) or high salt concentrations. The severity of stress and the frequency of [PSI(+)] induction were highly correlated. These findings support the hypothesis that [PSI(+)] is a mechanism to increase survival in fluctuating environments and might function as a capacitor to promote evolvability.
The environmentally responsive molecular chaperone Hsp90 assists the maturation of many key regulatory proteins. An unexpected consequence of this essential biochemical function is that genetic variation can accumulate in genomes and can remain phenotypically silent until Hsp90 function is challenged. Notably, this variation can be revealed by modest environmental change, establishing an environmentally responsive exposure mechanism. The existence of diverse cryptic polymorphisms with a plausible exposure mechanism in evolutionarily distant lineages has implications for the pace and nature of evolutionary change. Chaperone-mediated storage and release of genetic variation is undoubtedly rooted in protein-folding phenomena. As we discuss, proper protein folding crucially affects the trajectory from genotype to phenotype. Indeed, the impact of protein quality-control mechanisms and other fundamental cellular processes on evolution has heretofore been overlooked. A true understanding of evolutionary processes will require an integration of current evolutionary paradigms with the many new insights accruing in protein science.
Phenotypic plasticity and the exposure of hidden genetic variation both affect the survival and evolution of new traits, but their contributing molecular mechanisms are largely unknown. A single factor, the yeast prion [PSI(+)], may exert a profound effect on both. [PSI(+)] is a conserved, protein-based genetic element that is formed by a change in the conformation and function of the translation termination factor Sup35p, and is transmitted from mother to progeny. Curing cells of [PSI(+)] alters their survival in different growth conditions and produces a spectrum of phenotypes in different genetic backgrounds. Here we show, by examining three plausible explanations for this phenotypic diversity, that all traits tested involved [PSI(+)]-mediated read-through of nonsense codons. Notably, the phenotypes analysed were genetically complex, and genetic re-assortment frequently converted [PSI(+)]-dependent phenotypes to stable traits that persisted in the absence of [PSI(+)]. Thus, [PSI(+)] provides a temporary survival advantage under diverse conditions, increasing the likelihood that new traits will become fixed by subsequent genetic change. As an epigenetic mechanism that globally affects the relationship between genotype and phenotype, [PSI(+)] expands the conceptual framework for phenotypic plasticity, provides a one-step mechanism for the acquisition of complex traits and affords a route to the genetic assimilation of initially transient epigenetic traits.
Ordinary differential equations are often used to model the dynamics and interactions in genetic networks. In one particularly simple class of models, the model genes control the production rates of products of other genes by a logical function, resulting in piecewise linear differential equations. In this article, we construct and analyze an electronic circuit that models this class of piecewise linear equations. This circuit combines CMOS logic and RC circuits to model the logical control of the increase and decay of protein concentrations in genetic networks. We use these electronic networks to study the evolution of limit cycle dynamics. By mutating the truth tables giving the logical functions for these networks, we evolve the networks to obtain limit cycle oscillations of desired period. We also investigate the fitness landscapes of our networks to determine the optimal mutation rate for evolution.
One of the most solid generalizations of transmission genetics is that the phenotypic variance of populations carrying a major mutation is increased relative to the wild type. At least some part of this higher variance is genetic and due to release of previously hidden variation. Similarly, stressful environments also lead to the expression of hidden variation. These two observations have been considered as evidence that the wild type has evolved robustness against genetic variation, i.e., genetic canalization. In this article we present a general model for the interaction of a major mutation or a novel environment with the additive genetic basis of a quantitative character under stabilizing selection. We introduce an approximation to the genetic variance in mutation-selection-drift balance that includes the previously used stochastic Gaussian and house-of-cards approximations as limiting cases. We then show that the release of hidden genetic variation is a generic property of models with epistasis or genotype-environment interaction, regardless of whether the wild-type genotype is canalized or not. As a consequence, the additive genetic variance increases upon a change in the environment or the genetic background even if the mutant character state is as robust as the wild-type character. Estimates show that this predicted increase can be considerable, in particular in large populations and if there are conditionally neutral alleles at the loci underlying the trait. A brief review of the relevant literature suggests that the assumptions of this model are likely to be generic for polygenic traits. We conclude that the release of hidden genetic variance due to a major mutation or environmental stress does not demonstrate canalization of the wild-type genotype.
The extrachromosomal psi+ determinant in the yeast Saccharomyces cerevisiae enhanced the expression of Mendelian UAA suppressors by 6- to 10-fold. The psi+ determinant by itself is a weak UAA suppressor that caused the production of approximately 1% of the normal level of iso-1-cytochrome c in a strain containing the UAA mutation cycl-72.
