Sohrab Vatsia ’16
When you hear the word genocide, what comes to mind?
The Holocaust. Rwanda. Khmer Rouge. These are all terms we’ve become accustomed to associating with the word. Merriam Webster defines genocide as: the deliberate killing of people who belong to a particular racial, political, or cultural group. Quite simply, it’s one of the deepest forms of human atrocity.
Now, what if I told you that acts of genocide not only affect the everyday lives of victims, but also alter the fabric of their DNA, the blueprint of life? And, what if I went on to say that these changes in one’s genetic code could be passed down a generation, to the children of genocide?
These two questions form the basis of biological research exploring the fascinating relationship between an individual’s environment and genetic makeup. In particular, this mode of inquiry is typical of the emerging discipline of neuroepigenetics: a field dedicated to exploring the interaction between nature and nurture in the brain, and how it affects our behavior and mental health. With specific emphasis on the Rwandan Genocide and the Holocaust, this discussion considers the effects of genocide from both an intra and trans-generational perspective, paying special attention to the transmission and consequences of post-traumatic stress disorder (PTSD) amongst parental victims and their offspring. In the following pages, I will present research demonstrating that parents who were victims of genocide can pass on this traumatic experience to their offspring through the DNA the child inherits, and how this, in turn, predisposes the child to a lower stress tolerance and greater inability to cope with stress. Ultimately, these remarkable findings lead us to an intriguing conclusion: the effects of this horrific experience may, in fact, change the genetic blueprint, and be inherited from one generation to the other.
Before examining the literature of genocidal epigenetics, let’s become familiar with the biological language needed to understand the studies. DNA, the genetic material that makes up the book of life, contains countless sets of instructions to create a unique organism and make it function properly. A particular “set of instructions” for a function is called a gene. Think of it as a standalone chapter in a book. That chapter has a message, the gene, and the message is used to code for something in the body – like making the material of which hair is made of, for example.
A single human cell contains an astounding 1-meter of DNA, but, even if all cells in our bodies contain the same DNA sequences, they do not use all of it. To elaborate, a liver cell and a heart cell have identical genetic codes, but each uses only those sequences that it requires; the liver cell helps our bodies detoxify foreign substances, while a heart cell gives the heart its ability to pump blood throughout the body. It simply wouldn’t make sense for a heart cell to “turn on” the set of instructions – the genes – necessary to detoxify alcohol. As a result, the set of instructions in the DNA within these disparate cells is “turned on” and “turned off” through differential chemical tags.
DNA is composed of 21,000 genes. A gene can be turned on or off by adding or removing tiny chemical tags to or from the DNA. One of the tags that turns genes off is methylation. As its name suggests, methylation involves the addition of a “methyl group,” a simple carbon side chain that controls the expression of the gene, often by “silencing” or “turning it off,” as demonstrated below in Figure 1.
In discussing the epigenetics of genocide, there are two key genes that are methylated or “turned off” with respect to stress: NR3C1 and FKBP5. We perceive stress through the release of hormones that help us cope with it. These hormones, or chemical messengers, effectively facilitate communication throughout our bodies via receptor binding. Think of a receptor like a biological post office; it receives the information from the hormone messengers, and prompts a cellular response. Both NR3C1 and FKBP5 contain the information necessary to code for specific stress receptors called glucocorticoid receptors. Hormones called glucocorticoids are essential for day-to-day cellular function, mediating stress responses. Consider the last time you watched a scary movie – you probably noticed that your palms were sweaty or that your heart rate was elevated – these responses are due to glucocorticoids. As a general example, in Figure 2, let’s assume that the “steroid hormone” of note is a glucocorticoid called cortisol. Cortisol enters the cell and binds to the glucocorticoid receptors, and this bound complex “turns on” a gene, leading to a stress response, like an elevated heart rate.
Post-traumatic stress disorder (PTSD) is a psychiatric condition that manifests in response to a negative environmental influence. For instance, in a classic PTSD model, the sounds of fireworks might trigger a war veteran’s combat experiences and induce feelings of anxiety or panic. This experience is often associated with changes in the brain, often changing connections between brain cells that can affect how an individual processes emotion. Re-exposure to a stressor or “trigger,” like the sound of fireworks, leads to a chronic stress response and can have intense, detrimental physical effects. A recent study has implicated up-regulated methylation levels of the NR3C1 glucocorticoid receptor gene as a mechanism of interest in adult suicide victims who also suffered from child abuse, a formative traumatic event implicit in the onset of PTSD. Therefore, it is reasonable to assume that NR3C1 is also a gene of interest in the neuroepigenetic mechanisms of genocide.
In an international study run by Vanja Vukojevic and her team, researchers investigated the specific effects of methylation of the NR3C1 gene as linked to PTSD in Rwandan genocide survivors. Remember that the NR3C1 gene is a chapter-like excerpt from the DNA book of life – normally, this gene contains the set of instructions for making the NR3C1 glucocorticoid stress receptor, but methylation of this receptor “turns off” the gene, blocking the formation of these receptors. The team selected 152 male and female Rwandans suffering from PTSD and contrasted them against 72 mentally healthy Swiss adults, as a control. The two groups were asked to complete a number of timed picture-based memory tasks to assess the effects of PTSD on memory recall, and afterwards, DNA was extracted from subjects’ saliva in order to measure methylation status of the NR3C1 gene. Results of the study are highly indicative, as Rwandan males demonstrated a statistically significant increase in NR3C1 methylation, or NR3C1 gene “silencing” as compared to control Swiss males. These findings suggest that, in affected Rwandan males, genocide leads to the inactivation of the NR3C1 gene by DNA methyl “silencing,” preventing cells from making the NR3C1 receptor. This means that the effect of the stressor or PTSD “trigger” lingers in the body, because not enough NR3C1 receptors exist to bind glucocorticoid stress hormones. This directly translates to a reduced ability to cope with stress, fueling the severity of the stress response in these Rwandan Genocide survivors.
Although the previous study highlights the importance of up-regulated NR3C1 methylation, or increased NR3C1 gene “silencing” in male survivors of the Rwandan genocide, it does not provide conclusive evidence for NR3C1 methylation in female survivors or their offspring. However, in a paper published by Nader Perroud and his collaborators, researchers were able to determine that 25 expectant Rwandan mothers exposed to genocide showed higher NR3C1 methylation levels than 25 women of Rwandan descent free from genocide exposure as a function of glucocorticoid receptor levels. Moreover, the children of exposed mothers exhibited higher NR3C1 methylation levels and were more prone to PTSD than children of control mothers. In a similar vein as the previous experiment, the two groups were assessed for PTSD using an interview based Post-Traumatic checklist, and simultaneously, participants’ DNA was extracted from blood cells. Results of the glucocorticoid receptor levels in exposed, expectant mothers versus control mothers are captured in Figure 3, below. Mothers suffering from PTSD after exposure to the Rwandan Genocide and their offspring (visualized in black) demonstrate a statistically significant decrease in blood glucocorticoid receptors with respect to non-exposed mothers and their offspring (visualized in white). In other words, this study presents a clear indication that NR3C1 methylation/“silencing” blocks the formation of glucocorticoid stress receptors in expectant mothers exposed to genocide as well as their children, leading to higher levels of free glucocorticoid stress hormones and the characteristic PTSD diagnoses associated with genocide. These results affirm that genocide has a severe impact on stress receptor regulation not only in female survivors, but also in their children, providing groundbreaking evidence for the transmission of stress across multiple generations.
