Transgenerational Epigenetic Inheritance

Transgenerational epigenetic inheritance is the idea that epigenetic marks (i.e., DNA methylation, histone modifications) can be acquired on the DNA of one generation and stably passed on through the gametes (i.e., sperm and eggs) to the next generation. In other words, experiences and environmental exposures can change the way your DNA works (without changing the DNA itself) and this could be passed on to your offspring.

It was originally thought that the epigenome of the sperm and eggs was reprogrammedtwice – once during gamete formation and once during conception – however, we now know this isn’t completely true. By way of analogy, think of a read/write CD that you try to erase but some of the data is still left on the CD, and this residual data combines and impacts the newly recorded data. Epigenetic leftovers.

Transgenerational epigenetic inheritance absolutely does happen. There are some excellent and illustrative examples listed below. However, the scientific community is still trying to figure out to what extent this happens. So, does eating better and exercising more impact the health and happiness of your offspring? Likely. Is this because diet and exercise impact us epigenetically? Well, sure. Can these changes be inherited through the gametes? Sometimes, but we are still figuring this story out in real time. Stay tuned…

 

1. Parental allele-specific imprinting

There are a small subset of genes called imprint genes. Normally, we have two functional copies (i.e., alleles) of each gene – one from our mother and one from our father. For imprinted genes, either the maternal or paternal allele is methylated significantly such that only one copy produces protein. For reasons that still remain to be elucidated, this is critical; particularly for early development (e.g., embryogenesis). The vast majority of imprinted genes are involved in controlling embryo growth and development, including development of the placenta.

Poor embryogenesis and male infertility

Over the last few decades, numerous scientific studies have tried to understand the mechanisms behind male infertility. However, more than 50% of male factor infertility cases still have no known cause. Until very recently, people mostly thought sperm was simply delivering DNA to the egg. As the old saying goes, men just need to show up. Our increasing understanding of epigenetics has completely turned this view on its head. Numerous studies have found abnormal methylation of specific imprint genes of sperm are highly correlated to male infertility. This is precisely why Episona is investigating imprint genes in sperm to understand how aberrant methylation at these loci might be contributing to male infertility (i.e., poor embryogenesis after conception). You can find good reviews of the data by Douglas Carrell, Celine Boissonnas, and Singh Rajender. If you would like to receive copies of some of the scientific manuscripts, please feel free to contact us.

Seed, an innovative new male fertility test, looks at epigenetic markers to evaluate fertility potential.

Fetal development and imprint disorders

It is also thought that proper epigenetic inheritance of genomic imprinting is critical for later development as well. Particularly, some of the imprint genes seem to be important for early brain development and, when not properly methylated, can lead to diseases such as Prader-Willi syndrome, Beckwith-Wiedermann syndrome, Silver-Russell syndrome, and Angelman syndrome. It is also thought these imprint genes are involved with growth more broadly. Below is an excellent interview from EpiGenie with Dr. Gudrun Moore, who is studying the epigenetics of growth and early development at University College London.

 

2. The agouti mouse

Examples of transgenerational epigenetic inheritance within endogenous genes, other than imprinted genes, is relatively rare. However, one excellent example is that of the agouti viable yellow (Avy) gene. The Avy locus is actually a retrotransposon (i.e., jumping gene) that is inserted upstream of the agouti gene. Although Avy is unique to the mouse genome, the element is present in thousands of copies. Normally, these Avy elements are methylated, thus, shut off. However, in the Agouti mouse, they are unmethylated and active, leading to a yellow coat and very pronounced obesity.

Agouti mouse, an example of transgenerational epigenetic inheritance
The viable yellow agouti (Avy) mouse model, in which coat color variation is correlated to epigenetic marks established early in development. These two mice are genetically identical. However, they have a different epigenetic methylation pattern at a specific gene loci that impacts hair color and weight.

Mice whose agouti gene is “on” are also more likely to suffer from diabetes and cancer as adults. Additionally, these epigenetic modifications to the Axy elements can be transgenerationally inherited by the offspring. This suggests that there is a failure to clear the epigenetic marks that are established at the Axy locus in the germline. Thus, there is a clear transgenerational epigenetic inheritance via the gamete.

 

3. Environmental impact on inheritance

One of the most exciting areas of epigenetic research involves understanding how environment (e.g., exposures to toxins or broad experiences such as chronic stress) may cause epigenetic changes and whether or not these changes can be transgenerationally inherited. Can stress in the mother or father impact the health of a child before they are even conceived?

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The field of environmental epigenetics is an area of science that involves scientists from many different disciplines including molecular biology, epidemiology, and mathematics. Understanding how the environment impacts how the genome works would have massive implications on how we approach solving current diseases and think about inheritance. That being said, the data that supports the relationship between environment, epigenetics, and transgenerational inheritance is still nascent.

When thinking about transgenerational epigenetic inheritance, it is critical to establish that the inherited phenotype is dependent on being passed through the gametes (i.e., sperm and eggs). An illustrative example is that mice raised by stressed mothers are much more likely to be stressed themselves. Additionally, there are known associative changes in DNA methylation at the glucocorticoid receptor gene. This is an example of a inherited characteristic that is not inherited via the gametes, even though there is an epigenetic basis. In this case, the epigenetic changes in the offspring come from behavioral interaction with the parent, not from inheriting the epigenetics via the gametes.

However, there are examples of environment inducing epigenetic changes that are then inherited by the offspring through the gametes. Particularly, transgenerational epigenetic effects through the father are much less likely to be confounded by behavioral factors as the father contributes far less than the mother to the environment of the fetus and newborn. Michael Skinner’s team produced one of the first studies to support the idea that environment could cause epigenetic changes that could be inherited through the gametes. In this study, female rats were exposed to a fungicide (vinclozolin) and they found that epigenetic changes that occurred in the first generation male offspring were faithfully passed on through at least four generations.

It is probably unlikely that transgenerational epigenetic inheritance is a widespread phenomenon. Certainly epigenetics plays a major role in differentiating cell types within a given organism and “adapting” these tissues to environmental exposure. Further, there is significant evidence that these changes can occur in the gametes. But I believe that the most likely outcome from these epigenetic changes is decreased fertility (i.e., decreased embryonic viability) if they aren’t completely erased during reprogramming, rather than acquired traits that are then inherited across generations. That being said, a very different way of looking at epigenetics could be as a mechanism for “long-term adaptation” or “short-term evolution”. In this case, transgenerational epigenetic inheritance becomes essentially necessary for the survival of the species. Either way, the research in this area will continue to expand and excite over the coming years.