The Epigenetic Enigma
Right now, there’s quite a bit of a mystery surrounding what’s known as epigenetic inheritance, and this is a very serious concern. The transmission of epigenetic tags can affect the traits of offspring without alteration of the primary structure of someone’s DNA. So, for instance, in the image above, three generations are exposed to the same environmental condition of the mother smoking. Therefore, in order for an epigenetic inheritance to occur, a corresponding change would need to be observed in the fourth generation.
Your great grandmother’s experiences as a child, or choices as an adult, could have shaped your own epigenome. The question is, in what ways, and why? Personally, my great grandmothers came of age during the Great Depression and this affected my grandmothers and my mother. The thing is that because my grandfather was conceived during a time of famine, I have an increased life expectancy, not my father. For whatever reason, that’s just how that transgenerational epigenetic inheritance plays out. The opposite is true of grandsons of times of plenty.
This sort of thing also occurred with the Dutch famine. Many of the offspring born during the mid-20th-century were smaller than those born the year before the famine and in some cases, the effects lasted for two generations. So, the children grew up with an increased risk of glucose intolerance as they matured into adulthood. It’s currently hypothesized that inhibiting the PIM3 gene may have caused slower metabolism in later generations, but causation has not been proven, only correlation.
As another example of this, there are two different diseases that are caused by the exact same deletion of DNA. When a key sequence from Chromosome 15 is removed it will cause Angelman syndrome if the problem comes from the mother or Prader-Willi syndrome if it comes from the father. Angelman syndrome is a genetic disorder causing developmental disabilities and nerve-related symptoms. Prader-Willi syndrome is a genetic disorder that causes obesity, shortness, and intellectual disability. Clearly something other than genes is being passed from one generation to the next.
Understanding exactly how this all works is a really serious problem. The epigenetic enigma can also be thought of in terms of twins, or even clones. Think of it like this. If identical twins originate from the same DNA, then how can they turn out so different especially in traits that have a significant genetic component? For instance, how is it that one brother could develop serious heart disease at age 55, while his twin maintains perfect health? This is where epigenetic factors come into play.
Obviously DNA must interact with a multitude of smaller molecules found within our cells, which can activate and deactivate our genes. Since proteins are much of what determines a cell’s characteristics and function, epigenetic changes can either interpose or interfere with the transcription of specific genes. The most common way interference happens is that DNA, or the proteins it’s wrapped around, gets labeled with chemical tags. So, the set of all of the chemical tags that are attached to the genome of a given cell is the epigenome.
To make matters worse, biologists aren’t entirely sure how these things are imprinted. Granted, some of the culprits have been identified. Everyone has methyl molecules in their epigenome and sometimes these chemical tags can affix themselves directly to DNA near genes that then get shut down. Along with this, there are also histone proteins in your cells, and the methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached.
The thing is that your genome is more or less static, but your epigenome is dynamic. More importantly, epigenetic changes can survive cell division, which means they could affect you for your entire life. Over time, through the process of epigenetic reprogramming, some cells develop into heart cells and others into kidney cells. As part of this, each of the approximately 200 cell types in your body has essentially the same genome but its own distinct epigenome. This all then gets passed on to your children and their children and so on and so forth.
The epigenome also mediates a lifelong dialogue between genes and the environment. The chemical tags that turn genes on and off can be influenced by factors including your diet and chemical exposure. Unfortunately, the resulting epigenetic changes can eventually lead to disease. These environmentally-induced epigenetic changes are part of the reason why genetically identical twins can grow up to have very different lives. As twins age, their epigenomes diverge, affecting their susceptibility to disease.
This brings us back to where we started. As it currently stands, the relative importance of genetic and epigenetic inheritance is subject to debate. Still, modern medicine is closing in on the startling truth that epimutations can be very significant and potentially harmful. Just as one tragic example, childhood abuse, such as sexual contact or severe neglect, can lead to epigenetic modifications of glucocorticoid receptor expression which play an important role in hypothalamic-pituitary-adrenal activity.
The list of defects and diseases that can arise from epimutations is seemingly endless. Unfortunately, although hundreds of examples of epigenetic modification of phenotypes have been published, few studies have been conducted outside of the laboratory setting. Therefore, the genetic and epigenetic interactions with the environment cannot be inferred. So, experimental methodologies for manipulating mechanisms still require rigorous demonstration before studies explicitly testing the relative contributions of genotype, environment, and epigenotype are feasible.
Thus, we are left with an epigenetic enigma.