Biological consequences of dosage dependent gene regulatory systems

Abstract

Chromatin and gene regulatory molecules tend to operate in multisubunit complexes in the process of controlling gene expression. Accumulating evidence suggests that varying the amount of any one member of such complexes will affect the function of the whole via the kinetics of assembly and other actions. In effect, they exhibit a "balance" among themselves in terms of the activity of the whole. When this fact is coupled with genetic and biological observations stretching back a century, a synthesis emerges that helps explain at least some aspects of a variety of phenomena including aneuploid syndromes, dosage compensation, quantitative trait genetics, regulatory gene evolution following polyploidization, the emergence of complexity in multicellular organisms, the genetic basis of evolutionary gradualism and potential implications for heterosis and co-evolving genes complexes involved with speciation. In this article we will summarize the evidence for this potential synthesis.

Figure 1. Model showing effect of stoichiometry of gene regulatory complexes and its consequences in generating phenotypes

Panel A shows a stoichiometrically balanced regulatory complex depicted by sets of rectangles, circles and triangles (XX:YY:ZZ::1:1:1), which is able to properly communicate/interact with the cis factor of a target structural gene, which leads to a (normal) phenotype depicted by a thick green rectangle. In panel B the stoichiometry of the regulatory complex is altered and thus unbalanced (XX:Y:ZZ::2:1:2) so interaction with the cis elements of target loci is modified such that an abnormal phenotype (depicted by a thinner green rectangle) is produced. This phenotype might be selected against. Panel C shows modification in a cis factor (depicted by brown rectangle) such that a shift from the balanced regulatory complex (XX:YY:ZZ::1:1:1) to the unbalanced state (XX:Y:ZZ::2:1:2) is tolerated. Panel D depicts co-adaptation of the unbalanced regulatory complex over time to attain a new balance (X:Y:Z::1:1:1) leading to the normal phenotype.

Figure 2. Dosage Compensation

The copy number of a gene located on a chromosome varies with each change in chromosomal dose but the total amount of gene expression remains the same due to transacting regulatory dosage effects on the gene. In normal diploids there are two doses of each chromosome and each allele of the gene contributes 50% to the total gene expression. However, when there is only a single dose of the chromosome, as in monoploids, the transacting regulators interact such that the remaining allele contributes 100% to gene expression (complete green rectangle). On the other hand when chromosome dose is tripled as in trisomics, each of the three alleles contributes to only a third of the total gene expression (green red and blue rectangles).