The influence of DNA sequence on epigenome-induced pathologies

The inheritance of numerous genetic risk factors for human and plant diseases as well as biotic and abiotic stress susceptibility phenotypes are well established [1-6]. Particular DNA mutations and their mechanistic effect on the timing, level, or quality of gene expression produce the risk of disease. Thus, a clear cause-and-effect relationship is established between the inherited aberrant genotype and the risk phenotype (that is, the increased chance or certainty of presenting a disease).Epigenetics is cited as contributing to the risk of acquiring numerous diseases and aberrant phenotypes in human and plant populations based primarily on correlations between changes in chromatin structure and penetrance of the undesired phenotype [7-10]. There has been a growing suspicion, particularly since the 1980s, that - along with classical genetics - epigenetics is required to explain many complex phenotypes associated with disease [11,12]. The influences of age and environment (for example, chemicals, heat, nutrition, daylight) on various pathologies and the seemingly stochastic penetrance of developmental abnormalities are particularly difficult to interpret using purely molecular genetic models and are more easily explained by considering epigenetic control mechanisms [13-18]. However, few cause-and-effect relationships have been established that prove that that particular inherited cis-linked chromatin structures (epitypes) are in fact useful in predicting the inherited risk of acquiring disease phenotypes. Exceptions are the epigenetic silencing of the skeletal-muscle ryanodine-receptor gene (RYR1) that causes congenital myopathies and the MutL Homolog 1 gene (MLH1) that causes increased risk of colorectal or endometrial tumors, which are discussed in the following section.Inherited risk epitypes should evolve in populations in ways similar to the evolution of genotypes [19]. The problem is that the transgenerational inheritance of epigenetic controls is not well unde