The product of the yeast SUP45 gene (Sup45p) is highly homologous to the Xenopus eukaryote release factor 1 (eRF1), which has release factor activity in vitro. We show, using the two-hybrid system, that in Saccharomyces cerevisiae Sup45p and the product of the SUP35 gene (Sup35p) interact in vivo. The ability of Sup45p C-terminally tagged with (His)6 to specifically precipitate Sup35p from a cell lysate was used to confirm this interaction in vitro. Although overexpression of either the SUP45 or SUP35 genes alone did not reduce the efficiency of codon-specific tRNA nonsense suppression, the simultaneous overexpression of both the SUP35 and SUP45 genes in nonsense suppressor tRNA-containing strains produced an antisuppressor phenotype. These data are consistent with Sup35p and Sup45p forming a complex with release factor properties. Furthermore, overexpression of either Xenopus or human eRF1 (SUP45) genes also resulted in anti-suppression only if that strain was also overexpressing the yeast SUP35 gene. Antisuppression is a characteristic phenotype associated with overexpression of both prokaryote and mitochondrial release factors. We propose that Sup45p and Sup35p interact to form a release factor complex in yeast and that Sup35p, which has GTP binding sequence motifs in its C-terminal domain, provides the GTP hydrolytic activity which is a demonstrated requirement of the eukaryote translation termination reaction.
Termination of translation in higher organisms is a GTP-dependent process. However, in the structure of the single polypeptide chain release factor known so far (eRF1) there are no GTP binding motifs. Moreover, in prokaryotes, a GTP binding protein, RF3, stimulates translation termination. From these observations we proposed that a second eRF should exist, conferring GTP dependence for translation termination. Here, we have shown that the newly sequenced GTP binding Sup35-like protein from Xenopus laevis, termed eRF3, exhibits in vitro three important functional properties: (i) although being inactive as an eRF on its own, it greatly stimulates eRF1 activity in the presence of GTP and low concentrations of stop codons, resembling the properties of prokaryotic RF3; (ii) it binds and probably hydrolyses GTP; and (iii) it binds to eRF1. The structure of the C-domain of the X.laevis eRF3 protein is highly conserved with other Sup35-like proteins, as was also shown earlier for the eRF1 protein family. From these and our previous data, we propose that yeast Sup45 and Sup35 proteins belonging to eRF1 and eRF3 protein families respectively are also yeast termination factors. The absence of structural resemblance of eRF1 and eRF3 to prokaryotic RF1/2 and RF3 respectively, may point to the different evolutionary origin of the translation termination machinery in eukaryotes and prokaryotes. It is proposed that a quaternary complex composed of eRF1, eRF3, GTP and a stop codon of the mRNA is involved in termination of polypeptide synthesis in ribosomes.
We propose a mathematical model to analyze the evolution of canalization for a trait under stabilizing selection, where each individual in the population is randomly exposed to different environmental conditions, independently of its genotype. Without canalization, our trait (primary phenotype) is affected by both genetic variation and environmental perturbations (morphogenic environment). Selection of the trait depends on individually varying environmental conditions (selecting environment). Assuming no plasticity initially, morphogenic effects are not correlated with the direction of selection in individual environments. Under quite plausible assumptions we show that natural selection favors a system of canalization that tends to repress deviations from the phenotype that is optimal in the most common selecting environment. However, many experimental results, dating back to Waddington and others, indicate that natural canalization systems may fail under extreme environments. While this can be explained as an impossibility of the system to cope with extreme morphogenic pressure, we show that a canalization system that tends to be inactivated in extreme environments is even more advantageous than rigid canalization. Moreover, once this adaptive canalization is established, the resulting evolution of primary phenotype enables substantial preadaptation to permanent environmental changes resembling extreme niches of the previous environment.
The heat-shock protein Hsp90 supports diverse but specific signal transducers and lies at the interface of several developmental pathways. We report here that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations. Multiple, previously silent, genetic determinants produced these variants and, when enriched by selection, they rapidly became independent of the Hsp90 mutation. Therefore, widespread variation affecting morphogenic pathways exists in nature, but is usually silent; Hsp90 buffers this variation, allowing it to accumulate under neutral conditions. When Hsp90 buffering is compromised, for example by temperature, cryptic variants are expressed and selection can lead to the continued expression of these traits, even when Hsp90 function is restored. This provides a plausible mechanism for promoting evolutionary change in otherwise entrenched developmental processes.
