Epigenetics is the new genetics

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A couple new papers review the factors that play a role in determining an individual’s epigenotype and the role of said epigenotype in the aetiology of autism spectrum disorders.

We still do not understand the rules governing the establishment and maintenance of the epigenotype at any particular locus. The underlying DNA sequence itself and the sequence at unlinked loci (modifier loci) are certainly involved. