Germline Epigenetic Inheritance

Background

There is overwhelming evidence that early life experiences have long-term effects on our biology and health. This is not surprising - pre-natal and early childhood are times of great developmental change and sensitivity. But how early does the effect of the environment start? We know that in utero exposure - through nutritional or psychosocial stress to the mother - can have lasting consequences. In fact, because the mother’s body buffers the offspring from the external world, mom’s health even before conception can carry over into pregnancy and the development of her child.

But what of fathers? Clearly human males provide genetic material through DNA, and play a key role in pre- and post-natal care of mothers and infants. But do their own experiences before conception - or those of their fathers - affect their children in measureable ways?

Studies of inheritance and genetics has long held that this is impossible; germline (i.e. sperm or egg) DNA is sequestered early in development, and the only source of variation in hereditary material arises through random mutations and sexual recombination. In other words, the environment is not associated with the generation of phenotypic variation, only selection upon that variation once present in DNA. However, epigenetic processes do not always follow classical inheritance patterns (i.e. paramutation, imprinted genes), and are starting to change how we view the role of the environment on inheritance. Contrasting models of inheritance. (a) Classical inheritance after August Weismann. DNA is inherited through gametes (solid gray line) and interacts with the environment (solid colored lines) during development to produce phenotypes (soma). The environment of previous generations has no impact on the phenotype; (b) Inheritance under germline epigenetic inheritance (GEI). Environments affect the current generation but may also trigger epigenetic processes (dotted lines) that are transmitted back to gametes and passed onto subsequent generations. Acquired phenotypes may be inherited, in some cases across multiple offspring generations. From Ryan and Kuzawa 2020.

Emerging Research

Evidence that the environment around the time of conception - or even before - can affect the sperm epigenome and ultimately offspring development and health, is rapidly growing. This means that on a theoretical level, we may need to rethink some of our assumptions about the drivers of phenotypic variability, mechanisms of inheritance, and evolution. But these findings may also have important practical and public health implications: if losing weight or reducing stress shortly before conceiving could have long-term effects on child health health, public health officials, medical practitioners, and prospective parents ought to know.

However, most of what we know comes from mice, and research in this area in humans is still growing. While most epigenetic processes are shared, humans differ from rodents in important ways. This creates a number of challenges to studying this ‘germline epigenetic inheritance’ (GEI) in humans, and need to be carefully considered as we move forward. Our long lives mean that we can experience many exposures over the lifetime, and because of our complex societies, exposures (i.e. nutritional or social stress) are often correlated. Unlike in mice, exposures are rarely random, but are the product of hierarchies of power and structural inequalities. Furthermore, GEI provides only one pathway - parents who face nutritional or social adversity may transmit these effects onto their offspring through a number of non-biological pathways (e.g. changes in parenting behavior).

Nevertheless, there are a number of advantages of working with humans and non-human primates in this area. Researchers can capitalize on large, long-term datasets that have rich phenotypic, genetic, and health information, taking advantage of plethora of genetic and physiological tools available for our own species. We are also learning more about the potential ‘critical windows’ of sperm epigenomic changes, and the regions in the genome that might be most susceptible to epigenetic change. These insights will provide us with new opportunities to understand the effect of the pre-conceptional environment on future generations’ health in humans and our close relatives. Much of what we know about germline epigenetic inheritance through sperm (GEI) comes from worms, flies, or mice. These findings may or may not translate to humans, and research - especially in non-clinical settings - continues to be a challenge. Large, long-term, multigenerational human and non-human primate datasets with rich social and biological information common among biological anthropologists and human biologists may be key to testing this hypothesis.

Future Research

I have studied and written extensively on the topic of male germline epigenetic inheritance (i.e. Ryan and Kuzawa 2020), and been involved in the planning and design of several projects aimed at attacking this problem. These have varied from a study of the impacts of the 1918 flu on contemporaty residents of Utah, the effect of nuclear fallout from the Chernobyl nuclear disaster on growth and development of Norwegian children, and the impact of football team wins/loses on school performance of supporters’ children conceived during that time using a large database in Florida.

So far, the challenges of these projects have outweighed the opportunities. However, I continue to seek out opportunities to investigate this fascinating area using both human and non-human primates, and believe that anthropologists and human biologists will have an important role to play in this area. The careful consideration to both social and evolutionary forces, combined with foundations in genetics and molecular biology, promises advance us beyond mice models and clinical studies, and into non-clinical studies that emphasize natural human variation and health. Studying germline epigenetic inheritance is important not only for theoretical reasons (e.g. What do we mean by ‘inheritance’? How does the environment contribute to phenotypic variation?), but also practical reasons (e.g. Should men get as healthy as possible before conceiving a child? What changes in particular might have the most impact on the next generation?). Such questions also raise important ethical issues from the perspectives of both past generations and those to come.