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Monday, January 7, 2013

The Trouble with Epigenetics (Part 1)


“You keep using that word. I do not think it means what you think it means”. The insightful Inigo Montoya.

Epigenetics is a word that seems to have caught the public imagination. This is especially true among those, both in science and without, who decry what they see as genetic determinism or at least an overly “genocentric” point of view. Our genes are not our fate, because epigenetics! Such-and-such disorder is not really genetic, because epigenetics! Acquired characteristics can be inherited, because epigenetics!

The trouble with epigenetics is that the word means very different things in different contexts. Each of them may be quite valid, but when these meanings are conflated or when the intended meaning is not specified, the word becomes dangerously ambiguous. This is especially evident in the fields of behavioural and psychiatric research where the term is much abused, often, it seems to me, to give an air of mechanistic truthiness to ideas that are in reality both speculative and vague.

Originally coined by Conrad Waddington in his famous “epigenetic landscape”, the word signified the emergence of the eventual phenotype of an organism through the processes of development, starting from a particular genetic profile. It was derived from Aristotle’s term “epigenesis”, which means pretty much the same thing – that organisms emerge through a program of development, as opposed to the theory of preformationism (where a teeny organism is already formed inside an egg and simply grows). Waddington’s new term incorporated the idea of a genetic profile, which shapes the metaphorical landscape over which each individual developing organism travels, channeling them with greater or lesser probability toward certain outcomes. The epigenetic landscape was intended to show that the relationship between genotype and phenotype is non-linear and probabilistic, not deterministic. This importantly incorporates effects of chance or the environment on the eventual outcome.

A newer definition arose with the growth of molecular biology. Here, epigenetics refers to mechanisms of gene regulation that determine the state of a cell and that are heritable through cell divisions but that do not involve changes in DNA sequence. Essentially, this means all the processes that make one cell of an organism different from another, that keep it that way and that allow that state to be passed on to that cell’s descendants. It is often more specifically used to refer to chemical modifications (such as methylation or acetylation) of DNA or of the histone proteins associated with it in chromatin. These epigenetic marks can affect gene expression and can be stably inherited from one cell to another (i.e., through mitotic cell division).

This molecular biology definition has really only a loose relationship to Waddington’s usage. It is obviously true that molecular mechanisms of gene regulation effect (as in mediate) the development of an organism. That is what cellular differentiation and coordinated organismal development entail. Genes are turned on, genes are turned off. Epigenetic mechanisms make the profiles of gene expression that define a particular cell type more stable, with different sets of genes held in active or inactive chromatin conformations. These two usages thus relate to very different levels – one refers to the profile of gene expression of individual cell types and the other to the emergence of the phenotype of the organism.

Now, clearly, the phenotype of an organism depends largely (though by no means completely) on the profile of gene expression of its constituent cells. And there are indeed a number of examples where the behavioural phenotype of an organism has been linked to the epigenetic state of particular genes in cells in particular brain regions. Importantly, such mechanisms may provide one means whereby environmental factors or particular experiences can have long-lasting effects on an organism, by changing patterns of gene expression in particular cells in a stable manner.

This has been demonstrated so far mainly in rodents, but in several different instances (reviewed here and here). These include responses to maternal care, to various kinds of stressors, including that caused by early maternal separation and to other experiences, notably drug exposure. In all of these instances, some environmental trigger or experience induces a response in an animal. One aspect of this response is to alter the set point of the system so that its response to subsequent events of the same type is changed (i.e., learning). In some cases, this involves changes in gene expression and epigenetic marks may help make such changes long-lasting.

The examples above include several where pathways have been worked out in detail, which lead from detection of some stimulus to changes in the chromatin state of specific genes, which are involved in setting the responsiveness or gain of the system. (As in the adjacent figure, from Caldji et al., 2011, showing effects on methylation of the glucocorticoid receptor gene). These may well represent important mechanisms of biological memory for regulating reactivity of various brain systems, which thus influence subsequent behaviour in a long-lasting fashion.

Based on these kinds of examples, epigenetics has become quite a buzz-word in the fields of psychiatric and behavioural genetics, as if it provides a general molecular mechanism for all the non-genetic factors that influence an individual’s phenotype.

Twin studies looking at the heritability of psychiatric disorders or behavioural traits show a consistent pattern: monozygotic twins are considerably more similar to each other for these phenotypes than are dizygotic 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.

