The idea that the experiences of our ancestors shape who we are today is not a novel one. In fact, throughout history, great thinkers from around the world have proposed theories and ideas to explain how the experiences of our predecessors might shape our biology. In this blog, we will explore the concept of epigenetic inheritance – including the history of this field, some of the more notable case studies, and the significance and impact of their findings.
The age-old debate: Nature vs nurture
The term epigenetics was first coined in the 1940s by C.H Waddington, who famously proposed the concept of the “epigenetic landscape” (Figure 1) – a metaphor for cellular differentiation. The ball represents the cell, which rolls down a series of hills and valleys, each hill representing a different developmental fate. As the cell rolls down the landscape, various environmental factors influence its path, pushing it down one valley or another.
But centuries before Waddington came Aristotle. In his 350 BCE treatise, “On the generation of animals”, Aristotle objected to the prevailing notion at the time, which was that adult features were fully formed in the zygote. He instead proposed the theory that an organism develops gradually from undifferentiated material after genesis, or “epigenesis.” Importantly, he suggested that this development could be influenced by changes in the environment – likely one of the first links made between the environment and its influence on our genes.
Much later, the 19th century would become a period of intense debate among scientists and philosophers about the nature of evolution. One of the central issues that many scientists had with Darwin’s theory of evolution was the role of the environment in shaping inherited traits. Both Jean-Baptiste Lamarck – in his theory of evolution, “the inheritance of acquired characteristics” – and German naturalist Ernst Haeckel, suggested that the environment could exert direct influence on an organism, and that this influence could result in the transmission of certain traits to the next generation.
It was during the 19th century that Waddington became one of the first scientists to show that epigenetic changes could be passed from one generation to the next. Waddington exposed fruit flies to different environmental conditions, such as changes in temperature or chemicals. He then observed the effect of these changes and found that not only does the environment have a significant impact on their development, but that these changes can be passed on to the next generation.
In the many years since Waddington first coined the term, scientists have made leaps and bounds in our understanding of epigenetics. As the research into epigenetics has progressed, there has been a renewed interest in investigating whether changes caused by the environment could be passed onto future generations. In other words, epigenetic inheritance.
What is epigenetics?
Our genome is the complete set of our DNA – but there is a layer “upon” the genome, aptly named with the suitable Greek prefix – called the epigenome. The epigenome regulates gene expression through modifications of DNA and DNA-associated proteins, such as DNA methylation, chromatin interactions, and histone modifications.
Epigenetics is the study of these modifications and the consequent changes in gene expression. Importantly, these epigenetic modifications can be altered by the environment – and those alterations can be passed on. So, epigenetics can explain how changes caused by our environment can be passed on, albeit not in the “direct” way Lamarck and Haeckel proposed. Instead, epigenetic modifications alter how our genes are expressed.
But where does our modern understanding of this epigenetic inheritance come from? The discovery of epigenetic inheritance challenged the previous assumption that genes were the primary determinant of an individual’s development, and that the environment played a less significant role. As evidence on the complexity and bidirectionality of gene expression-related processes grew, the gene-centred model of molecular biology proposed by Crick in 1958 faced a reckoning. This led to a new era of research that highlighted the role of the environment, particularly during critical and sensitive periods of development, and revealed it had a greater influence on an individual’s development than previously thought. As a result, the scientific community became increasingly aware of the role of the environment in shaping an individual’s development.
The new understanding of how environmental factors could affect gene expression led to the discovery of epigenetic markers that could be passed on to offspring, impacting their development and potentially leading to heritable changes in behaviour or physiology. This finding was significant because it expanded our understanding of inheritance beyond the classical Mendelian model of inheritance, where only changes in DNA sequence were thought to be heritable. Epigenetic inheritance opened up new avenues of research, revealing the importance of environmental factors in shaping development and potentially providing insights into how certain diseases or conditions might be passed down through generations.