While the previous two studies have provided conclusive evidence for methylation driven by the NR3C1 gene, a paper published by Rachel Yehuda and her laboratory at the Mount Sinai School of Medicine explores these familial, or trans-generational, methylation effects by way of the FKBP5 gene. Although FKBP5 does not contain a set of instructions for the formation of glucocorticoid stress receptor like NR3C1 does, it is responsible for interacting with stress hormones and their component receptors. In fact, altered FKBP5 gene expression levels are correlated with PTSD and depression. With this in mind, researchers recruited a sample of 32 Jewish Holocaust survivors and 22 of their adult offspring as an experimental test group, and recruited a cohort of 8 unexposed Jewish parents and 9 of their adult offspring as the control group. Both groups were asked to complete a PTSD questionnaire and FKBP5 methylation levels were measured by salivary sample. Results of the study lend substantial perspective – children born to parents who were exposed to the Holocaust demonstrated an increase in depression and anxiety self-ratings on the PTSD questionnaire in comparison to the controls, and also demonstrated significantly lower methylation levels than control counterparts in a specific region of the FKBP5 gene. In comparison, parents exposed to the Holocaust demonstrated a significant increase in methylation levels in this exact same region of the FKBP5 gene in addition to higher levels of depression and anxiety. On the surface, these results, captured on the rightmost graph of panels “A” and “B” on Figure 4, below, seem paradoxical. After all, how can methylation levels increase in one generation, but decrease in the following one, though both generations report higher levels of depression and anxiety? In response, Dr. Yehuda and her team candidly suggest that an underlying factor other than methylation or gene “silencing” might contribute to elevated PTSD-like stress levels in these Holocaust children. While the team’s response feel unsatisfying, it’s important to note that this was the first study of its kind, and further research will no doubt be geared towards exploring epigenetic factors other than methylation. Nevertheless, the results of this study demonstrate an association of pre-conception stress effects with epigenetic changes in both parents and their offspring as adult study participants.
While it’s significantly evident that genocide is responsible for sweeping historical, political, and sociological changes, it may also cause genetic change across multiple generations. Through recent scientific studies of survivors of the Rwandan Genocide and the Holocaust, it has become increasingly clear that genocidal trauma can have a biological basis. The sad history of such acts of atrocity is not only narrated by its victims – by our grandparents and parents – but also is written in our genes. Ultimately, use of this transgenerational approach to neuroepigenetics may serve as a benchmark for future studies exploring the reversal of these effects.
References
Genocide. (n.d.). Retrieved March 16, 2016, from http://www.merriam-webster.com/dictionary/genocide
Mcgowan, Patrick O., Aya Sasaki, Ana C. D’alessio, Sergiy Dymov, Benoit Labonté, Moshe Szyf, Gustavo Turecki, and Michael J. Meaney. “Epigenetic Regulation of the Glucocorticoid Receptor in Human Brain Associates with Childhood Abuse.” Nature Neuroscience 12.3 (2009): 342-48. Web. 16 Mar. 2016.
Perroud, Nader, Eugene Rutembesa, Ariane Paoloni-Giacobino, Jean Mutabaruka, Léon Mutesa, Ludwig Stenz, Alain Malafosse, and Félicien Karege. “The Tutsi Genocide and Transgenerational Transmission of Maternal Stress: Epigenetics and Biology of the HPA Axis.” The World Journal of Biological Psychiatry 15.4 (2014): 334-45. Web. 16 Mar. 2016.
Vukojevic, V., I.-T. Kolassa, M. Fastenrath, L. Gschwind, K. Spalek, A. Milnik, A. Heck, C. Vogler, S. Wilker, P. Demougin, F. Peter, E. Atucha, A. Stetak, B. Roozendaal, T. Elbert, A. Papassotiropoulos, and D. J.- F. De Quervain. “Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors.” Journal of Neuroscience 34.31 (2014): 10274-0284. Web. 16 Mar. 2016.
Yehuda, Rachel, Nikolaos P. Daskalakis, Linda M. Bierer, Heather N. Bader, Torsten Klengel, Florian Holsboer, and Elisabeth B. Binder. “Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation.”Biological Psychiatry (2015): n. pag. Web. 16 Mar. 2016.
Images
https://www2.estrellamountain.edu/faculty/farabee/BIOBK/steract_1.gif
http://www.sciencedirect.com/science/article/pii/S0006322315006526
http://www.tandfonline.com/doi/full/10.3109/15622975.2013.866693
Featured Image Source
Exclamation mark icon flat style caution stock vector (royalty free) 1360035611. Shutterstock. (n.d.). Retrieved September 7, 2022, from https://www.shutterstock.com/image-vector/exclamation-mark-icon-flat-style-caution-1360035611