Biomedical subjects

Christopher G Knight

Publications and source records attributed to Christopher G Knight.

5 recordsLinked to original sources

PubMed2025

Deciphering the Impact of Temperature on Pleiotropic Consequences of RNA Polymerase Mutations.

Despite occurring in an essential molecule, mutations in RNA polymerase readily emerge and elicit complex pleiotropic effects across different levels of biological organization, which are all modulated by environment. We investigated the impact of temperature on the effects of six mutations on sequence, structure, transcriptome, and organismal traits. We found temperature altered the transcriptomic response and key organismal traits such as growth rate and biofilm formation in a genotype-specific manner. Critically, mechanistic insights into the possible drivers of mutational effects emerged only when examining the relationships between different levels of organization: location of mutations in the tertiary structure and distance to key interacting molecules partly explained the observed transcriptomic differences, which in turn drove the impact of mutations on organismal traits. While falling short of capturing the full complexity of the system, our findings underscore the benefits of integrating insights across multiple biological levels to understand the relationship between environment and mutational effects in molecules with extensive pleiotropic effects.

Mutation↗

PubMed2006

Unraveling adaptive evolution: how a single point mutation affects the protein coregulation network.

Understanding the mechanisms of evolution requires identification of the molecular basis of the multiple (pleiotropic) effects of specific adaptive mutations. We have characterized the pleiotropic effects on protein levels of an adaptive single-base pair substitution in the coding sequence of a signaling pathway gene in the bacterium Pseudomonas fluorescens SBW25. We find 52 proteomic changes, corresponding to 46 identified proteins. None of these proteins is required for the adaptive phenotype. Instead, many are found within specific metabolic pathways associated with fitness-reducing (that is, antagonistic) effects of the mutation. The affected proteins fall within a single coregulatory network. The mutation 'rewires' this network by drawing particular proteins into tighter coregulating relationships. Although these changes are specific to the mutation studied, the quantitatively altered proteins are also affected in a coordinated way in other examples of evolution to the same niche.

Adaptation, Physiological↗

PubMed2004

Global analysis of predicted proteomes: functional adaptation of physical properties.

The physical characteristics of proteins are fundamentally important in organismal function. We used the complete predicted proteomes of >100 organisms spanning the three domains of life to investigate the comparative biology and evolution of proteomes. Theoretical 2D gels were constructed with axes of protein mass and charge (pI) and converted to density estimates comparable across all types and sizes of proteome. We asked whether we could detect general patterns of proteome conservation and variation. The overall pattern of theoretical 2D gels was strongly conserved across all life forms. Nevertheless, coevolved replicons from the same organism (different chromosomes or plasmid and host chromosomes) encode proteomes more similar to each other than those from different organisms. Furthermore, there was disparity between the membrane and nonmembrane subproteomes within organisms (proteins of membrane proteomes are on the average more basic and heavier) and their variation across organisms, suggesting that membrane proteomes evolve most rapidly. Experimentally, a significant positive relationship independent of phylogeny was found between the predicted proteome and Biolog profile, a measure associated with the ecological niche. Finally, we show that, for the smallest and most alkaline proteomes, there is a negative relationship between proteome size and basicity. This relationship is not adequately explained by AT bias at the DNA sequence level. Together, these data provide evidence of functional adaptation in the properties of complete proteomes.

Animals↗

PubMed2002

Evolution of germ-line signals that regulate growth and aging in nematodes.

We show that a signal from the germ line represses growth in the nematode Caenorhabditis elegans. Laser-microbeam ablation of cells that give rise to the germ line causes adults to become giant. Ablation of these cells in self-sterile mutant worms also causes gigantism, suggesting that the germ line represses growth because it is the source of a growth-antagonizing signal rather than because of a sink of resources required for reproduction. The C. elegans germ line also emits a signal that represses longevity. This longevity-repressing signal requires the activity of DAF-16, a forkhead/winged-helix transcription factor, but we find that that the growth-repressing signal does not. The growth-repressing signal also does not require the activity of DBL-1, a transforming growth factor beta-related protein that promotes growth in worms. By ablating the germ-line precursors of other species of free-living nematodes, we also found that both the growth-repressing and longevity-repressing signals are evolutionarily variable. Some species have both signals; others have just one or the other. We suggest that variation in germ-line signaling contributes to body size and life-history diversity in the nematodes.

Aging↗

PubMedDate not supplied

A novel mode of ecdysozoan growth in Caenorhabditis elegans.

Whereas growth in many ecdysozoa is associated with only molting, larval growth in nematodes, specifically Caenorhabditis elegans, is thought to be continuous and exponential. However, this has never been closely investigated. Here we report several detailed studies of growth in wild-type and dwarf C. elegans strains. We find that apparent exponential growth between hatching and adulthood comprises a series of linear phases, one per larval stage, with the linear growth rate increasing at successive molts. Although most structures grow continuously, the buccal cavity does not; instead, it grows saltationally at molts, like arthropod structures. We speculate that these saltational changes in mouth size permit changes in growth rate and that molting exists in nematodes to facilitate rapid growth. We study the cellular basis of this growth in the hypodermis. At each larval stage, lateral seam cells produce daughters that fuse with hyp7, a syncytium covering most of the worm. We find that seam cells and fusing daughter cells obtain larger sizes in successive molts. The total seam cell volume remains constant relative to the size of the worm. However, fusing daughter cells contributes only a very small amount directly to hypodermal growth, suggesting that most hyp7 growth must be intrinsic. Thus, dwarfism mutations studied principally act via adult syncytial growth, with cell size being near normal in both dbl-1 and dpy-2 mutant worms. We speculate that the main function of seam cell proliferation may be to supply the hypodermis with additional genomes for the purpose of growth.

Animals↗