The concept of epigenetic inheritance does not refute our current understanding of evolution, but instead adds an extra layer. While genetic changes occur gradually through random mutation and natural selection, requiring numerous generations for a trait to become widespread in a population, the epigenome is capable of swift and dynamic transformation in response to environmental cues. Moreover, epigenetic changes can occur simultaneously in multiple individuals. By means of epigenetic inheritance, some of our ancestor’s experiences can be passed on to forthcoming generations. At the same time, the epigenome retains its adaptability to changing environmental conditions. As a result, epigenetic inheritance could enable an organism to constantly alter its gene expression to suit its surroundings, all without modifying its DNA code.
Overall, epigenetic inheritance represents a major paradigm shift in our understanding of development and inheritance. It demonstrates how the environment can impact gene expression and shape not only an individual’s development, but potentially the development of future generations.
“We’re all ghosts. We all carry, inside us, people who came before us.” ― Liam Callanan, The Cloud Atlas.
Starvation is hereditary
The Dutch Hunger Winter was a period of severe food shortages in the Netherlands between 1944-1945, during the final months of World War II. Several studies on individuals who were exposed to the famine while in utero revealed that they shared some unusual traits – high cholesterol, and higher rates of obesity, diabetes and schizophrenia. In 2018, Dr Heijmans and Lumey – who had collected blood samples from these individuals in the 1990s – used modern epigenomic profiling techniques to reveal that DNA methylation patterns were altered in these individuals.
The Chinese Famine of 1959-1961 has also been studied extensively and researchers have uncovered similar findings. . Also known as The Great Chinese Famine, this was a period of extreme food shortages. Again, studies found that individuals exposed to the famine in utero had altered epigenetic profiles. A 2022 study showed that these effects persisted in the second and even third generation, causing a series of health problems.
There is also some evidence to suggest that the ancestors of those who experienced famine during British Rule in India and South Asia (1858-1947) may have inherited epigenetic modifications that make them predisposed to diabetes, obesity and other health problems. According to a study at Brown University, surviving just one famine doubles the risk of diabetes and obesity in the next generation. Given that under British Rule, those in the region were subjected to at least 31 famines, it’s not surprising that the effects may have been passed on.
Other case studies which investigate the epigenetic inheritance of starvation/famine include:
- The “Overkalix Study” – “Change in paternal grandmothers´ early food supply influenced cardiovascular mortality of the female grandchildren” by Bygren, et al. (2014)
- A study looking into the children of rural Gambians, who experience dramatic seasonal fluctuations in nutritional status – “Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles” by Waterland, et al. (2010)
“The parents are not broken conspicuously, yet their children, all of whom were born after the Holocaust, display severe psychiatric symptomatology. It would almost be easier to believe that they, rather than their parents, had suffered the corrupting, searing hell.”- Dr. Vivian Rakoff (1966). “Long term effects of the concentration camp experience.”
The concept of intergenerational trauma was first introduced in the psychiatric literature through observations of behavioural and clinical problems in the offspring of Holocaust survivors. In an influential 1966 paper, Dr Vivian Rakoff (a prominent psychologist) described the case of three patients who sought psychiatric treatment. He noted that their parents, who had survived the Holocaust, did not exhibit severe psychological symptoms, but their children did. This initial report was met with scepticism and some negative reactions, but many other studies found behavioural difficulties in Holocaust offspring, including issues with self-esteem, anxiety, and interpersonal functioning.
In 2016, Rachel Yehuda and her team showed for the first time that epigenetic changes caused by exposure to trauma can be passed on to children born after the event – in this case, Holocaust survivors and their adult children. In this study, they focused on the FKBP5 gene, which has been linked to a number of mental health conditions, such as PTSD, depression, and mood and anxiety disorders. By studying blood samples of Holocaust survivors and their adult children, as well as a control group of Jewish parents who were not exposed to the Holocaust, the researchers were able to identify changes in the methylation of FKBP5. The researchers found that Holocaust exposure had an effect on the methylation of FKBP5 in both the parents and their offspring.