[PSI+] is a protein-based heritable phenotype of the yeast Saccharomyces cerevisiae which reflects the prion-like behaviour of the endogenous Sup35p protein release factor. [PSI+] strains exhibit a marked decrease in translation termination efficiency, which permits decoding of translation termination signals and, presumably, the production of abnormally extended polypeptides. We have examined whether the [PSI+]-induced expression of such an altered proteome might confer some selective growth advantage over [psi-] strains. Although otherwise isogenic [PSI+] and [psi-] strains show no difference in growth rates under normal laboratory conditions, we demonstrate that [PSI+] strains do exhibit enhanced tolerance to heat and chemical stress, compared with [psi-] strains. Moreover, we also show that the prion-like determinant [PSI+] is able to regulate translation termination efficiency in response to environmental stress, since growth in the presence of ethanol results in a transient increase in the efficiency of translation termination and a loss of the [PSI+] phenotype. We present a model to describe the prion-mediated regulation of translation termination efficiency and discuss its implications in relation to the potential physiological role of prions in S.cerevisiae and other fungi.
Propagation of the yeast protein-based non-Mendelian element [PSI], a prion-like form of the release factor Sup35, was shown to be regulated by the interplay between chaperone proteins Hsp104
and Hsp70. While overproduction of Hsp104 protein cures cells of [PSI], overproduction of the Ssa1 protein of the Hsp70 family protects [PSI] from the curing effect of Hsp104. Here we demonstrate that another protein of the Hsp70 family, Ssb, previously implicated
in nascent polypeptide folding and protein turnover, exhibits effects on [PSI] which are opposite those of Ssa. Ssb overproduction increases, while Ssb depletion decreases, [PSI] curing by the overproduced Hsp104. Both spontaneous [PSI] formation and [PSI] induction by overproduction of the homologous or heterologous Sup35 protein are increased significantly in the strain lacking
Ssb. This is the first example when inactivation of an unrelated cellular protein facilitates prion formation. Ssb is therefore
playing a role in protein-based inheritance, which is analogous to the role played by the products of mutator genes in nucleic
acid-based inheritance. Ssb depletion also decreases toxicity of the overproduced Sup35 and causes extreme sensitivity to
the [PSI]-curing chemical agent guanidine hydrochloride. Our data demonstrate that various members of the yeast Hsp70 family have
diverged from each other in regard to their roles in prion propagation and suggest that Ssb could serve as a proofreading
component of the enzymatic system, which prevents formation of prion aggregates.
Sequences in certain mRNAs program the ribosome to undergo a noncanonical translation event, translational frameshifting, translational hopping, or termination readthrough. These sequences are termed recoding sites, because they cause the ribosome to change temporarily its coding rules. Cis and trans-acting factors sensitively modulate the efficiency of recoding events. In an attempt to quantitate the effect of these factors we have developed a dual-reporter vector using the lacZ and luc genes to directly measure recoding efficiency. We were able to confirm the effect of several factors that modulate frameshift or readthrough efficiency at a variety of sites. Surprisingly, we were not able to confirm that the complex of factors termed the surveillance complex regulates translational frameshifting. This complex regulates degradation of nonsense codon-containing mRNAs and we confirm that it also affects the efficiency of nonsense suppression. Our data suggest that the surveillance complex is not a general regulator of translational accuracy, but that its role is closely tied to the translational termination and initiation processes.
The distinction between deleterious, neutral, and adaptive mutations is a fundamental problem in the study of molecular evolution. Two significant quantities are the fraction of DNA variation in natural populations that is deleterious and destined to be eliminated and the fraction of fixed differences between species driven by positive Darwinian selection. We estimate these quantities using the large number of human genes for which there are polymorphism and divergence data. The fraction of amino acid mutations that is neutral is estimated to be 0.20 from the ratio of common amino acid (A) to synonymous (S) single nucleotide polymorphisms (SNPs) at frequencies of > or =15%. Among the 80% of amino acid mutations that are deleterious at least 20% of them are only slightly deleterious and often attain frequencies of 1-10%. We estimate that these slightly deleterious mutations comprise at least 3% of amino acid SNPs in the average individual or at least 300 per diploid genome. This estimate is not sensitive to human population history. The A/S ratio of fixed differences is greater than that of common SNPs and suggests that a large fraction of protein divergence is adaptive and driven by positive Darwinian selection.
