Biomedical subjects

Suzannah Rutherford

Publications and source records attributed to Suzannah Rutherford.

3 recordsLinked to original sources

PubMed2007

Hsp90 and developmental networks.

The most abundant cytoplasmic chaperone of eukaryotic cells, Hsp90 is a hub in developmental regulatory networks and the first example described of the phenomenon of molecular buffering. As a chaperone for many different signaling proteins, Hsp90 maintains the clarity and strength of communication within and between cells, concealing developmental and stochastic variations that otherwise cause abrupt morphological changes in a large variety of organisms, including Drosophila and Arabidopsis. The chapter provides a framework for understanding how Hsp90 controls the sudden appearance of novel morphologies. We start with a discussion of the longstanding problem of hidden polygenic variation and then introduce the idea of signal transduction thresholds in mediating the effect of Hsp90 on the expression of phenotypic variation. This leads to a discussion of the role of nonlinearity in creating thresholds for sudden changes in cellular responses to developmental signals. We end with speculation on the potentially pivotal role of Hsp90 in controlling the developmental networks that determine morphological stasis and change in evolution.

Animals↗

PubMed2006

Control of canalization and evolvability by Hsp90.

Partial reduction of Hsp90 increases expression of morphological novelty in qualitative traits of Drosophila and Arabidopsis, but the extent to which the Hsp90 chaperone also controls smaller and more likely adaptive changes in natural quantitative traits has been unclear. To determine the effect of Hsp90 on quantitative trait variability we deconstructed genetic, stochastic and environmental components of variation in Drosophila wing and bristle traits of genetically matched flies, differing only by Hsp90 loss-of-function or wild-type alleles. Unexpectedly, Hsp90 buffering was remarkably specific to certain normally invariant and highly discrete quantitative traits. Like the qualitative trait phenotypes controlled by Hsp90, highly discrete quantitative traits such as scutellor and thoracic bristle number are threshold traits. When tested across genotypes sampled from a wild population or in laboratory strains, the sensitivity of these traits to many types of variation was coordinately controlled, while continuously variable bristle types and wing size, and critically invariant left-right wing asymmetry, remained relatively unaffected. Although increased environmental variation and developmental noise would impede many types of selection response, in replicate populations in which Hsp90 was specifically impaired, heritability and 'extrinsic evolvability', the expected response to selection, were also markedly increased. However, despite the overall buffering effect of Hsp90 on variation in populations, for any particular individual or genotype in which Hsp90 was impaired, the size and direction of its effects were unpredictable. The trait and genetic-background dependence of Hsp90 effects and its remarkable bias toward invariant or canalized traits support the idea that traits evolve independent and trait-specific mechanisms of canalization and evolvability through their evolution of non-linearity and thresholds. Highly non-linear responses would buffer variation in Hsp90-dependent signaling over a wide range, while over a narrow range of signaling near trait thresholds become more variable with increasing probability of triggering all-or-none developmental responses.

Animal Structures↗

PubMed2006

Modularity and intrinsic evolvability of Hsp90-buffered change.

Hsp90 controls dramatic phenotypic transitions in a wide array of morphological features of many organisms. The genetic-background dependence of specific abnormalities and their response to laboratory selection suggested Hsp90 could be an 'evolutionary capacitor', allowing developmental variation to accumulate as neutral alleles under normal conditions and manifest selectable morphological differences during environmental stress. The relevance of Hsp90-buffered variation for evolution has been most often challenged by the idea that large morphological changes controlled by Hsp90 are unconditionally deleterious. To address this issue, we tested an Hsp90-buffered abnormality in Drosophila for unselected pleiotropic effects and correlated fitness costs. Up to 120-fold differences in penetrance among six highly related selection lines, started from an initially small number of flies and rapidly selected for and against a deformed eye trait (dfe), did not translate into measurable differences in any of several tests of viability, lifespan or competitive fitness. Nor were 17 dfe Quantitative Trait Loci (QTL) associated with fitness effects in over 1,400 recombinant lines. Our ability to detect measurable effects of inbreeding, media environment and the white mutation in the selection line backgrounds independent of dfe penetrance suggests that, within the limitations of laboratory tests of fitness, this large morphological change controlled by Hsp90 was selectable independent of strong, correlated and unconditionally deleterious effects--abundant, polygenic variation hidden by Hsp90 allows potentially deleterious alleles to be readily replaced during selection by less deleterious alleles with similar phenotypic effects. Hsp90 links environmental stress with the expression of developmental variation controlling unprecedented morphological plasticity. As outlined here and in the companion paper of this issue, the complex genetic architecture of Hsp90-buffered variation supports a remarkable modularity of Hsp90 effects on quantitative and qualitative phenotypes, consistent with the 'Hsp90 capacitor hypothesis' and standard quantitative genetic models of threshold traits.

Alleles↗