The epigenetic lorax: gene-environment interactions in human health

Abstract

Over the last decade, we have witnessed an explosion of information on genetic factors underlying common human diseases and disorders. This 'human genomics' information revolution has occurred as a backdrop to a rapid increase in the rates of many human disorders and diseases. For example, obesity, Type 2 diabetes, asthma, autism spectrum disorder and attention deficit hyperactivity disorder have increased at rates that cannot be due to changes in the genetic structure of the population, and are difficult to ascribe to changes in diagnostic criteria or ascertainment. A likely cause of the increased incidence of these disorders is increased exposure to environmental factors that modify gene function. Many environmental factors that have epidemiological association with common human disorders are likely to exert their effects through epigenetic alterations. This general mechanism of gene-environment interaction poses special challenges for individuals, educators, scientists and public policy makers in defining, monitoring and mitigating exposures.

Figure 1. Interaction of endogenous (genetic and developmental) and exogenous (environmental) factors in generating changes in the epigenome during an individual’s lifespan

Environmental factors include chemicals, toxins, physical agents and behavioral, dietary, social and other lifestyle factors. These exert effects preferentially at different times during development. Genetic variation affects developmental processes, responses to environmental factors and the molecular mechanisms that mediate epigenetic change. The arrows indicate that these three forces continue to interact throughout life to modify the epigenome. Maximum epigenetic change occurs when genotype, developmental stage and environmental exposure operate additively (exposure at sensitive stage in individual genetically predisposed to effect).

Figure 2. Relationship between epigenetic state, disease threshold and environment

Individual A represents a reference pattern, wherein the epigenome changes at a given rate throughout life and reaches a threshold to elicit a disease or disorder. Individual B experienced an acute early-life exposure that resulted in a parallel path of change, but reaching the threshold earlier than individual A. Individual C experienced a change in environment that increased the rate of change. Individual D began life at a different epigenetic state (this could be higher or lower) and then progressed in parallel with individual A. Individual E experienced a change in environment that lessened the pace of acquiring epigenetic change, such as an improvement in environment. Individual F experienced an acute drop in epigenetic change, perhaps as a result of a sudden improvement of environment, and then progressed in parallel with individual A.