The prion-like behavior of Sup35p, the eRF3 homolog in the yeast Saccharomyces cerevisiae, mediates the activity of the cytoplasmic nonsense suppressor known as [PSI(+)]. Sup35p is divided into three regions of distinct function. The N-terminal and middle (M) regions are required for the induction and propagation of [PSI(+)] but are not necessary for translation termination or cell viability. The C-terminal region encompasses the termination function. The existence of the N-terminal region in SUP35 homologs of other fungi has led some to suggest that this region has an adaptive function separate from translation termination. To examine this hypothesis, we sequenced portions of SUP35 in 21 strains of S. cerevisiae, including 13 clinical isolates. We analyzed nucleotide polymorphism within this species and compared it to sequence divergence from a sister species, S. paradoxus. The N domain of Sup35p is highly conserved in amino acid sequence and is highly biased in codon usage toward preferred codons. Amino acid changes are under weak purifying selection based on a quantitative analysis of polymorphism and divergence. We also conclude that the clinical strains of S. cerevisiae are not recently derived and that outcrossing between strains in S. cerevisiae may be relatively rare in nature.
relative to genes. A microarray study shows that some dORFs are expressed even though they carry multiple disablements, and thus may be more resistant to nonsense-mediated decay. Many of the dORFs may be involved in responding to environmental stresses, as the largest functional groups include growth inhibition, flocculation, and the SRP/TIP1 family. Our results have important implications for proteome evolution. The characteristics of the dORF population suggest the sorts of genes that are likely to fall in and out of usage (and vary in copy number) in a strain-specific way and highlight the role of subtelomeric regions in engendering this diversity. Our results also have important implications for the effects of the [PSI+] prion. The dORFs disabled by only a single stop and the mORFs (together totalling 35) provide an estimate for the extent of the sequence population that can be resurrected readily through the demonstrated ability of the [PSI+] prion to cause nonsense-codon read-th
Recent studies have found high frequencies of bacteria with increased genomic rates of mutation in both clinical and laboratory populations. These observations may seem surprising in light of earlier experimental and theoretical studies. Mutator genes (genes that elevate the genomic mutation rate) are likely to induce deleterious mutations and thus suffer an indirect selective disadvantage; at the same time, bacteria carrying them can increase in frequency only by generating beneficial mutations at other loci. When clones carrying mutator genes are rare, however, these beneficial mutations are far more likely to arise in members of the much larger nonmutator population. How then can mutators become prevalent? To address this question, we develop a model of the population dynamics of bacteria confronted with ever-changing environments. Using analytical and simulation procedures, we explore the process by which initially rare mutator alleles can rise in frequency. We demonstrate that subsequent to a shift in environmental conditions, there will be relatively long periods of time during which the mutator subpopulation can produce a beneficial mutation before the ancestral subpopulations are eliminated. If the beneficial mutation arises early enough, the overall frequency of mutators will climb to a point higher than when the process began. The probability of producing a subsequent beneficial mutation will then also increase. In this manner, mutators can increase in frequency over successive selective sweeps. We discuss the implications and predictions of these theoretical results in relation to antibiotic resistance and the evolution of mutation rates.
Evolvability is an organism's capacity to generate heritable phenotypic variation. Metazoan evolution is marked by great morphological and physiological diversification, although the core genetic, cell biological, and developmental processes are largely conserved. Metazoan diversification has entailed the evolution of various regulatory processes controlling the time, place, and conditions of use of the conserved core processes. These regulatory processes, and certain of the core processes, have special properties relevant to evolutionary change. The properties of versatile protein elements, weak linkage, compartmentation, redundancy, and exploratory behavior reduce the interdependence of components and confer robustness and flexibility on processes during embryonic development and in adult physiology, They also confer evolvability on the organism by reducing constraints on change and allowing the accumulation of nonlethal variation. Evolvability may have been generally selected in the course of selection for robust, flexible processes suitable for complex development and physiology and specifically selected in lineages undergoing repeated radiations.
The paper employs methods of multitype branching processes to evaluate the probability of survival of mutable clones under environmental conditions which are unfavorable to the original parent of the clone. When other factors are taken to be constant, the long-term survival probability of a clone is implicitly demonstrated as a function of the intrinsic rate of mutation carried by this clone. The existence of a mutation rate which maximizes clone survival probability is shown and the effects of environmental deterioration on this optimal rate are studied. Finally, rigorous quantitative results are obtained for the classical situation of a Poisson distribution of offspring numbers. These results are then applied to the biological problem of indirect selection (Eshel (1972)).
