Homeostasis and dynamic stability of the phenotype link robustness and plasticity.
Journal Article (Journal Article)
Phenotypes are remarkably robust to genetic and environmental variation. Although the general control principles of robustness are well understood in simple systems, the actual mechanisms that convey robustness in realistically complex systems have been little studied. We have studied the origins and properties of robustness in a complex metabolic system that is relevant to human health: folate-mediated one-carbon metabolism (FOCM). The FOCM network consists of several interlocking cycles, and reactions in the system contain the rate-limiting steps for DNA synthesis, the reactions for DNA methylation, and the synthesis of glutathione, the primary endogenous anti-oxidant. Defects in FOCM can arise from mutations in enzymes, or from nutritional deficiencies such as folic acid and vitamins B6 and B12, and are associated with birth defects, anemia, cardiovascular disease, and cancer. We show that this metabolic network has evolved as diverse homeostatic mechanisms that stabilize critical reactions against genetic and environmental variation. These mechanisms achieve stability dynamically, by continually altering some reaction rates in order to keep critical reactions stable. Robustness is a systems property and exists only in restricted regions of genotype space, and we show that natural standing genetic variation in human populations is concentrated in these regions. We show how genetic perturbations and/or environmental shifts that disrupt the homeostatic regime can increase phenotypic variation and the correlation between standing genetic variation and phenotypic variation. Robustness and stability are never perfect and, because they are maintained dynamically, can be readily perturbed by both genetic and environmental factors. The tightrope between stability and change sways easily and, through the release of genetic variation, may be an important enabler of rapid phenotypic evolution. Although we use examples from a metabolic system in which quantification of mechanism is particularly accessible, we note that the same principles obtain in other homeostatic systems in physiology and development.
Full Text
Duke Authors
Cited Authors
- Nijhout, HF; Reed, MC
Published Date
- July 2014
Published In
Volume / Issue
- 54 / 2
Start / End Page
- 264 - 275
PubMed ID
- 24729131
Electronic International Standard Serial Number (EISSN)
- 1557-7023
International Standard Serial Number (ISSN)
- 1540-7063
Digital Object Identifier (DOI)
- 10.1093/icb/icu010
Language
- eng