DNA methylation and Z-DNA formation as mediators of quantitative differences in the expression of alleles

With draft copies of several model genomes available in the near future, attention is turning towards the genetic mechanism that determine differences between individuals. While mutations in protein coding regions affect the structure of gene products, polymorphisms outside such regions may cause quantitative differences in gene expression. Here we summarize observations indicating that such differences may be mediated by allele-specific alterations in the modification or structure of DNA. Mono-allelic expression of the rat T-cell differentiation marker RT6 in a subpopulation of cells is associated with allele-specific differences in DNA methylation in the RT6 promoter. In contrast to previously described examples of mono-allelic expression, these are determined neither stochastically nor by parental origin, but by cis-acting elements within the alleles. An attractive candidate is a rodent identifier (ID) element exclusively present in the RT6a allele. In the case of the rat nucleolin gene, a polymorphic dinucleotide repeat in the 5' region modulates promoter strength and forms left-handed Z-DNA in vivo. Models explaining putative effects of Z-DNA formation on transcription are presented. These observations suggest novel mechanisms by which repetitive DNA, an abundant source of polymorphism in the mammalian genome, may exert quantitative effects on gene expression.