A statistical mechanism of long-run selection is formulated in order to explain the evolution of modifying features governing mutation, recombination, sexual behavior, demographic mobility, and other factors that do not directly increase the individual fitness of their carrier but which are, supposedly, essential for future evolution of a population. Survival probability of a clone, rather than that of the individual, is shown to play the main role in this mechanism. Changing environment proves to be the main factor affecting it.A theoretical possibility of a long-run adaptation to the dynamics of an environmental change—rather than to a static situation resulting from it—is demonstrated.
1. Two replicate experiments were made, in which treatment by ether vapour was given to the eggs of Drosophila melanogaster 2 1/2--3 1/2 hours after laying, and selection practised either for the tendency to produce bithorax-like phenocopies ('upward selection'), or against it ('downward selection'). The two foundation stocks were both Oregon-K wild types, but had been bred separately for some considerable time. 2. Selection was effective in both directions, but its progress was not followed in detail owing to the death of many extreme phenocopies in the puparia. 3. In the 8th and 9th generations of the Up selected line of Experiment II, flies which showed a slight enlargement of the halteres appeared among the untreated individuals. These gave rise to a series of stocks, which were found to contain a dominant allele of Bxl with recessive lethal effect. 4. In the 29th generation of the Up selected line of Experiment I, similar flies were again found among untreated individuals. These gave rise to a stock (He 17), which contained a factor which was indistinguishable from that mentioned in para. 3. It might, indeed, have arisen through contamination by flies carrying that gene; but the numbers involved in the experiment (c. 150,000) make it conceivable that both occurrences of the gene were due to independent chance mutations. 5. In the 29th generation of the Up selected line of Experiment I there also occurred, among untreated individuals, some showing the metathorax partially converted into a mesothorax. These gave rise to a stock He*, in which the bithorax phenotype appears in high frequency and extreme grade. The genetic basis of the character is partly a recessive gene which causes females to produce eggs developing into bithorax phenotypes (a maternal effect), and partly a number of minor genes on both the second and third chromosomes. 6. Selection for sensitivity to one type of environmental stimulus does not necessarily produce susceptibility to stimuli of a different type. 7. The fact that such a bizarre phenotype as bithorax can be assimilated, with high grade expression, in less than 30 generations, suggests that the genetic assimilation mechanism is a very powerful one, which could have far-reaching effects during evolution.
How might several independent genetic changes occur in concert to produce a new form or function? One solution is to posit the existence of mechanisms that allow changes to accumulate in a temporarily neutral fashion. Such a mechanism was proposed in 1972 when Koch1 extended Ohno's recognition of the importance of gene duplications in the evolution of new functions2 to include inactivation, modification and reactivation. A duplicated gene that is retained in an inactive state would be free to accumulate varia- tions that might compromise fitness, and beneficial combinatorial change could occur upon reactivation1. Gene duplications are common and these genes frequently acquire divergent functions3-5, indicating that such a mechanism may have operated widely in evolution. However, the known mechanisms for the reactivation of inactive genes work sporadically, act infrequently and provide no obvious means for sampling coding changes in several genes simultaneously6. Here we report that a protein-based element of inheritance (a prion) in the yeast Saccharomyces cerevisiae provides a means to expose this and other types of silent protein-coding information. The prion (PSI+) reduces the fidelity with which ribosomes termi- nate translation at stop codons in a metastable, heritable manner7-9. The reduction in translational fidelity caused by (PSI+) is routinely
1. The phenocopy “dumpy”, produced by 40°C treatment of 16–18 hour pupae, was selected for 30 generations. The duration of
treatment was gradually reduced from 4 1/2 to 2 hours. Phenocopy frequency in the last generation was 95%.
2. In untreated flies weakly dumpy wings first appeared in generation 25. From these an assimilated stock was established
in which, after 8 generations of selection, penetrance was 58%.
3. The genetical analysis of this stock showed that assimilated dumpy is produced only in the presence of the recessive lethal
genedp
TP2.
4. There is evidence that a second recessive lethal gene, which forms withdp
TP2 a balanced lethal system, enhances, and possibly is obligatory for, the production of the dumpy phenotype bydp
TP2.
5. The frequency ofdp
TP2, and possibly also of the second gene, was increased by phenocopy selection; the frequency of both genes was increased by
selection without treatment.
6. Successful selection for expression in the assimilated dumpy stock indicated that modifying genes are also involved. The
assimilation of dumpy, like that of crossveinless, appears therefore to have depended on major-genes and modifiers.
