Protein Homeostasis and the Phenotypic Manifestation of Genetic Diversity: Principles and Mechanisms

Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute, Cambridge, Massachusetts 02142, USA.
Annual Review of Genetics (Impact Factor: 15.72). 12/2010; 44(1):189-216. DOI: 10.1146/annurev.genet.40.110405.090412
Source: PubMed


Changing a single nucleotide in a genome can have profound consequences under some conditions, but the same change can have no consequences under others. Indeed, organisms can be surprisingly robust to environmental and genetic perturbations. Yet, the mechanisms underlying such robustness are controversial. Moreover, how they might affect evolutionary change remains enigmatic. Here, we review the recently appreciated central role of protein homeostasis in buffering and potentiating genetic variation and discuss how these processes mediate the critical influence of the environment on the relationship between genotype and phenotype. Deciphering how robustness emerges from biological organization and the mechanisms by which it is overcome in changing environments will lead to a more complete understanding of both fundamental evolutionary processes and diverse human diseases.

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Available from: Daniel Jarosz, Feb 26, 2015
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    • "Indeed, we observe that Ssn6 repeat expansion can, in some instances, have beneficial outcomes (e.g., higher fitness in alternative carbon sources). Chaperones like Ssa2 might help buffer the potentially negative effects of repeat variation , except in times of stress where the chaperone system can be overstretched, which can lead to the uncovering of the previously buffered effects of Q-repeat variation (Jarosz et al., 2010). Our results agree with previous studies that show correlations between variation in TRs and phenotypes (Gemayel et al., 2010). "
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    ABSTRACT: Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator's innate function, with the inherent risk of pathogenic repeat expansions. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Molecular cell 08/2015; 59(4). DOI:10.1016/j.molcel.2015.07.003 · 14.02 Impact Factor
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    • "Two phenomena are worthy of particular mention. First, there is now a large body of evidence to suggest that HSP90 acts as a buffer against phenotypic variation by masking the effects of genetic polymorphisms (Jarosz et al, 2010). "
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    ABSTRACT: Aneuploidy is a hallmark of cancer and is associated with malignancy and poor prognosis. Recent studies have revealed that aneuploidy inhibits proliferation, causes distinct alterations in the transcriptome and proteome and disturbs cellular proteostasis. However, the molecular mechanisms underlying the changes in gene expression and the impairment of proteostasis are not understood. Here, we report that human aneuploid cells are impaired in HSP90-mediated protein folding. We show that aneuploidy impairs induction of the heat shock response suggesting that the activity of the transcription factor heat shock factor 1 (HSF1) is compromised. Indeed, increased levels of HSF1 counteract the effects of aneuploidy on HSP90 expression and protein folding, identifying HSF1 overexpression as the first aneuploidy-tolerating mutation in human cells. Thus, impaired HSF1 activity emerges as a critical factor underlying the phenotypes linked to aneuploidy. Finally, we demonstrate that deficient protein folding capacity directly shapes gene expression in aneuploid cells. Our study provides mechanistic insight into the causes of the disturbed proteostasis in aneuploids and deepens our understanding of the role of HSF1 in cytoprotection and carcinogenesis.
    The EMBO Journal 09/2014; 33(20). DOI:10.15252/embj.201488648 · 10.43 Impact Factor
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    • "As shown in Fig. 1, low scores on both genetic variables were clearly associated with higher EF scores, but little difference was noted among the other three groups shown in the figure, i.e., individuals who were high on one and not the other, or those high on both. This pattern of interaction between the two genetic variables suggests antagonistic epistasis (Jarosz et al., 2010), i.e., no additional adverse effects are seen when both types of genetic risks are high, as compared to when a single one is high. One possible reason for this pattern is that the two genetic factors may act on similar neurodevelopmental pathways. "
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    ABSTRACT: Background Cognitive deficits are prominent in schizophrenia and represent promising endophenotypes for genetic research. Methods The current study investigated the importance of two conceptually distinct genetic aggregates, one based on copy number variations (uncommon deletion burden), and one based on single nucleotide polymorphisms identified in recent risk studies (genetic risk score). The impact of these genetic factors, and their interaction, was examined on cognitive endophenotypes defined by principal component analysis (PCA) in a multi-center sample of 50 patients with schizophrenia and 86 controls. PCA was used to identify three different types of executive function (EF: planning, fluency, and inhibition), and in separate analyses, a measure general cognitive ability (GCA). Results Cognitive deficits were prominent among individuals with schizophrenia, but no group differences were evident for either genetic factor. Among patients the deletion burden measures predicted cognitive deficits across the three EF components and GCA. Further, an interaction was noted between the two genetic factors for both EF and GCA and the observed patterns of interaction suggested antagonistic epistasis. In general, the set of genetic interactions examined predicted a substantial portion of variance in these cognitive endophenotypes. Limitations Though adequately powered, our sample size is small for a genetic study. Conclusions These results draw attention to genetic interactions and the possibility that genetic influences on cognition differ in patients and controls.
    Schizophrenia Research 06/2014; 156(1). DOI:10.1016/j.schres.2014.03.022 · 3.92 Impact Factor
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