Differences in the outcome of neural development can and do arise because the cellular events controlling cell migration, axon guidance, synapse formation and other developmental processes are inherently probabilistic. They are determined by the interactions of thousands of different gene products and affected by intrinsic noise at the levels of gene expression and molecular interactions between proteins. The outcome is never the same twice. This is epigenetics in Waddington’s usage – the emergence of a unique organism from a not necessarily unique starting point (the genotype). There is no reason to think epigenetic mechanisms of chromatin regulation are involved in these kinds of differences in neural circuitry.

Note that there are plenty of examples where mutations affecting proteins that mediate or regulate chromatin states (such as MeCP2, CHD7, CHD8 and many others) cause neurodevelopmental disorders such as intellectual disability, Rett syndrome and autism. But these are genetic effects, which disrupt the epigenetic molecular machinery. That is, the important difference between people in these instances is a good, old-fashioned DNA mutation.

So, while epigenetic mechanisms may indeed play a role in the stable expression of certain behavioural tendencies (at least in rodents), it remains unclear how general this phenomenon is. In any case, there is no reason to think of “epigenetics” as a source or cause of phenotypic variance at the level of the organism. And here is a plea: if you are tempted to use the term epigenetic, make it clear which meaning you intend. If you simply mean non-genetic, there is a more precise term for this: non-genetic.

In part 2, I consider a more egregious trend emerging in the literature of late – the idea that transgenerational epigenetic inheritance can provide a mechanism of heredity that explains the so-called “missing heritability” of psychiatric disorders. (It can’t).

38 comments:

  1. Nice Perspective on things.

    Epigenetic mechanisms are molecular mechanisms, just like synaptic transmission is a molecular mechanism: design is in the blue print.. look forward to Part II.

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    1. Thanks Shane. Yes, that's right - there's nothing revolutionary in the idea of epigenetics, it's just a mechanism of gene regulation, one that has been appreciated for a long time. Yet may people seem to think of it as a revolutionary new paradigm that overturns classical genetics.

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  2. Interesting overall, but I cannot understand two things. First, you say "There is no reason to think epigenetic mechanisms of chromatin regulation are involved in these kinds of differences in neural circuitry." Why not? Say a fetal germ cell is heavily exposed to synthetic steroid hormone drugs, resulting in aberrations in epigenetic programming resulting from the interference with germline reprogramming that occurs in the first half of gestation. Then, decades later, that germ cell joins with another (egg or sperm, as the case may be), resulting in profound neurodevelopmental abnormality/autism in the resulting child. Is that autism due to "noise" or to the ancestral exposure to the potent synthetic compound completely novel in the scheme of 4 billion years of evolution?
    Second, what's wrong with transgenerational epigenetic inheritance? If a fetal germcell (the F3 generation) is exposed and epigenetically altered, why wouldn't the F4 generation inherit the marks?

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    1. Thanks for your comments. Let me try and answer your two questions. First, I meant that epigenetic mechanisms are unlikely to be involved in mediating the kinds of differences in neural circuitry that emerge as a consequence of intrinsic variability in neurodevelopmental processes. Clearly, they can be involved in mediating some other kinds of effects, including environmental or experiential ones, like the examples I gave. The scenario you cite sounds reasonable enough, but then lots of things could happen - the question is what kinds of things do we actually have evidence for?

      As for what's wrong with transgenerational epigenetic inheritance, I will get to that in Part 2! (Coming as soon as I get some time to finish it).

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    2. Thanks, Kevin. What kind of things do we have evidence for? Work by Skinner, Crews, Gore, Rissman and others finds fetal germline perturbations caused by exposure to endocrine disrupting/synthetic hormone-mimicking compounds. And neurobehavioral consequences were found. So, again, are those consequences "noise" or did they result from the epigenetic impairment of the exposed germ cells?

      I shall look forward to Part 2 -- I apologize for mislabeling the generations in my comment. The exposed fetal germcell is F2 (with F0 being the pregnant female and F1 the exposed fetus). I wonder why you think F3 would also not be affected by the exposure.