7. It is suggested thatdp
TP2 arose during the course of phenocopy selection as a consequence of the hot-shock treatment, and that this is the major difference
between the dumpy and crossveinless experiments.
1. A wild Edinburgh strain of D. melanogaster produced no flies showing a break in the posterior crossvein when bred at 25⚬ C., but a certain number occurred (as phenocopies) when the pupae aged 21-23 hours were subjected to 40⚬ C. for four hours. 2. Selection was practised for and against the appearance of the phenocopy, and rapid progress occurred in both directions. After about 14 generations of selection, some flies in the upward selected strain were found to show the effect even when not exposed to the heat shock. From these, lines were built up which threw a high proportion of crossveinless individuals when kept continuously at 25⚬ C. (and even more at 18⚬ C.). 3. The crossveinless character, originally a typical 'acquired character,' has become incorporated into the genetic make up of the selected races. A process of 'genetic assimilation' is described by which this might be supposed to happen; it depends on the tendency of selection not merely to increase the frequency of any favorable character, but also to stabilise its development. A similar suggestion has been advanced by Schmalhausen (1947). 4. The genetic basis of the assimilated crossveinless character is polygenic. There is little evidence of any definite distinction between canalising and switch genes.
Complex Adaptations and the Evolution of Evolvability +representation problem: "evolvability critically depends on the way genetic variation maps onto phenotypic variation" +Evidence that phenotypic variation is under genetic control: canalization; mutant phenotypes often show more variation than the wild phenotype (see p.7) "the variability of the traits itself can evolve" +cites Halder1995: Drosophila eyeless - out-of-place eye production can be triggered by a single signal +"genotype-phenotype map underlying theme of: genetic canalization, developmental constraints, biological versatility, developmental dissociability, morphological integration" and more +genotype-phenotype map evolves, main selective forces: epistatic mutations, creation of new genes +"Variability needs to be distinguished from variation" (variability: potential to vary [*dispositional* concept, not actual state but expected development of a phenotypic trait in response to genetic and environmental influences] - variation: actually realized differences between individuals) +cites Levinton1988: generation of variability needs to be studied +Evolution of complex adaptations requires a match between the functional relationships of the phenotypic characters and their genetic representation - cites Riedl1975: "If the epigenetic regulation of gene expression 'imitates' the functional organization of the traits then the improvement by mutation and selection is facilitated" (helps when sexual recombination, p.11) +cites Wright1968 "Pleiotropy cannot be wholly universal" - how limit: modularity, interaction mainly short range, less frequent between members of different complexes +evolution of modularity: origin of differentiated animals dominated by parcellation / detachment (opposed to integration of distinct parts) but where shall we put delimitations???
In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by approximately 6500-fold. Their average mutation rates per base pair vary by approximately 16,000-fold, whereas their mutation rates per genome vary by only approximately 2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates.
The joint evolution of major genes under viability selection and a modifier locus that controls recombination between the major genes, mutation at the major gene, or migration between two demes is studied. The modifying locus is selectively neutral and may have an arbitrary number of alleles. For each case a class of polymorphic equilibria exists in which the frequencies of the modifying alleles are those computed by assuming that the recombination, mutation, or migration rates were viabilities and in which the major and modifier loci are not statistically associated. These are called viability-analogous Hardy-Weinberg (VAHW) equilibria. A new allele introduced near these equilibria will enter the population if its marginal average rate of recombination, mutation, or migration (whichever applies) is less than the population average prior to its introduction. Stability properties of these VAHW equilibria are also reported.
Mutants of [ psi ] a cytoplasmically inherited factor in the yeast Saccharomyces cerevisiae were isolated after treatment with a variety of agents including conventional mutagens and a number of compounds which cause loss of [ psi ] at high frequencies, namely methanol, KCl, dimethyl sulphoxide and guanidine hydrochloride. In [ psi ⁻ ] mutants the suppressor SUQ5 does not suppress ochre mutations such as ade.2.1 .
Reversion analysis of the [ psi ⁻ ] mutants revealed three classes: (1) a class of agents producing [ psi ⁻ ] mutations which could readily revert to [ psi ⁺ ] (methanol, KCl and dimethyl sulphoxide belong to this class), (2) those which could not be shown to revert (GuHCl) and (3) the conventional mutagens which produced both revertible and apparently non-revertible [ psi ⁻ ] mutations. We conclude that GuHCl causes a deletion or loss of the [ psi ] factor. Methanol may cause an alteration of ‘state’ for example, of a promoter, and KCl may be selecting or inducing low copy number variants of [ psi ⁺ ] strains. It is possible that DMSO may be involved in regulation of [ psi ].
