The Unsolved Mystery Of Inheritance: Genes Aren’t The Only Way Mice Inherit Obesity

In 1890, German evolutionary biologist August Weisman spent his days breeding rodents and cutting off their tails. His goal: to see if, after a sufficient number of generations, the animals would be born without tails. As he expected, all of the animals developed their tails normally. At the time, this was not a universally expected outcome – some still held to the ideas of French naturalist Jean-Baptiste Lamarck, who famously suggested that giraffes evolved long necks by stretching to reach higher and higher branches.

After the acceptance of Mendel’s invisible ‘heredity units’ (genes), and our later understanding of DNA as the basis of inheritance, the idea that a characteristic you acquired in life could be passed on to your offspring became laughable. Yet 100 years later, it appears that some acquired characteristics can be passed on, and we now have the most detailed evidence to date about how this happens.

Over the past few decades, studies have found that an animal’s exposure to environmental factors can have an effect on its offspring. For example, exposure to certain chemicals can cause the animal’s offspring to be infertile. This, it seems, is not because of changes in the genetic code itself, but rather in the way in which the code is read. Epigenetic alterations are changes to the DNA molecule or its associated proteins that don’t alter the meaning of the genetic code. Rather, they determine which sections of the DNA molecule are ‘read’ to make proteins, and which are skipped.

There’s evidence that this could happen in humans too. The most famous example is perhaps the Dutch famine at the end of World War II. Offspring of mothers exposed to famine prior to conception or during pregnancy suffered significantly higher rates of obesity and heart disease. More recently, research has suggested that fathers who smoke produce sperm cells bearing epigenetic alterations. However, it’s not possible to prove a causal relationship in these examples. It has also been suggested that, since one’s genetic code could influence the propensity to epigenetic changes, a perceived inheritance of an epigenetic modification might actually be the result of inherited gene variants.

This new study suggests not only that epigenetic changes themselves can indeed be passed on in mammals, but that these changes can be very persistent, and are maintained through a mechanism we don’t know about. Scientists deliberately introduced epigenetic modifications near two genes in mouse embryonic stem cells. The type of modification used, known as DNA methylation, is a process in which molecular ‘tags’ called methyl groups are added to specific sites on the DNA molecule in order to activate or silence a gene. In this case two genes were silenced: Ankrd26 (whose inactivity causes obesity) and Ldlr (inactivity causes high cholesterol).

Not only did the mice develop with more obesity or higher cholesterol depending on which sites were methylated, but the epigenetic changes were inherited by their offspring, and their offspring’s offspring. In the case of the Ldlr gene, no reduction in methylation was detected for six generations after the change was introduced.

This is remarkable not just because the epigenetic changes lasted a long time, but because of the implications for how they are passed down. Almost all cell types in the body carry the same set of genes, yet a heart cell looks very different to a brain cell. These differences between cells are largely due to epigenetic modifications locking away regions of the genome. Since an embryo must be able to generate every cell type in the body, any epigenetic modifications have to be reset at each new generation, a process that occurs both when the gametes (sperm and egg cells) are produced, and again during gestation. How, then, did the DNA methylation introduced by the researchers survive this process again and again?

When the researchers studied the mice’s gametes, they found that the epigenetic changes had been successfully erased. However, the changes reappeared later on during development. This suggests that, in addition to the epigenetic changes themselves, there’s an ‘epigenetic memory’ that can cause previously erased changes to spring back. Exactly how this happens is unknown. One possible explanation is that proteins and RNA molecules that regulate epigenetic modifications could persist during reprogramming, then reintroduce the methylation during early embryonic development. 

This research highlights the need to answer some pressing questions. Are epigenetic changes also inherited in humans? How long do they persist? Could exposure to pollutants, pesticides and other chemicals be affecting public health not only today, but also for generations to come? 

The findings could also have implications for rejuvenation research. As we age, our cells accumulate epigenetic changes that turn important genes off, or activate genes that shouldn’t be expressed in that particular cell type. This disrupts the ability of the cell to function properly and is thought to contribute to the ageing process. One approach to reversing the ageing process is to reverse these epigenetic changes through a process called partial reprogramming. This has been used successfully to restore cultured cells to a youthful state, and there is even some animal evidence that it can delay age-related disease. But if reprogrammed cells revert to their aged state at a later point, this could hamper the effectiveness of such a therapy.