Debunking myths on genetics and DNA

Sunday, April 20, 2014

Was Lamarck right after all? A look at epigenetic inheritance

Myths © EEG

From the Wikipedia definition of epigenetics:
"In biology, and specifically genetics, epigenetics is the study of heritable changes in gene activity that are not caused by changes in the DNA sequence."
Wait a minute... how can we inherit anything that's not encoded in the DNA? All the information we inherit from our parents is coded in the DNA ... Right?

That's correct. However, there's something very important that goes hand in hand with the information contained in the genes: how and when to use those genes. Not all genes are expressed in all cells at all times: different cells express different genes, depending on the tissue and function they need to fulfill. Epigenetics studies the changes inside the nucleus that determine which genes are expressed and which are, instead, silenced. It turns out, these changes happen throughout our life. And even though they are not "written" in our DNA, in some instances these acquired changed can indeed be passed on to future generations.

This should be surprising. A mouse that loses its tail can still have offsprings with tails because the loss of the tail has not altered the DNA inside the mouse's cells. Yet, studies have altered in a similar way the eye color in fruit flies and the coat color in mice and shown that the changes were preserved in the next generation. In humans, there have been studies indicating that changes established not only through the mother's diet, but even through the father's diet could possibly affect the health of the embryo and be carried down to future generations.
"Animal models have also revealed that these diet-induced epigenetic changes are not limited to one generation, but can ripple down to descendants. Females with an increased disposition to metabolic problems during pregnancy can transfer this to their offspring [3]."
Why is this relevant? Because some of these changes can increase the risk of diseases like cancer.

For years we've been looking at associations between genetic variants and disease risks. Yet for most of the observed heritable diseases and cancers no responsible genes or alleles have been found. Could this be because the majority of heritable diseases are caused not by genetic mutations, but by epigenetic ones?

As Heard and Martienssen state in a recent review Cell [1]:
"Since the human genome was sequenced, the term epigenetics is increasingly being associated with the hope that we are more than just the sum of our genes [1]."
Epigenetics makes you rethink genetics. Back in school we studied that Darwin was right and Lamarck was wrong: Lamarck's view of evolution was that phenotypes developed out of necessity to survive to the environment. For example, according to Lamarck, giraffes developed a long neck because they kept reaching for higher branches when feeding, and then this acquired trait was passed on to the next generations. Darwin, on the other hand, pointed out that the longer neck was just a random trait that appeared at some point during the evolution of giraffes. Giraffes with longer necks experienced an advantage over the ones with shorter necks because they could reach for better food. The long-neck giraffes had an advantage and had more and stronger offsprings than short-neck giraffes, and were therefore selected for.

This view has led to two common misconceptions:

Misconception #1: All genes we have today have been selected for. This is absolutely not true. Many of the mutations we see in the human genome today are due to random drift, basically the "reshuffling" of genes that happens from one generation to the next.

Misconception #2: The environment cannot change our genome and therefore environmental exposures on one generation bear no effect on the following generation. Though this is what Darwin taught us, today we know that Lamarck was not completely wrong after all: while the environment cannot change our genes, it can indeed alter the way the genes work, and these changes can indeed be passed on to future generation. This has been the most surprising lesson epigenetics has taught us in the past few decades.

Jean-Baptiste Lamarck was wrong because acquired traits cannot be inherited -- they need to be encoded in the genome in order to be passed on to the next generation. If you cut the tail of a mouse, the offsprings will still have tails. The theory that giraffes elongated their necks by stretching it farther to higher branches and that by doing so, their offsprings would naturally acquire a longer neck is wrong. However, it's interesting to note that Lamarck was a botanist and plants do employ epigenetics to pass acquired traits on to the next generation, a phenomenon called "epigenetic inheritance."

The key point is this: the environment cannot change our genome, but it can indeed change the way our genes work (the "epigenome"). Epigenetics studies how these changes can be inherited across generations without being encoded in the genome.

The paradox is the following: we, as individuals, constantly adapt to the environment around us. The best example is certainly the immune system, which, throughout our lifetime, learns to recognize pathogens and kill them. So, what pathogens we are exposed to can induce epigenetic changes. Stress and diet can also affect our metabolism through, again, epigenetic changes. These environment-induced changes affect different cells in our body. Yet, when an offspring is conceived, the very first cells during embryonic development have to be completely reset as they are the cells that will make all different organs in the new organism. It's like completely erasing your hard drive so you can start over. Mother nature does that through a mechanism called "epigenetic reprogramming:" all the lifelong acquired information from the parents is erased in the germline (cells that originate oocytes and spermcytes) and erased again during the first phases of embryonic development.
Epigenetic changes not only take place during embryonic development, but also throughout the lifetime of an organism. The same mechanisms—notably DNA methylation and histone modification—have a role in the acquisition and maintenance of epigenetic changes induced by dietary or other environmental factors. [...] For a long time, scientists assumed that these environmentally induced changes lasted, at most, for the lifetime of the individual organism, but did not influence its offspring because gametogenesis would ‘wipe the slate clean' and the offspring would inherit a completely unadulterated set of genes. However, the specific mechanisms that cause the epigenetic modification of gene expression are now known to be involved in non-Mendelian—i.e. non-genetic—inheritance [3].
Though the mechanism of "epigenetic inheritance" is not yet fully understood, scientists hypothesize that it could happen during this reprogramming when some markers are not completely erased. Another theory is that the intestinal flora could be transmitting information across generations. And finally, the information could be carried on to the next generation through modifications in the RNA.

[1] Heard E, & Martienssen RA (2014). Transgenerational Epigenetic Inheritance: Myths and Mechanisms. Cell, 157 (1), 95-109 PMID: 24679529
[2] Lim JP, & Brunet A (2013). Bridging the transgenerational gap with epigenetic memory. Trends in genetics : TIG, 29 (3), 176-86 PMID: 23410786
[3] Hunter, P. (2008). We are what we eat. The link between diet, evolution and non-genetic inheritance EMBO reports, 9 (5), 413-415 DOI: 10.1038/embor.2008.61

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