[URE3] is a non-Mendelian genetic element that mimics recessive mutations in the chromosomal URE2 gene making cells derepressed for nitrogen catabolic enzymes. [PSI] is a non-Mendelian enhancer of readthrough of translational termination similar in its effects to some mutations in the chromosomal SUP35 gene. Three lines of evidence led to the proposal that both [URE3] and [PSI] are prions, infectious proteins analogous to the scrapie agent mediating transmissible spongiform encephalopathies of mammals. 1) Both [PSI] and [URE3] are reversibly curable. 2) [PSI] propagation requires SUP35 and [URE3] propagation requires URE2 with recessive chromosomal mutants having the same phenotypes as the presence of the respective dominant non-Mendelian element. 3) Overproduction of Sup35p and Ure2p increases the frequency of cells acquiring [PSI] or [URE3], respectively.
Saccharomyces cerevisiae prion [PSI ] is a self-propagating isoform of the eukaryotic release factor eRF3 (Sup35p). Sup35p consists of the evolutionary conserved release factor domain (Sup35C) and two evolutionary variable regions - Sup35N, which serves as a prion-forming domain in S. cerevisiae, and Sup35M. Here, we demonstrate that the prion form of Sup35p is not observed among industrial and natural strains of yeast. Moreover, the prion ([PSI + ]) state of the endogenous S. cerevisiae Sup35p cannot be transmitted to the next generations via heterologous Sup35p or Sup35NM, originating from the distantly related yeast species Pichia methanolica. This suggests the existence of a 'species barrier' in yeast prion conversion. However, the chimeric Sup35p, containing the Sup35NM region of Pichia, can be turned into a prion in S. cerevisiae by overproduction of the identical Pichia Sup35NM. Therefore, the prion-forming potential of Sup35NM is conserved in evolution. In the heterologous system, overproduction of Pichia Sup35p or Sup35NM induced formation of the prion form of S. cerevisiae Sup35p, albeit less efficiently than overproduction of the endogenous Sup35p. This implies that prion induction by protein overproduction does not require strict correspondence of the 'inducer' and 'inducee' sequences, and can overcome the 'species barrier'.
A major enigma in evolutionary biology is that new forms or functions often require the concerted effects of several independent genetic changes. It is unclear how such changes might accumulate when they are likely to be deleterious individually and be lost by selective pressure. The Saccharomyces cerevisiae prion [PSI+] is an epigenetic modifier of the fidelity of translation termination, but its impact on yeast biology has been unclear. Here we show that [PSI+] provides the means to uncover hidden genetic variation and produce new heritable phenotypes. Moreover, in each of the seven genetic backgrounds tested, the constellation of phenotypes produced was unique. We propose that the epigenetic and metastable nature of [PSI+] inheritance allows yeast cells to exploit pre-existing genetic variation to thrive in fluctuating environments. Further, the capacity of [PSI+] to convert previously neutral genetic variation to a non-neutral state may facilitate the evolution of new traits.
In yeast, a modified protein known as a prion generates variation in growth rate across diverse environments. Is this an example of an agent that has evolved in order to promote its possessor's adaptability?
Natural selection can adjust the rate of mutation in a population by acting on allelic variation affecting processes of DNA replication and repair. Because mutation is the ultimate source of the genetic variation required for adaptation, it can be appealing to suppose that the genomic mutation rate is adjusted to a level that best promotes adaptation. Most mutations with phenotypic effects are harmful, however, and thus there is relentless selection within populations for lower genomic mutation rates. Selection on beneficial mutations can counter this effect by favoring alleles that raise the mutation rate, but the effect of beneficial mutations on the genomic mutation rate is extremely sensitive to recombination and is unlikely to be important in sexual populations. In contrast, high genomic mutation rates can evolve in asexual populations under the influence of beneficial mutations, but this phenomenon is probably of limited adaptive significance and represents, at best, a temporary reprieve from the continual selection pressure to reduce mutation. The physiological cost of reducing mutation below the low level observed in most populations may be the most important factor in setting the genomic mutation rate in sexual and asexual systems, regardless of the benefits of mutation in producing new adaptive variation. Maintenance of mutation rates higher than the minimum set by this "cost of fidelity" is likely only under special circumstances.
