The Trouble with Epigenetics (Part 2)

In Part 1 of this blog, I considered the various definitions of the term epigenetics and the confusion that can arise when they are conflated. Molecular epigenetic mechanisms modify chromatin structure and provide a means to stabilize a particular profile of gene expression. They also allow that profile to be passed on to a cell’s descendants, through mitosis. For this reason, epigenetic profiles have been called “heritable” (meaning through cell division). It is easy to see how that definition can be extrapolated to the idea that epigenetics could provide a means of heredity from one generation to the next.

This idea has attracted substantial interest, with many people seeming to think it overturns classical genetics (the inheritance of characters based on DNA sequence), and rehabilitates Lamarckian evolution by supplying a respectable molecular mechanism. This view has gained particular prominence of late in the study of behaviour and psychiatry, with the proposal that transgenerational epigenetic inheritance can provide a mechanism of heredity that explains the so-called “missing heritability” of psychiatric disorders.

The idea of transgenerational epigenetic inheritance is that epigenetic marks laid down in the cells of one generation (in response to some environmental factor or experience) can be stably passed through meiosis (into the germ cells) and thus affect some traits in the next generation. This kind of thing is indeed known to happen in some very specific circumstances, which are highly illustrative. This review by Daxinger and Whitelaw gives an excellent, up-to-date synthesis of this field. Most of the known examples involve the establishment of specific chromatin structures at DNA repeats or transposable elements – i.e., it occurs in very particular genomic contexts. In many cases, the transmission of this chromatin state through the gametes depends on an RNA molecule, as opposed to the more traditional DNA or histone protein modifications.

This is a fascinating area of biology (though more an embellishment than an overthrowing of normal mechanisms of inheritance), but is it relevant to psychiatric disorders? In particular, can it contribute to the heritability of such conditions?

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), which look for differences in frequency of common genetic variants 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.

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, large-scale GWAS have not found any replicable SNPs associated with the disease. For schizophrenia, recent (still unpublished) 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 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.

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 – 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.

Moreover, the evidence that epigenetic mechanisms can provide a means of heredity for behavioural traits is not strong. In Part 1 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.

For that to happen, the epigenetic marks laid down in the brain by experience would have to also be laid down in the germ cells, maintained through the genomic “rebooting” that happens in the fertilized zygote (where the vast majority of epigenetic marks are wiped clean), carried through subsequent development, surviving the epigenetic upheavals entailed in the generation of all the embryonic cell-types that are ancestors of the eventual cells in the brain where the effect on this specific behaviour is mediated.

This is more an intuition than an argument, but this scenario seems inherently far-fetched to me. One expects experiences to modify gene expression in the brain, but not in the gametes. Scientists should, of course, be prepared to be surprised and delighted by unimagined discoveries that overturn our preconceptions. On the other hand, a healthy level of skepticism is usually a good idea, especially in cases where such discoveries are not attended by strong evidence.

So, is there any evidence that this can happen? Given the possible confounds attending maternal transmission, several groups have looked for evidence of transmission through the paternal germline. A study by Isabelle Mansuy and colleagues illustrates some of the problems that I see with this literature. This is definitively entitled “Epigenetic Transmission of the Impact of Early Stress Across Generationsand is cited over 100 times, so it has clearly been influential. This study involved stressing a young animal by unpredictably removing its mother for several hours at a time. When these animals grow up they show residual effects of this maltreatment (details below). So far, so good. It is further claimed, however, that this effect is passed on to the next generation and even to the subsequent one, through the male germline. Now, this is an extraordinary claim, one that should require extraordinary evidence. Instead, the bar seems to have been lowered.

I do not mean to pick on this one paper, but it exemplifies a general problem in this field – that of too many researcher degrees of freedom. This refers to studies that are exploratory in nature and that do not define a specific hypothesis to be tested in sufficient detail prior to collecting data. Researchers looking for a difference between two groups may carry out a range of tests and report any test that shows a difference or may decide, after the fact, to look for effects just in one sex or the other, or just in one age group, or just at one time-point, etc., etc. If there is no reason, a priori, to expect the effect to be specific in such a manner, then this is just significance-fishing. If the significance estimates are not corrected for the multiple tests carried out, then they do not accurately convey how surprised we should be by any one finding. (This is the difference between the odds of you winning the lottery and the odds of the lottery being won). See this xkcd cartoon for a great illustration.

