Disease from opposing forces in regulatory control

Abstract

Danger requires a strong rapid response. Speedy triggers are prone to false signals. False alarms can be costly, requiring strong negative regulators to oppose the initial triggers. Strongly opposed forces can easily be perturbed, leading to imbalance and disease. For example, immunity and fear response balance strong rapid triggers against widespread slow negative regulators. Diseases of immunity and behavior arise from imbalance. A different opposition of forces occurs in mammalian growth, which balances strong paternally expressed accelerators against maternally expressed suppressors. Diseases of overgrowth or undergrowth arise from imbalance. Other examples of opposing forces and disease include control of dopamine expression and male versus female favored traits.

Keywords: IGF2; genomic conflict; genomic imprinting; immune system disorder; psychiatric disorder; sexual antagonism.

Figure 1.

One way in which opposing forces from conflict may lead to disease. Two conflicting parties, β and δ, favor different trait values. (A) The conflicting parties develop opposing forces acting on the trait. (B) Over time, the conflict favors stronger opposing forces, leading to exaggeration. (C) With strongly opposing forces, any perturbation in the delicate balance may lead to dominance by one party and overexpression of the trait past its favored value, causing disease. In this case, the “X” represents a knockout of one side in the conflict or a mismatch in the mediation of the conflict that leads to dominance by one party and imbalance in trait expression. (D) Similarly when the alternative party dominates. The example in the text of genetic conflict over mammalian growth provides one well-established case. The example of male–female conflict described in the text may be another case. Other cases arising from genomic conflicts have been described [5–8]. This figure evokes only a very rough intuitive sense of the idea and is not meant to be interpreted precisely.

Figure 2.

One way in which the speed versus accuracy tradeoff may lead to opposing forces and disease. A fast trigger (T) responds a potential signal of danger. Negative regulators (N) oppose the trigger to correct false signals. (A) Low danger frequency favors relatively slow and weak triggers and negative regulators. (B) High danger frequency favors fast and strong triggers with a higher rate of false alarms, which leads to faster and stronger negative regulators. (C) Individuals that have strong triggers and weak negative regulators tend to be overly responsive, potentially causing pathological response. (D) Individual that have weak triggers and strong negative regulators tend to be overly repressed, potentially causing pathological response. Mismatch between triggers and negative regulators may arise by mutation, regulatory perturbation or mating between parents with genes that are tuned to different levels of environmental danger. This figure evokes only a very rough intuitive sense of the idea and is not meant to be interpreted precisely.

Figure 3.

Knockouts of paternally expressed growth promoters cause severe undergrowth in mice. Knockouts of maternally expressed growth suppressors cause large overgrowth. The bottom shows the percent decrease in size of the fetus and placenta for each single independent knockout of six different paternally expressed growth promoter genes. Similarly, the top shows the size increase for single independent knockouts of five different maternally expressed growth suppressor genes. The placental measure for Slc38a4 is missing. Data from Table 1 of Fowden et al. [2].