Epigenetics & Inheritance

We used to think that a new embryo's epigenome was completely erased and rebuilt from scratch. But this isn't completely true. Some epigenetic tags remain in place as genetic information passes from generation to generation, a process called epigenetic inheritance.

Epigenetic inheritance is an unconventional finding. It goes against the idea that inheritance happens only through the DNA code that passes from parent to offspring. It means that a parent's experiences, in the form of epigenetic tags, can be passed down to future generations.

As unconventional as it may be, there is little doubt that epigenetic inheritance is real. In fact, it explains some strange patterns of inheritance geneticists have been puzzling over for decades.

Baby Animals

Overcoming the Reprogramming Barrier

Most complex organisms develop from specialized reproductive cells (eggs and sperm in animals). Two reproductive cells meet, then they grow and divide to form every type of cell in the adult organism. In order for this process to occur, the epigenome must be erased through a process called "reprogramming."

Reprogramming is important because eggs and sperm develop from specialized cells with stable gene expression profiles. In other words, their genetic information is marked with epigenetic tags. Before the new organism can grow into a healthy embryo, the epigenetic tags must be erased.

At certain times during development (the timing varies among species), specialized cellular machinery scours the genome and erases its epigenetic tags in order to return the cells to a genetic "blank slate." Yet, for a small minority of genes, epigenetic tags make it through this process and pass unchanged from parent to offspring.

Baby Animals

Reprogramming resets the epigenome of the early embryo so that it can form every type of cell in the body. In order to pass to the next generation, epigenetic tags must avoid being erased during reprogramming.

In mammals, about 1% of genes escape epigenetic reprogramming through a process called Imprinting.

Bypassing Reproductive Cells

Epigenetic marks can pass from parent to offspring in a way that completely bypasses egg or sperm, thus avoiding the epigenetic purging that happens during early development.

Most of us were taught that our traits are hard-coded in the DNA that passes from parent to offspring. Emerging information about epigenetics may lead us to a new understanding of just what inheritance is.


Nurturing behavior in rats
Rat pups who receive high or low nurturing from their mothers develop epigenetic differences that affect their response to stress later in life. When the female pups become mothers themselves, the ones that received high quality care become high nurturing mothers. And the ones that received low quality care become low nurturing mothers. The nurturing behavior itself transmits epigenetic information onto the pups' DNA, without passing through egg or sperm.


TRY YOUR HAND AT BEING A RAT MOTHER: LICK YOUR RATS!

Gestational diabetes
Mammals can experience a hormone-triggered type of diabetes during pregnancy, known as gestational diabetes. When the mother has gestational diabetes, the developing fetus is exposed to high levels of the sugar glucose. High glucose levels trigger epigenetic changes in the daughter's DNA, increasing the likelihood that she will develop gestational diabetes herself.

LEARN MORE: IMPRINTING


  • Examples of Epigenetic Inheritance

    There is no doubt that epigenetic inheritance occurs in plants and fungi. There is also a good case for epigenetic inheritance in invertebrates. While many researchers remain skeptical about the possibility of epigenetic inheritance in mammals, there is some evidence that it could be happening.

  • Toadflax

    (Linaria vulgaris)

    Common toadflax and peloric toadflax are identical in every way, except for the shape of their flowers. They are two variants of the same plant with a difference in one gene. But it’s not a difference in the DNA code. It’s an epigenetic difference. And peloric toadflax can pass on this “epimutation” to its offspring.

  • Wild radish

    (Raphanus raphanistrum)

    When radish plants are attacked by caterpillars, they produce distasteful chemicals and grow protective spines. The offspring of caterpillar-damaged radishes also produce these defenses, even when they live in a caterpillar-free environment. The evidence of epigenetic inheritance in this case is indirect, though it’s highly likely that the information passes from parent to offspring through the reproductive cells.

  • Water flea

    (Daphnia)

    Female water fleas respond to chemical signals from their predators by growing protective helmets. The offspring of helmeted water fleas are also born with helmets - even in the absence of predator signals. This effect continues to the next generation, though the helmets in the grandchildren are much smaller.