The study by Mansuy and colleagues illustrates the cardinal sins of significance-fishing. The male mice that are directly stressed by having their mothers removed show “depressive-like” behaviours on two tests – the forced swim test and the sucrose preference test. These males were then bred to female animals that have not been stressed in any way and the behaviour of their offspring was tested. The result? Females, but not males in the next generation showed a significant difference (p < 0.1) on the forced swim test, but not the sucrose preference test. So, four tests were carried out and one was “significant”. In the next generation (breeding from what were phenotypically normal males), the pattern was reversed! – males showed a difference (p < 0.5, again, only on one test), while females showed none. (Additional tests of sensitivity to stress showed an effect in first-generation females but this time in second-generation females, while males showed no difference). None of these results was corrected for multiple testing, nor is there any putative mechanism or a priori hypothesis to explain the sex-specificity of the effects (which, to any impartial observer, seems like random noise).

Despite the weakness and selectivity of the actual data, the claim in the abstract of this paper is both forceful and sweeping: Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation”. This is clearly not supported by a proper statistical evaluation of the actual observations. Actually, I don’t know if I worded that strongly enough: the data in this paper do not support any conclusion of a behavioural effect being transmitted across generations. That’s better.

The same problems are evident in a recent paper claiming epigenetic transgenerational inheritance of a “cocaine-resistance” phenotype. In this case, it was expected that cocaine exposure in one generation would lead to increased sensitivity to it in subsequent generations. In fact, the reverse was found, and only in one sex. So, the direction of this effect was a surprise and presumably there would have still been a paper if the mice were more sensitive, rather than less. Similarly, there was no a priori expectation of a sex effect or hypothetical mechanism to explain it. If it had only shown up in females, I expect we would have heard about that too. That’s four bites of the statistical cherry.

Adding genomics to these studies (looking at profiles of gene expression or methylation, for example), and highlighting those genes that show a “significant” difference when considered alone, compounds this problem of multiple testing – the poor cherry is just being gnawed on now in the most unseemly fashion.

In general, the evidence of a real behavioural effect being transmitted through males to the next generation is not compelling. These studies also suffer from an additional possible confound – the possibility that interacting with a stressed or strung-out male animal will alter the behaviour of the female, post-mating, so that maternal care is also changed. This would be quite different from the model that some experience causes an epigenetic mark in the male germ cells that, in effect, transmits a “memory” of that experience to the next generation. The best way to test for such an effect is to see if it is really transmitted through the male gametes themselves using in vitro fertilization. One study that did just that found effectively no such transmission (again taking multiple tests into account).

So, while epigenetic mechanisms are implicated in the long-term effects of certain experiences, the evidence that such effects can be transmitted through the germline to subsequent generations is, to my mind at least, extremely weak. And even if they could be, they certainly cannot represent a solution to the mystery of the “missing heritability” for psychiatric disorders. These disorders are as heritable as they ever were and that still implicates differences in DNA sequence. Jut because we haven’t found them yet doesn’t mean we should start looking somewhere else. 

Because real genetics.


  1. I don't disagree that "the evidence that such effects can be transmitted through the germline to subsequent generations is extremely weak."

    There is an important exception however, and that's the phenomenon of direct germline exposures, particularly during windows of susceptibility such as fetal germline reprogramming, which occurs in roughly weeks 6-18 of human gestation. During this window, the fetal germline is susceptible to epigenetic perturbations via intrauterine exposures, for example, by pharmaceutical drugs that may interfere with methylation or histone acetylation.

    In utero exposures, particularly at acute pharmaceutical doses, may impair the development of the fetal gametes, permanently fixing an altered form of gene expression, resulting much later in the individuals who develop from those gametes, in disease or altered development.

    While you might argue "that's pathological, that's not evolution," I would argue precisely the same epigenetic mechanisms are involved, whether the exposure is positive, negative, or neutral. Epigenetic germline modification via direct exposure is no doubt an important piece of the evolutionary puzzle, but I agree with you that post-natal, lifetime events have little effect on germline (except during certain additional susceptible windows in germline development).

    1. I agree with you actually. At least I think it's much easier to see how drug or toxin exposure could alter epigenetic profiles in germ cells, which could be passed on to the next generation. I have not looked into the evidence for that actually happening though. In general, for disorders like autism and schizophrenia, there are few convincing data for any specific environmental risk factors.

  2. Kevin;
    Just last year environmental researchers have discovered that increasing levels of exposure to benzene and PCB congeners as measured in blood, urine and air are associated with increased frequency of specific sperm mutations associated with risk for de novo 1p36 deletion syndrome (Benzene) and increased frequency of XY sperm mutations associated with Klinefelter Syndrome (PCB Congeners). 1p36 deletion syndrome and Klinefelter are both associated with increased autism risk. Klinefelter Syndrome is not inherited and almost all cases of 1p36 deletion syndrome are not inherited.