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    3. Klinefelter Syndrome is the most common genetic syndrome that occurs in males only. Klinefelter Syndrome is not inherited and 1 in 500 to 1,000 newborn male infants are diagnosed with Klinefelter Syndrome. The cause of Klinefelter Syndrome is an egg or sperm mutation that produces the XXY genotype. About half the cases are caused by an XY sperm mutation and half are caused by an XX egg mutation.

      http://ghr.nlm.nih.gov/condition/klinefelter-syndrome

      The prevelance of XY sperm mutations increases with advancing paternal age. A few months ago McCAullife and co-workers discoverd that increasing levels of exposure to PCB congeners as measured in blood increased the production of XY sperm mutations.

      http://www.ncbi.nlm.nih.gov/pubmed/11582569

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339457/pdf/ehp.1104017.pdf


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    4. I'm not sure if you're implying that Klinefelter's somehow has an epigenetic mechanism? It doesn't. You've outlined the causes very clearly above and none involves epigenetics. Environmental mutagens causing mutations (or chromosomal non-disjunction) is not epigenetics.

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  3. No doubt there is debate and argument over the definition of epigenetics and the contributions of epigenetics especially with respect to how does epigenetics produce human disease.

    My defintion of epigenetics comes from AIDS researchers. Common copy number variations in a single gene CCL3L1 located on chromosome 17q.21.1 is associated with HIV-1 infection risk. Copy number variations in this gene can be inherited or de novo. By itself CNV's in CCL3L1 does not appear to have any deliterious effect. Liu et al in a meta analysis found that lower copy numbers relative to population norms increases risk for infection while higher copy numbers relative to population norms confers protection against infection after exposure to the HIV-1 virus.

    I would call this a classic example of how epigenetics works to produce human disease and even how epigenetics can work to prevent disease, What would you call this?

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012711/



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  4. I can't see why molecular epigenetic mechanism can't be a source of variance.
    Once a molecular epigenetic modification varies randomly (due to Waddington's epigenetics) it can become a source of variance in response to an environmental factor.

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    1. Yes, epigenetic mechanisms are clearly sources of variance. Chimps and humans share almost all the same protein-coding genes, the differences lie mainly how those genes are expressed via epigenetic mechanisms. Moreover, epigenetics are genetics function together, in a tight dance, and not separately. For example, methylation deserts caused by toxic exposures can destabilize DNA leading to higher risk for CNVs.

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    2. Epigenetic mechanisms can only be a source of variance if they vary. They sometimes do vary - due to mutations in components of the epigenetic machinery. Those are genetic effects. And if they are affected by environmental factors, then those are environmental effects - that is, epigenetics can provide a mechanism through which other factors have an effect but are not a source of variance in themselves - the variance comes from somewhere else.

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  5. I'd like to note that there are some reasons for epigenetic fever.

    Mutations and developmental differences are primarily before conception, and before birth. Environmental factors of the average human after birth are not as influential in actual changes genetically or developmentally. However the expression will determine much more so how much the environment affects development after birth. Obviously factors such as famine and radiation can change things drastically.

    The point being that while we are born with developmental differences or mutations, the only thing we have left to us is epigenetics. For example, lets say a womb if very stable and twins are progressing very well, very similar. But when one is born there is a mild difference in epigenetic expression that makes Twin 2 somehow more sensitive to environmental factor X. Twin 2 develops conditions. Twin 2 is not like Twin 1. But the fascinating thing that can happen is that through conditioning Twin 2 may become more like Twin 1 because epigenetic expression can change.

    Also epigenetic expression is a modifiable factor for humans to approach before deciding to conceive a child. It may not change the actual genetics of the offspring, it can create a more and less stable environment for development as well as increase the likelihood of proper transcription (avoid mutations).

    I think there is a lot of reason to be excited about epigenetics. And then there is the factor that while the subjects epigenetic expression may not be accountable, may not be the correct reference, the subjects parents' epigenetics may very well be. Not too hard to sum the two together and just use the poorly references word.

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  6. Just in time...

    http://www.nature.com/news/no-easy-answer-1.12157

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    Replies
    1. Looking for answers in his DNA sequence to why Adam Lanza went on a rampage is absurd, offensive, idiotic, willfully ignorant, I could go on. I hope you're not suggesting it was epigenetics that made him do it!

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    2. No no! My point was that you talking about how the connections people want, may not be how they want them, or there at all. That is why I posted the link. We need people talking about how first DNA wouldn't even come close to pre-disposable profiling, and then explaining how much of a person isn't even attached to quantifiable thing in their own DNA and Epigenetics will much more so make them less interested in an endeavor that just isn't really quantifiable.

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