Department of Medicine, Molecular Biology and Genetics, and Oncology; Johns Hopkins University School of Medicine
Although the human genome sequence has been complete for several years, few common diseases have been explained by common variants in the coding sequence of genes, suggesting that noncoding sequence and/or epigenetic variants are at least as important. Analysis of constrained sequence elements suggest that most is noncoding, and the challenge is to relate this information to phenotype and human disease. Another conundrum is the increasing incidence and severity of common disease with age, despite the fact rare highly penetrant Mendelian disorders generally appear congenitally or in early childhood. Epigenetic alterations represent an attractive potential mechanism for common disease as they involve noncoding sequence, increase with age, and are affected by diverse environmental agents including diet. An important role for somatically occurring epigenetic changes in cancer is now well established. I will discuss how epigenetic changes in apparently normal cells may also contribute to risk of cancer and other common diseases, and suggest how these epigenetic alterations may arise and act with genetic alterations to cause disease.