Position-Effect Variegation

It has long been known that the organization of eukaryotic DNA into chromatin is related to gene expression. For example, actively transcribed DNA is more susceptible to degradation by nucleases such as DNAse I suggesting that it is more "open" (less highly condensed by scaffolding proteins or into 30nm chromatin fiber) than non-transcribed DNA.

It is also well established that gene expression levels are well correlated with chromatin structure. Most eukaryotic genes are located within euchromatic regions - those regions that are less highly condensed. Further genes located within heterochromatin are usually expressed at a low level. This leads to the concept of position-effect.

Position-Effect: This refers to the effect of chromosome position on the expression (and, therefore, function) of a gene. If a gene that is typically located in a euchromatic region is moved (experimentally or by a chromosome rearrangement) to a heterochromatic region, it usually fails to function. This is because it is now a part of highly condensed DNA which is not accessible to the transcription machinery. As a result the gene is not being expressed and so there is no gene product to function within the cell.

Position-Effect Variegation: This refers to the result of position-effect when a particular gene is located in euchromatin within some cells of an individual but in heterochromatin in other cells of the same individual. Again, this can arise experimentally or by a somatic mutation. The result is that the gene functions (is expressed) in some cells - those where it is in euchromatin - but not in others, resulting in a variegation effect.

A classic example of position-effect variegation is from Drosophila. A particular chromosome inversion resulted in the relocation of the white gene to a heterochromatic region, resulting in a lack of expression (and, thus, function). The inversion was a somatic change so in some cells the white gene was euchromatic while in others it was heterochromatic. Since a lack of function of this gene results in white eyes, a fly in which this inversion occurs somatically has a variegated eye: some areas are wild type red while others are white.

Not only does this example shed light on the relationship between euchromatin and gene expression but it also allows us to discuss some of the proteins that are responsible for for the formation of heterochromatin (proteins that are involved in higher-order chromatin structure). A mutation that suppressed the position-effect variegation of the white gene (that is, a mutation in this gene resulted in wild type eyes - no variegation) was found to code for the protein HP1 (Heterochromatin Protein 1: the mutation itself was called Su(var)205⁴). A loss-of-function mutation in this gene, which is homozygous lethal, leads to a decondensation of heterochromatin, so one effect was the ability to express the white gene in all cells which leads to the loss of variegation. The exact role of HP1 is not certain but it plays a significant role in chromatin structure, and it is known to interact with methylated histones. Therefore, this histone modification is typically associated with heterochromatic regions.