  • Laboratory Rats

    Vinclozolin is a fungicide commonly used on grape plants. Feeding vinclozolin to pregnant rats causes lifelong epigenetic changes in the pups. As adults, male offspring have low sperm counts, poor fertility, and a number of disease states including prostate and kidney disease. The great-grandsons of the exposed male pups also have low sperm counts.

    Two lines of evidence in this case support epigenetic inheritance. First, the low sperm count persisted into the third generation. Second, the sperm had an abnormally high level of methyl tags (a type of epigenetic tag that usually silences genes). This is the best case for epigenetic inheritance in mammals to date (Feb 2009).

  • Humans?

    Making a case for epigenetic inheritance in humans remains especially challenging.

    — Humans have long life spans, making it time consuming to track multiple generations.
    — Humans have greater genetic diversity than laboratory strains of animals, making it difficult to rule out genetic differences
    — Ethical considerations limit the amount of experimental manipulation that can take place.

    But we do have a few hints that suggest that it could be happening.

  • Humans?

    Geneticists analyzed 200 years worth of harvest records from a small town in Sweden. They saw a connection between food availability (large or small harvests) in one generation and the incidence of diabetes and heart disease in later generations.

    The amount of food a grandfather had to eat between the ages of 9 and 12 was especially important. This is when boys go through the slow growth period (SGP), and form the cells that will give rise to sperm. As these cells form, the epigenome is copied along with the DNA. Since the building blocks for the epigenome come from the food a boy eats, his diet could impact how faithfully the epigenome is copied. The epigenome may represent a snapshot of the boy’s environment that can pass through the sperm to future generations.

The Challenges of Proving Epigenetic Inheritance

Proving epigenetic inheritance is not always straightforward. To provide a watertight case for epigenetic inheritance, researchers must:

  • Rule out the possibility of genetic changes
    In organisms with larger genomes, a single mutation can hide like a needle in a haystack.

  • Show that the epigenetic effect can pass through enough generations to rule out the possibility of direct exposure
    In a pregnant mother, three generations are directly exposed to the same environmental conditions at the same time. An epigenetic effect that continues into the 4th generation could be inherited and not due to direct exposure.

Researchers face the added challenge that epigenetic changes are transient by nature. That is, the epigenome changes more rapidly than the relatively fixed DNA code. An epigenetic change that was triggered by environmental conditions may be reversed when environmental conditions change again.

Three generations at once are exposed to the same environmental conditions (diet, toxins, hormones, etc.). In order to provide a convincing case for epigenetic inheritance, an epigenetic change must be observed in the 4th generation.

Implications for Evolution

Epigenetic inheritance adds another dimension to the modern picture of evolution. The genome changes slowly, through the processes of random mutation and natural selection. It takes many generations for a genetic trait to become common in a population. The epigenome, on the other hand, can change rapidly in response to signals from the environment. And epigenetic changes can happen in many individuals at once. Through epigenetic inheritance, some of the experiences of the parents may pass to future generations. At the same time, the epigenome remains flexible as environmental conditions continue to change. Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment - without changing its DNA code.

References

References

Fish, E.W., Shahrokh, D., Bagot, R., Caldji, C., Bredy, T., Szyf, M., and Meaney, M.J. (2004).Epigenetic programming of stress responses through variations in maternal care. Annals of the New York Academy of Science 1036: 167-180 (subscription required).

Youngson, N.A. and Whitelaw, E. (2008).Transgenerational epigenetic effects. Annual Reviews in Genomics and Human Genetics 9: 233-57 (subscription required).

Kaati, G., Bygren, L.O., Pembrey, M., and Sjostrom, J. (2007).Transgenerational response to nutrition, early life circumstances and longevity. European Journal of Human Genetics 15: 784-790.

Chong, S., and Whitelaw, E. (2004).Epigenetic germline inheritance. Current Opinion in Genetics & Development. 14: 692-696 (subscription required).