    McAuliffe et al (2012). Environmental Exposure to Polychlorinated Biphenyls and p,p´-DDE and Sperm Sex-Chromosome Disomy. Environ Health Perspect 120:535–540 (2012). [Online 21 December 2011]

    Marchetti et al (2012). Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environmental Perspectives. 2012 Feb;120(2):229-34. doi: 10.1289/ehp.1103921. Epub 2011 Nov 15.

    1. That's all fine. None of that is anything to do with epigenetics. It's environmental factors acting as mutagens.

    2. I hope semantics -- mutagens v epimutagens -- doesn't get in the way of concern about how environmental exposures may be altering human germ cells. The precise molecular mechanisms of germline disruption are being investigated, but there is by now plenty of research indicating that certain compounds, particularly endocrine disruptors, are capable of impairing germline development, resulting in various abnormal outcomes in offspring, including in some cases impaired neurodevelopment.

      This should be of tremendous concern to the autism community and the research community in general. As for myself, I was heavily exposed in utero to a soup of synthetic steroid hormone drugs (somewhat popular as an anti-miscarriage protocol in the 1960s; it didn't really work btw), and in a study published in 1977 was found to have suffered a number of mild developmental problems as a result. Now my children have "idiopathic" severe autism, with normal genetics, no family risk factors, normal pregnancies, etc. The growing consensus among the scientists familiar with my story is that the acute germline exposures led to epigenetic perturbations of my developing oocytes.

      Some in evolutionary biology may stalwartly hold onto a paradigm of genetic determinism, but while the debate roars, let my story serve as a warning to anyone who would expose a fetus to potentially germline-disrupting drugs. Whether these drugs were mutagens or epimutagens, it hardly matters. My eggs were (probably) fried, my kids utterly disabled.

    3. Dear PHE;
      Kevin is a behavioral geneticist. I agree with Sir Michael Rutter who has recently stated that the behavioral geneticists are on their way to extinction and that behavioral geneticists consider the environment to be an irritant to be ignored. To be fair, Rutter also considers 'epigenetics' to be the 'flavor of the moment', but that in epigenetics the claims rather outstrips the evidence.

      I also agree with you that I won't get into an argument with Kevin over semantics.

  3. Thanks, RAJ. "It is unhelpfully reductionistic to ignore origins and look only at effects." I couldn't agree more with Sir Rutter, but that statement unfortunately pretty much sums up autism and neurodevelopment research to date.

    I am merely a pragmatist, the ideological battles that roar within the autism and evolutionary biology communities (both seething with heated debate) are of little interest to me except when some dismiss the role environmental triggers on the genetic/epigenetic integrity of our germline.

    There is by now little question that environmentally induced perturbances in germline can lead to abnormal neurodevelopment of resulting organisms, including humans. All I ask is that those who purport to be expert in neurodevelopment recognize this fact and simply add it to their ever-growing quiver of tools used to explain some of the catastrophic phenomena we encounter today. Rather than dismissing the autism epidemic, these so-called experts need solid historical perspective, and that includes recognition of the 1950s-70s mass medicating of pregnant women with all sorts of drugs (synthetic hormones, anti-nausea drugs, sedatives, many more), an onslaught of intense fetal/germline exposure to synthetic molecules unprecedented in millions of years of human history. And of course that's just one dimension of exposure -- in Vietnam, for example, the horrific third-generation effects of Agent Orange are now being seen. We have changed our environment; now the environment is changing us.

  4. Great post, refuting Epigenetics and GWAS at once :-)
    But I have some comments:
    The missing heritability is a big subject but as Zuk and colleagues showed recently chances are that heritabilty estimates are highly inflated.
    This means that the genetic component in psychiatric disorders is probably lower than what we think. Combined with the fact that even the rare variants studies (CNVs and SNVs together) explain no more than 15% of autism cases I think that we should reduce our expectations to explain autism (and other behavioral disorders) by genetics alone.
    Despite that the genetic factor is probably the best place to start revealing mechanisms that cause autism. Doing so will also help us find non-genetic factors that affect the same mechanisms.