Importantly, the study did not demonstrate “transmission” of PTSD from parent to child, but rather that the parent’s experience is somehow related to their offspring’s phenotype and biology. Phenotype refers to an organism’s physical appearance and behaviour, which is determined by both genetic and environmental factors. In this case, the researchers observed changes in the methylation of FKBP5 in both the Holocaust survivors and their children, but in opposite directions. This suggests that the children of traumatized parents may not simply be born with a PTSD-like biology, but rather may inherit traits that promote both resilience and vulnerability.
Other case studies investigating epigenetic inheritance of trauma include:
- “The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis” by Perroud, et al. (2014)
- “Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor” by Radtke, et al. (2011)
- “An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci” by Logue et al. (2020)
Recent research: That’s just my personality!
At the recent Festival of Genomics and Biodata, researcher Uri Bertocci spoke about the Alpha Project. The Alpha project plans to recruit 1,500 couples and follow them from the pre-pregnancy stage through the first and third trimesters of pregnancy, the birth of their first child, and every significant step in the child’s life until the age of 20. DNA methylation samples will be collected at every important milestone to measure the epigenetic development of the child’s life and compare it to that of their parents. Behavioural tasks will be performed using a neuroimaging device called FNIRS and the genomes of both parents and the child will be sampled. The project has already recruited 125 couples who are at the pre-pregnancy stage, 30 pregnant couples, and has had 12 Alpha babies born.
For the research, vast amounts of psychological data on personality, relationships, attachment, and psychopathology were collected. The focus of the study were traits of extroversion and introversion. Extroverts are outgoing, talkative, and energetic, while introverts are more reflective and reserved. Twin studies have shown that 40-60% of extroversion is genetically influenced, and extroverts have greater brain activity in sensory and emotional experience related brain areas.
To narrow down the research, the neurotransmitter oxytocin, which plays a role in social bonding, reproduction, and childbirth, was focused on. Often referred to as the “love hormone,” it is released in large quantities during physical touch and plays a critical role in the formation and continuation of social bonds. This neurotransmitter is important for extroversion, which is highly influenced by how individuals connect and react to their social environment.
So far, samples have been collected from 46 couples, and their “extroversion levels” assessed. The samples were processed using Illumina’s methylation epi-kit, which produces 850,000 CpG sites. From those sites, 1,400 CpG sites that were positioned on oxytocin signalling pathway genes were selected. A series of robust mixed effect regression models were conducted on these 1,400 CpG sites, and 15 CpGs on the CACN family genes – which play an important role in regulating the flow of calcium and sodium ions to the neuron cell and are essential for action potential and neural activity – were identified. Two more CpGs on the RYR2 gene, which is also important for neural activity, were also identified. The models showed that gene expression is regulated by the environment, among other things, through DNA methylation.
The results of the study provide evidence that oxytocin signalling pathway genes are associated with extroversion levels, and DNA methylation of these genes can impact extroversion levels. Overall, the Alpha Project aims to provide a better understanding of the epigenetic and genetic foundation of psychological development. By following families from the pre-pregnancy stage through the child’s early adulthood, we can gain insights into how DNA methylation and genetic factors contribute to the development of personality traits like extroversion and introversion. The project presents an exciting opportunity to explore the complex interplay between genes and the environment and to answer some of the most fundamental questions about human psychology.
Do we inherit our history?
Despite advances in epigenomic profiling technology like next-generation sequencing and spatial-omics, we still don’t have all the answers. Until now, most epigenomics research has focussed on answering acute questions about human biology and disease – how cancer develops, or how neurodegeneration occurs – rather than understanding whether the past plays a role in our future.
So, despite advances in the tech, there are still a lot of questions to be answered. However, the suggestions and findings from these studies certainly pose significant biological, but also societal, historical, and personal implications – and could reshape our understanding of who we are.
If you are interested in learning more about epigenetic inheritance, take a look at some of these fantastic books, studies, and reviews:
- The Epigenetics Revolution by Nessa Carey
- Epigenetics: The Ultimate Mystery of Inheritance by Richard Francis
- Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms by Rachel Yehuda and Amy Lehrner (2018)
- Social epigenomics: are we at an impasse? By Amy L Non (2021)