The experimental evidence accumulated for the last half of the century clearly suggests that inherited variation is not restricted to the changes in genomic sequences. The prion model, originally based on unusual transmission of certain neurodegenerative diseases in mammals, provides a molecular mechanism for the template-like reproduction of alternative protein conformations. Recent data extend this model to protein-based genetic elements in yeast and other fungi. Reproduction and transmission of yeast protein-based genetic elements is controlled by the "prion replication" machinery of the cell, composed of the protein helpers responsible for the processes of assembly and disassembly of protein structures and multiprotein complexes. Among these, the stress-related chaperones of Hsp100 and Hsp70 groups play an important role. Alterations of levels or activity of these proteins result in "mutator" or "antimutator" affects in regard to protein-based genetic elements. "Protein mutagens" have also been identified that affect formation and/or propagation of the alternative protein conformations. Prion-forming abilities appear to be conserved in evolution, despite the divergence of the corresponding amino acid sequences. Moreover, a wide variety of proteins of different origins appear to possess the ability to form amyloid-like aggregates, that in certain conditions might potentially result in prion-like switches. This suggests a possible mechanism for the inheritance of acquired traits, postulated in the Lamarckian theory of evolution. The prion model also puts in doubt the notion that cloned animals are genetically identical to their genome donors, and suggests that genome sequence would not provide a complete information about the genetic makeup of an organism.
For over 30 years a central question in molecular evolution has been whether natural selection plays a substantial role in evolution at the DNA sequence level. Evidence has accumulated over the last decade that adaptive evolution does occur at the protein level, but it has remained unclear how prevalent adaptive evolution is. Here we present a simple method by which the number of adaptive substitutions can be estimated and apply it to data from Drosophila simulans and D. yakuba. We estimate that 45% of all amino-acid substitutions have been fixed by natural selection, and that on average one adaptive substitution occurs every 45 years in these species.
Inactivation of Hsp104 by guanidine is contended to be the mechanism by which guanidine cures yeast prions. We now find an Hsp104 mutation (D184N) that confers resistance to guanidine-curing of the yeast [PSI(+)] prion. In an independent screen we isolated an HSP104 allele altered in the same residue (D184Y) that dramatically impairs [PSI(+)] propagation in a temperature-dependent manner. Directed mutagenesis of HSP104 produced additional alleles that conferred varying degrees of resistance to guanidine-curing or impaired [PSI(+)] propagation. The mutations similarly affected propagation of the [URE3] prion. Basal and induced abundance of all mutant proteins was normal. Thermotolerance of cells expressing mutant proteins was variably resistant to guanidine, and the degree of thermotolerance did not correlate with [PSI(+)] stability. We thus show that guanidine cures yeast prions by inactivating Hsp104 and identify a highly conserved Hsp104 residue that is critical for yeast prion propagation. Our data suggest that Hsp104 activity can be reduced substantially without affecting [PSI(+)] stability, and that Hsp104 interacts differently with prion aggregates than with aggregates of thermally denatured protein.
Evolvability is an organism's capacity to generate heritable phenotypic variation. Metazoan evolution is marked by great morphological and physiological diversification, although the core genetic, cell biological, and developmental processes are largely conserved. Metazoan diversification has entailed the evolution of various regulatory processes controlling the time, place, and conditions of use of the conserved core processes. These regulatory processes, and certain of the core processes, have special properties relevant to evolutionary change. The properties of versatile protein elements, weak linkage, compartmentation, redundancy, and exploratory behavior reduce the interdependence of components and confer robustness and flexibility on processes during embryonic development and in adult physiology. They also confer evolvability on the organism by reducing constraints on change and allowing the accumulation of nonlethal variation. Evolvability may have been generally selected in the course of selection for robust, flexible processes suitable for complex development and physiology and specifically selected in lineages undergoing repeated radiations.
: The problem of complex adaptations is studied in two largely disconnected research traditions: evolutionary biology and evolutionary computer science. This paper summarizes the results from both areas and compares their implications. In evolutionary computer science it was found that the Darwinian process of mutation, recombination and selection is not universally effective in improving complex systems like computer programs or chip designs. For adaptation to occur, these systems must possess "evolvability", i.e. the ability of random variations to sometimes produce improvement. It was found that evolvability critically depends on the way genetic variation maps onto phenotypic variation, an issue known as the representation problem. The genotype-phenotype map determines the variability of characters, which is the propensity to vary. Variability needs to be distinguished from variation, which are the actually realized differences between individuals. The genotype-phenotype map is the ...
- M Kirschner
- J Gerhart
Kirschner, M., and J. Gerhart. 1998. Evolvability. Proc. Natl. Acad.
Sci. U.S.A. 95:8420–8427.