The Mutagenic Consequences of DNA Methylation within and across Generations

Abstract

DNA methylation is an epigenetic modification with wide-ranging consequences across the life of an organism. This modification can be stable, persisting through development despite changing environmental conditions. However, in other contexts, DNA methylation can also be flexible, underlying organismal phenotypic plasticity. One underappreciated aspect of DNA methylation is that it is a potent mutagen; methylated cytosines mutate at a much faster rate than other genetic motifs. This mutagenic property of DNA methylation has been largely ignored in eco-evolutionary literature, despite its prevalence. Here, we explore how DNA methylation induced by environmental and other factors could promote mutation and lead to evolutionary change at a more rapid rate and in a more directed manner than through stochastic genetic mutations alone. We argue for future research on the evolutionary implications of DNA methylation driven mutations both within the lifetime of organisms, as well as across timescales.

Keywords: DNA methylation; environmental epigenetics; evolution; mutation.

Figure 1

Connecting DNA methylation within individual and across generations. The environmental factors that shape DNA methylation patterns in individuals are numerous and occur throughout the lifetime of an individual: these vary from maternal hormones derived during development to predation events and resource availability (Panel (A)). Further, exposure to environmental stimuli can lead to variable methylation patterns at particular CpG sites through life, which can lead to variable phenotypes (denoted by two-directional arrows in Panel (B)). If environmental stimuli and resulting methylation are stable across generations (Panel (C), top), the CpG site is more likely to become methylated and mutate over time, possibly fixing that phenotype; if, on the other hand, environmental stimuli vary between generations (Panel (C), bottom), methylation is more likely to continue to regulate the phenotype at that CpG site. Here, we use a fictitious example in which puffins are exposed to either variable temperatures (Panel (C), bottom) or stable temperatures (Panel (C), top). When the environment is cold, more CpG sites are methylated and high levels of methylation confers the orange feet phenotype, an advantageous trait in cold environments. When the environment warms, fewer CpG sites are methylated and foot color becomes blue, an advantageous trait in warmer environments. If temperature persistence across generations leads to predictable methylation of CpG sites, this could lead to CpG to TpG or CpA mutations (denoted by a red star in Panel (C), top). These mutations may fix the orange foot phenotype, even in the absence of the colder temperatures (i.e., genetic assimilation); this represents the loss of epigenetic potential, leading to less flexibility in phenotype. In cold environments, this fixation of the phenotype could be advantageous if offspring are “primed” for predicted environmental conditions. However, if the environment changes and becomes warmer over time, this once advantageous mutation might become deleterious. If there is exposure to a variety of different environmental cues between generations, CpG sites may not be lost as methylation was variable (denoted by yellow boxes in Panel (C), bottom). Consequently, epigenetic potential is maintained, and the capacity for phenotypic plasticity is preserved. Note: the figure and phenotypes (e.g., foot color) represent a fictional example; there is no evidence that foot color is derived via epigenetic mechanisms, as depicted. This figure was created by Katie Brust.