A Gene's Ability to Buffer Variation Is Predicted by Its Fitness Contribution and Genetic Interactions

BACKGROUND: Many single-gene knockouts result in increased phenotypic (e.g., morphological) variability among the mutant's offspring. This has been interpreted as an intrinsic ability of genes to buffer genetic and environmental variation. A phenotypic capacitor is a gene that appears to mask phenotypic variation: when knocked out, the offspring shows more variability than the wild type. Theory predicts that this phenotypic potential should be correlated with a gene's knockout fitness and its number of negative genetic interactions. Based on experimentally measured phenotypic capacity, it was suggested that knockout fitness was unimportant, but that phenotypic capacitors tend to be hubs in genetic and physical interaction networks. METHODOLOGY/PRINCIPAL FINDINGS: We re-analyse the available experimental data in a combined model, which includes knockout fitness and network parameters as well as expression level and protein length as predictors of phenotypic potential. Contrary to previous conclusions, we find that the strongest predictor is in fact haploid knockout fitness (responsible for 9% of the variation in phenotypic potential), with an additional contribution from the genetic interaction network (5%); once these two factors are taken into account, protein-protein interactions do not make any additional contribution to the variation in phenotypic potential. CONCLUSIONS/SIGNIFICANCE: We conclude that phenotypic potential is not a mysterious "emergent" property of cellular networks. Instead, it is very simply determined by the overall fitness reduction of the organism (which in its compromised state can no longer compensate for multiple factors that contribute to phenotypic variation), and by the number (and presumably nature) of genetic interactions of the knocked-out gene. In this light, Hsp90, the prototypical phenotypic capacitor, may not be representative: typical phenotypic capacitors are not direct "buffers" of variation, but are simply genes encoding central cellular functions

Environmental Stress-Dependent Effects of Deletions Encompassing Hsp70Ba on Canalization and Quantitative Trait Asymmetry in Drosophila melanogaster

Hsp70 genes may influence the expression of wing abnormalities in Drosophila melanogaster but their effects on variability in quantitative characters and developmental instability are unclear. In this study, we focused on one of the six Hsp70 genes, Hsp70Ba, and investigated its effects on within-and among-individual variability in orbital bristle number, sternopleural bristle number, wing size and wing shape under different environmental conditions. To do this, we studied a newly constructed deletion, Df(3R)ED5579, which encompasses Hsp70Ba and nine non-Hsp genes, in the heterozygous condition and another, Hsp70Ba304, which deletes only Hsp70Ba, in the homozygous condition. We found no significant effect of both deletions on within-individual variation quantified by fluctuating asymmetry (FA) of morphological traits. On the other hand, the Hsp70Ba304/Hsp70Ba304 genotype significantly increased among-individual variation quantified by coefficient of variation (CV) of bristle number and wing size in female, while the Df(3R)ED5579 heterozygote showed no significant effect. The expression level of Hsp70Ba in the deletion heterozygote was 6 to 20 times higher than in control homozygotes, suggesting that the overexpression of Hsp70Ba did not influence developmental stability or canalization significantly. These findings suggest that the absence of expression of Hsp70Ba increases CV of some morphological traits and that HSP70Ba may buffer against environmental perturbations on some quantitative traits

Heterozygous Yeast Deletion Collection Screens Reveal Essential Targets of Hsp90

Hsp90 is an essential eukaryotic chaperone with a role in folding specific “client” proteins such as kinases and hormone receptors. Previously performed homozygous diploid yeast deletion collection screens uncovered broad requirements for Hsp90 in cellular transport and cell cycle progression. These screens also revealed that the requisite cellular functions of Hsp90 change with growth temperature. We present here for the first time the results of heterozygous deletion collection screens conducted at the hypothermic stress temperature of 15°C. Extensive bioinformatic analyses were performed on the resulting data in combination with data from homozygous and heterozygous screens previously conducted at normal (30°C) and hyperthermic stress (37°C) growth temperatures. Our resulting meta-analysis uncovered extensive connections between Hsp90 and (1) general transcription, (2) ribosome biogenesis and (3) GTP binding proteins. Predictions from bioinformatic analyses were tested experimentally, supporting a role for Hsp90 in ribosome stability. Importantly, the integrated analysis of the 15°C heterozygous deletion pool screen with previously conducted 30°C and 37°C screens allows for essential genetic targets of Hsp90 to emerge. Altogether, these novel contributions enable a more complete picture of essential Hsp90 functions

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion