Epigenetics is the study of heritable changes in gene function that occur without a change in the sequence of the DNA, for example DNA methylation and histone modifications. The epigenetic machinery and the underlying DNA and protein on which the machinery acts form the potential for numerous transinteractions which make them good candidate genes for complex phenotypes with expected multigenic inheritance. Furthermore, epigenetic genes often appear to buffer some of the natural genetic variation in a variety of organisms. We have suggested that a combined epigenetic and genetic model (Common Disease, Genetic and Epigenetic) might explain some of the differences between common and Mendelian diseases. In this dissertation we examine the potential role of epigenetics in the pathogenesis of common human disease.

The central assumptions of the CDGE model are that epigenetic modifications demonstrate population variation, even at birth, and that the variability of epigenetic modifications increases with age. Utilizing quantitative allele-specific assays we have found population variation of allele-specific expression of imprinted genes at birth. In addition, we have measured global DNA methylation by luminescent methylation analysis in two independent cohorts sampled at the beginning and end of a 10-20 year period. Both cohorts showed individual-level changes in methylation over time.

We have also demonstrated that a known disease causing epigenetic defect, loss of imprinting of IGF2, is highly specific and localized to a single location in the human genome. If other disease causing epimutations demonstrate similar specificity our quest for disease causing epimutations will require high throughput methods. Therefore, we have developed an assay, Functional Allelotyping, for high throughput allele-specific expression analysis. We have optimized and validated this assay and by using it we have been able to discover some novel imprinted genes.

In conclusion, there is population variation of epigenetic modifications and it is probable that this variability plays a role in the pathogenesis of common human disease. Although the scope is yet to be determined the potential reversibility of epigenetic defects delineates them as an interesting disease subgroup with some unique potential for disease monitoring, prevention and treatment.