    And last thing the cocaine study.
    Brief look at the graphs reveals that if there was any trans-generational effect of cocaine it was increased sensitivity to cocaine and not increased resistance. The rats consumed less cocaine, so they needed less cocaine to achieve the same effect (only no consequence of cocaine consumption was tested in the study, not even activity levels). If this trans-generational effect is true then it is probably not specific to the brain and it affects the entire organism.
    But I must agree with you that the effects they found are very iffy, in particular figure 3 where the difference seems to come from a strange elevation in the saline sired group. I wouldn't bet my money that this study can be replicated.

    1. Hi Guy, thanks. I found that paper by Zuk et al to be written in a really weird way. It seems like they are saying that many disorders are actually less heritable than we thought, but they are not (at least I don't think they are). What I think they are trying to show is that the *missing* heritability may be less than we thought because epistatic interactions amongst the already identified loci could explain more of the heritability than purely additive interactions. Their model just reinforces the known limitations of assuming all the heritability is additive (narrow-sense). It does not, as far as I can tell, undermine the broad-sense heritability, which does not make that assumption. I think the way it is written is really confusing.

  5. Hi Kevin,

    I hope I am not going beyond the scope of the blog.
    In this post you correctly attacked the "proposal that transgenerational epigenetic inheritance can provide a mechanism of heredity that explains the so-called “missing heritability” of psychiatric disorders."
    This "missing heritability" is coming from inflated estimates of narrow sense heritability as Zuk et al pointed.
    The broad sense heritability is rarely studied and we (geneticists) neglect large part of the picture that is factors that interact with the genetic factors.
    The idea that by more sequencing we will find the genetic variants,either common or rare, that explain the missing heritabilty is probably close to exhaustion (I would be surprised if more than 25% of autism cases can be explained by genetics alone), we should move on and start studying the interactions and in particular the GxE interactions.

    1. I agree that the additive, narrow-sense heritability can be inflated. That is really obvious in autism, where it works out at significantly greater than 1, if you assume all additive interactions (since MZ twins are much more concordant for autism diagnosis than DZ twins). However, that does not mean that the actual, broad-sense heritability is any less - it simply means the assumptions and models that quantitative geneticists typically use are unjustified and simplistic. (De novo mutations also being ignored in such models).

      Nothing I saw in the Zuk paper makes me think the actual heritability of these disorders is any lower. I think, as we have only begun to do the sequencing to detect rare variants, that it is WAY to early to call time on that effort. If the mutational target is very large (mutations in many different genes can cause these disorders) then we will need very large samples sequenced to get statistical evidence of causality from multiple hits.

  6. The estimates of heritability that we have for some behavioral disorders are ~90%, but our ability to explain them by current genetic models and data is ~15%.
    The questions is what is in the rest of the 75% that we can't explain.
    If this is mostly additive heritability, then yes a major sequencing effort will explain most of it.
    But if it is mainly interactions it will not.
    Sequencing efforts will definitely add more data, but we should also update our models, and there is no reason to wait for another 10,000 or 100,000 sequenced samples to do that.
    Sequencing studies published last year had surprisingly small overlap of SNVs within studies, between studies and with CNV studies.
    I am not saying that we should call time on sequencing efforts.
    I do say that we should not expect sequencing alone to explain much more of the "missing heritability" and that we should change our experimental design in a way that will allow us to detect factors that interact with sequence variation.

    1. I absolutely 100% agree that non-additive interactions are likely to be very important. I just think the important ones are more likely to be between rare mutations than common variants. And as we have not looked for rare variants properly (by sequencing lots of people) that is what I think we should do now, while also developing better ways to look for the non-linear effects of combinations of mutations.

  7. I get the impulse to go expansive, to do something more than write a blog post journal clubbing a few papers and instead make a point about "the state of things." But your take home message--epigenetics isn't the answer--is incoherent. You obviously like hypothesis driven studies over exploratory research, yet in the context of this post, you forget to mention that GWAS, also exploratory and which you correctly defend, is highly susceptible to p-value fishing and high false negative rates. Maybe you just don't like/get epigenetics. Can you point to any sound epigenetic papers out there or are they all just like that xkcd cartoon?

    And then there's this.
    "Jut because we haven’t found them yet doesn’t mean we should start looking somewhere else."

    That's special pleading. For instance, why not? I only see this statement as meaningful if you qualified it by showing that looking elsewhere has been proven to drain precious resources from a sure thing. Notably you haven't laid out what that is other than exclaiming "GENETICS" at us. More better GWA studies? Maybe. There will be no single answer to missing heritability in complex neurological disorders. A good place to look will be phenotypic variation within populations due to hidden environmental structures within those populations effecting genes (GxE). The proper time to consider dismissing epigenetic contributions to complex neurological disorders is when the equivalent GWAS have been done and have shown to produce no reproducible effects. Those studies just aren't there on any comparable scale.

