Environment-Sensitive Epigenetics and the Heritability of Complex Diseases

Abstract

Genome-wide association studies have thus far failed to explain the observed heritability of complex human diseases. This is referred to as the “missing heritability” problem. However, these analyses have usually neglected to consider a role for epigenetic variation, which has been associated with many human diseases. We extend models of epigenetic inheritance to investigate whether environment-sensitive epigenetic modifications of DNA might explain observed patterns of familial aggregation. We find that variation in epigenetic state and environmental state can result in highly heritable phenotypes through a combination of epigenetic and environmental inheritance. These two inheritance processes together can produce familial covariances significantly higher than those predicted by models of purely epigenetic inheritance and similar to those expected from genetic effects. The results suggest that epigenetic variation, inherited both directly and through shared environmental effects, may make a key contribution to the missing heritability.

Intergenerational Health Responses to Adverse and Enriched Environments

“…A primary methyl donor in DNA methylation is delivered via a cycle that is catalyzed by many enzymes when folate, choline, betaine, B vitamins, and other micronutrients are present in food (1). Etiological moments from conception onward combine with preconceptional adverse, enriched, and normal environments, exposing ancestors across their reproductive ages (23). The great interest in this science is understandable because the mechanism comes so early in the pathophysiologic chain of events and because one can manipulate gene expression with nutrition (56), medication, and other public health interventions.…”

Homosexuality as a Consequence of Epigenetically Canalized Sexual Development

“…It is now well established that a parent's epi-marks sometimes carryover across generations and influence the phenotypes of offspring (reviewed in Morgan and Whitelaw 2008). Epigenetics is a relatively new subdiscipline in genetics and its importance in evolution, especially as a major contributor to realized heritability, is currently being developed and debated (e.g., Slatkin 2009;Furrow et al 2011). Nonetheless, there is now clear evidence that environmentally induced epigenetic modifications of genes expressed in male mice (e.g., DNA methylation; Franklin et al 2010) that feminize their brains and behavior can be transgenerationally inherited by their offspring (Morgan and Bale 2011).…”

The Evolution of Phenotypic Switching in Subdivided Populations

“…The mode of inheritance in such cases can depart from straightforward Mendelism (Bonduriansky and Day 2009;Danchin and Wagner 2010). In particular, there can be interactions between inherited environmental conditions and epigenetic effects (see, e.g., Furrow et al 2011) that contribute to the statistical heritability of phenotypes.Why do these genetically identical populations exhibit such switching behaviors? Stochastic switching is often interpreted as a bet-hedging strategy (Starrfelt and Kokko 2012) that could confer a fitness advantage in volatile environments (Thattai and van Oudenaarden 2004;Kussell and Leibler 2005).…”

“…The mode of inheritance in such cases can depart from straightforward Mendelism (Bonduriansky and Day 2009;Danchin and Wagner 2010). In particular, there can be interactions between inherited environmental conditions and epigenetic effects (see, e.g., Furrow et al 2011) that contribute to the statistical heritability of phenotypes.…”