View Full Version : "The Trouble With Epigenetics"


Amtram
01-13-13, 09:57 PM
Part one (http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-1.html), in which the author describes the origins of the term, how it can mean different things in different contexts, what it means in molecular biology, and what it is as a process:

Twin studies looking at the heritability (http://en.wikipedia.org/wiki/Heritability) of psychiatric disorders or behavioural traits show a consistent pattern: monozygotic (http://en.wikipedia.org/wiki/Monozygotic#Monozygotic_.28.22identical.22.29_twin s) twins are considerably more similar to each other for these phenotypes than are dizygotic (http://en.wikipedia.org/wiki/Dizygotic#Fraternal_.28dizygotic.29_twins) twins, but are usually not completely identical. This demonstrates an effect of shared genes on phenotypic resemblance (i.e., heritability) but also highlights the limits of that effect – even genetically identical individuals are not phenotypically identical. Some other, non-genetic factors must be contributing to the phenotype of an individual and making monozygotic twins less similar to each other. But does “non-genetic” necessarily mean “epigenetic”?

The fact that environmental factors or extreme experiences can influence an organism’s phenotype is not news. In specific cases like those described above, the effects of such factors may indeed be mediated by molecular epigenetic mechanisms. But here’s the important thing – even though epigenetic mechanisms may be involved in maintaining some stable traits over the lifetime of the animal, they are just that: mechanisms. Not causes. Epigenetics is not a source of variance, it is part of the mechanism whereby certain environmental factors or experiences have their effects. Furthermore, these few examples do not imply that this mechanism is involved in mediating the effects of non-genetic sources of variance more generally.


I'll be keeping an eye out for part two, exploring some of the links, and I might be poking around this blog more, as the author is a neuroscience researcher.

Amtram
01-18-13, 12:05 PM
Part two (http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-2.html) was quite interesting. Several studies that showed changes in animals and humans have been used to infer that epigenetic changes in offspring caused by their parents' exposure to one environmental factor or another resulted in a heritable genetic change. I myself thought that this was potentially compelling evidence until reading this article.

Apparently, followup studies showed that this type of change was generally not carried forward to subsequent generations unless the same environmental factor was present in those generations as well - meaning that the DNA itself had not actually been changed by the environmental factor. The only things that actually cause a permanent heritable change are mutations and pathogens. Chemical exposures will cause a change in the individual exposed to them, which will not be heritable.

The author talks in this part about heritable psychiatric disorders. He specifically mentions autism and schizophrenia, but only as examples. ADHD is classified as a heritable psychiatric disorder because of its, um, heritability, and it comes up in the comment section as likely to be subject to the same mechanisms.

He also mentions the cocaine tolerance article I linked recently, and I don't think he likes it very much. He has access to the full text, and I don't, so I'm going to go with the idea that he's right and I'm wrong about the study's impact. My bad.

An excerpt:

Twin and family studies have clearly shown that many psychiatric disorders are highly heritable (with h2 values around 65-70% for schizophrenia and 75-85% for autism). Nevertheless, large-scale studies aimed at detecting DNA differences that contribute to this heritability have not turned up much. At least, this is true for genome-wide association studies (GWAS (http://en.wikipedia.org/wiki/Genome-wide_association_study)), which look for differences in frequency of common genetic variants (http://en.wikipedia.org/wiki/Single-nucleotide_polymorphism) between large numbers of cases and controls. Some people are interpreting the failure to identify specific causal variants as implying that the traits are really not that genetic after all. This is a complete fallacy.

http://2.bp.blogspot.com/-FYL-jw-4QJg/UPRDWR-347I/AAAAAAAAAYk/QphXyzDNOlk/s320/GWAS.jpg (http://2.bp.blogspot.com/-FYL-jw-4QJg/UPRDWR-347I/AAAAAAAAAYk/QphXyzDNOlk/s1600/GWAS.jpg)
GWAS analyse only the parts of the genome that harbor a common variant or single-nucleotide polymorphism (SNP) – these are positions in the DNA sequence where two forms commonly exist in the population (some might have an “A” base, while others might have a “T” in that position, for example). For autism (http://www.ncbi.nlm.nih.gov/pubmed/22843504), large-scale GWAS have not found any replicable SNPs associated with the disease. For schizophrenia, recent (still unpublished (http://www.schizophreniaforum.org/new/detail.asp?id=1819)) very large GWAS have reportedly found 62 replicated SNP associations, but collectively these still only explain ~3% of the heritability. Does this mean that the observed heritability is really not accounted for by variation in DNA sequence? Not at all.

It has become clear over the last few years that rare mutations (http://www.wiringthebrain.com/2011/08/welcome-to-your-genome.html) make a very large contribution to individual phenotypes, especially to the occurrence of diseases. GWAS do not survey these rare mutations and their failure to fully account for the heritability of the disorders therefore means nothing - really nothing at all - regarding that heritability. These disorders are still just as heritable and that heritability still means that most of the variance in whether people get the disease or not is down to genetic differences (in the DNA sequence). We do not need epigenetics to come to the rescue here. Unless rare mutations are also exhaustively surveyed and found to be unable to collectively account for the observed heritability, there is nothing to explain.

http://3.bp.blogspot.com/-7-EMhPuKxbk/UPRDe18QlVI/AAAAAAAAAYs/XuutMXxcyQs/s320/twins+in+utero.jpg (http://3.bp.blogspot.com/-7-EMhPuKxbk/UPRDe18QlVI/AAAAAAAAAYs/XuutMXxcyQs/s1600/twins+in+utero.jpg)
More to the point, even if there were, transgenerational epigenetic inheritance could not explain it. The heritability of these disorders has been estimated mainly from twin studies (http://en.wikipedia.org/wiki/Twin_study) – these show that monozygotic twins are much more phenotypically similar than dizygotic twins. As the twins in each case share the same uterine and family environment, we can conclude that the reason MZ twins are more similar phenotypically to each other is because they are more similar genetically. The heritability of a trait or a disorder can be estimated from the strength of this effect and is defined as the proportion of phenotypic variance across the population that can be attributed to genetic variance. So, unless the supposed epigenetic marks affect MZ twins more consistently than DZ twins (and there’s no reason why they should), this mechanism provides no explanation for the key observation. Even if epigenetic mechanisms can provide some means of heredity from one generation to the next, that is not what heritability measures.

http://1.bp.blogspot.com/-XpqYcjKYeaQ/UPRErC1IEaI/AAAAAAAAAZE/To4d-c7T4QI/s1600/rat+maternal+behaviour.jpg (http://1.bp.blogspot.com/-XpqYcjKYeaQ/UPRErC1IEaI/AAAAAAAAAZE/To4d-c7T4QI/s1600/rat+maternal+behaviour.jpg)
Moreover, the evidence that epigenetic mechanisms can provide a means of heredity for behavioural traits is not strong. In Part 1 (http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-1.html) of this blog I cited a few examples where particular experiences have a lasting effect on behaviour of an organism, in part by stably altering gene expression in particular cells in the brain through molecular epigenetic mechanisms. These kinds of effects can indeed be perpetuated across generations, for example, in the well-known observation that stressed female rats have stressed offspring. That is because stress reduces maternal care of the newborns, which is itself stressful and which sets up long-term changes in expression of the glucocorticoid receptor. But this is a behavioural transmission: mom’s behaviour affects offspring’s behaviour – repeat. This is not an example of epigenetic inheritance via the gametes, which is what has been proposed as a possibly important mechanism.


I hope this inspires further inquisition. We need to decrease the number of blind alleys to be explored for answers. I had no idea that these kinds of results had already been found.