    If you haven't read it already: "Transgenerational genetic effects on phenotypic variation and disease risk" Human Molecular Genetics, 2009.

    "GWASs currently focus on DNA sequence polymorphisms or on DNA copy number variation. But if offspring phenotype can be impacted through epigenetic inheritance, then it should be possible to survey methylation and histone marks as well as parentally-derived RNAs and proteins to test for the molecular changes that account for traits and diseases in offspring.

    1. As much as I think GWAS are looking in the wrong place (at common variants only), they are now very well controlled and very rigorous, statistically (especially in controlling for false positives). But I reiterate the fact that just because these kinds of studies have not found genetic variants that can explain the observed heritability of various disorders does not mean that these disorders are not in fact caused by differences in DNA sequence. So, until we have properly surveyed rare mutations (which are much more likely to have a phenotypic effect), there is no need to jump ship and start invoking epigenetic mechanisms. Especially when there is no good evidence of their involvement in these disorders and they cannot explain heritability as determined from twin studies. I am not dismissing the possibility that epigenetic mechanisms are involved in some way in the etiology or pathogenesis of these conditions - I am just saying there is not currently any good evidence for it or any need for that hypothesis. Given that is the case, skepticism seems the appropriate position.

    2. Oy vey, Kevin, my head is spinning at your comment that "there is not currently any good evidence for (epigenetic mechanisms) or any need for that hypothesis." Your position is scientifically illiterate and reactionary in the extreme.

      The autism/neurodevelopment literature over the past five or so years has positively exploded with evidence for such g x e etiology. Would you like me to supply a complete list of references?

      Thanks to Guy and Caynazzo for their wise observations.

    3. I would indeed be interested in any literature that shows convincing evidence for a gene-by-environment effect in autism etiology (or even a straight-up environmental effect for that matter). But please note that that is not what these posts were about. They were about (i) whether epigenetics can be considered a *source* of variance for behavioural traits and psychiatric disorders (I say no), as opposed to a mechanism by which other causes can have their effects (I'm perfectly happy with that). And (ii) whether there is good evidence for transgenerational epigenetic inheritance for these kinds of traits (i.e., transmission of acquired behaviours by epigenetic marks in gametes) - again, I say no. And there is no need for that hypothesis because these disorders are demonstrably highly heritable and those kinds of mechanisms can't contribute to that.

      I do not doubt that some environmental factors can cause epigenetic changes as well as genetic changes, which could, in theory, contribute to risk of some disorders in those exposed. That is a separate topic and one I will happily accept can occur, given some good evidence (that they happen at all, and that they contribute to overall risk). If environmental factors are being invoked to explain the supposed "autism epidemic", I think it is pretty clear now that that rise is due mainly to increased recognition and diagnosis.

      Finally, you may think these are semantic distinctions, but that was the whole point of these posts - that it is important to define these terms so people don't get confused between the multiple possible meanings.

  8. I should read the paper you linked to in your original post, but I thought there were reproducible SNPs among autistic populations. A similar challenge exists in late-onset alzheimer's, where the strongest associated signal is APOE e4. This variant isn't enough to cause AD and the etiology varies a lot between populations.
    There is a genic CpG island in exon 4 of this gene, the exon with the mutations. APOE exon4 also has a strong transcriptional element within this hypermethylated region, an enhancer that is differentially modified according to the different alleles and with cell type specificity. It alters promoter activity of APOE locus genes, APOE, TOMM40 and APOC1. Knowing that AD effects behavior and this hypermethylated CpG affects expression of the most well-known gene associated with AD how would you go about testing whether, as you say, epigenetics are a source for variation as opposed to a mechanism by which other causes can have their effects. I don't actually see much of a distinction between the two.

    Environmental effects on disease etiology are often very difficult to show even for seemingly obvious candidates. Take obesity for instance. Some scientists say the obesity epidemic is due to the overproduction of food. But that can't be the whole story. What's making people want to "over eat"? Pernicious advertising, poverty, genetics, etc?

    I'm not invoking environmental factors as the main cause of autism. Is this an argument in the scientific community? I will point out that increased recognition and diagnosis can be influenced by technology and industry (e.g., ADHD and Ritalin).

  9. "unless the supposed epigenetic marks affect MZ twins more consistently than DZ twins (and there’s no reason why they should)"

    If the epigenetic mark occurs heterogeneously in the female germline--some eggs have it, some don't--it would cause MZ twins to be affected more consistently than DZ twins. I don't know if this actually occurs, but it's a testable hypothesis.

    1. Thanks Matt. The scenario you suggest should indeed increase heritability (de novo mutations have the same effect). That is not generally what has been proposed in the field, however - that epigenetic markers of some experience affect some germ cells and not others. Still, it's clearly testable, as you say.

  10. See here for very relevant article by Montgomery Slatkin on: Epigenetic inheritance and the missing heritability problem

    This reinforces the point that epigenetic inheritance, even if it is a general phenomenon, can not contribute to heritability.

  11. Another evidence against this model of epigenetic inheritance is that increased paternal age is a risk factor of autism but increased maternal age is not.

  12. Let's see, I am no expert, my 64 years I have seen such a change in "values" from one generation to the next and the next(and I have been alive for 3 generations...), you would have to convince me that conditions such as autism (a term which is an invention of the late 20th century I believe), was not around when I was a youngster.

    I dont know why this "label" exists. Do we label visibly disabled people as "cripples" or worse? Please do not "label" kids!!

    Its funny how on skimming briefly through the posts here, I picked up on the fact that it was a crime of uneducated parents who swallowed potions way back when, to ease symptoms of pregnancy, that were probably to blame for certain modern anti-social behaviour from small children. (I acknowledge the thalidomide tragedy as the travesty that it was, and that this has been scientifically proven to have been a direct result of the drug) - but how about those modern parents feeding drugs to their toddlers and young children, which they are able to supposedly justify (to their own great relief) because their child's unacceptable behaviour has a name now, ADHD or Autism?? I will bet you anything that good old-fashioned discipline has NEVER been dished out to any of these children when they were toddlers? Were long explanations and sophisticated "reasoning" more the order of the day? I will bet they were!

    Some parents think there isnt a happy medium between a sharp smack on the backside to a 3yr old for rotten behaviour, and the other extreme of broken bones and bruises! Give me a break!

    Spare the rod and spoil the child.. we have come a long way from those Victorian principles thank God, but yes, there IS a happy medium, and we need to get back to the parental DUTY of reasonable disciplining of small children. This is how we show children we love them when we balance this discipline with affection and nurturing for the great majority of the time. We hope that by our efforts, we will release them into a world where they will be loved and lovable, respectful and respectable, aspiring to better themselves, humble and yet confident, and more. We want this for them.

    Children are not stupid..they constantly "test", its how they learn their boundaries... they DO know when their parent has any reservations about dishing out the discipline they ought to get- on the spot! A recipe for on-going behavioural problems from kids for sure is to show any self-doubt or inconsistency in management of their kids' bad behaviour. Way too many of the youngest generation have way too many negative behaviours which we adults are not handling well in my opinion and which seem to be getting more prevalent over time from my own observations.

    Kids need leadership and love. And yes, discipline is most definitely a part of that. You will not convince me otherwise, having raised our kids and seeing the values we used as our guidelines to raising well-balanced, loveable individuals pay off, as our grandchildren are a modern reflection of our success at being parents to their parents.

    Claims to the contrary have no substance, we will always find excuses in the name of scientific statistics. But this new-age idea of treating young children as small adults is a recipe for trouble. We do already have enough evidence in the up-and-coming teenage generation to back this up. There is a very sinister element out there which is becoming more and more obvious and I believe is a direct indictment of parental permissiveness on an out-of-control scale.

    There are certainly heritable behavioural conditions I definitely believe, such as schizophrenia, panic disorders, depression and more which do need addressing, often on an ongoing long-term basis, but I am plainly not talking about those.

  13. I agree very much with your points. The problem, when one wants to cite something to support a bit more caution with throwing that explanation around when genetic explanations exist and are better validated, is that, there are few journal articles to cite for this position (perhaps it's usually vented in a blog or on Twitter), but so many that make very all-encompassing conclusions from little data (e.g. Jablonka & Raz, 2009) or scientists who don't really care about the pathway for their result and just throw in a small "or it could be epigenetics" somewhere to please the crowd.
    Can you recommend any neutral articles that emphasise how implausible it is that aberrant epigenetic variation plays a large role in complex traits? I mean other than textbooks that emphasise the whole "rebooting" thing (I mean this is a thing that people not very familiar with genetics may just not know, but it seems condescending to cite a textbook).

    1. Thanks for those comments. Here are a couple recent relevant articles that make similar points: and

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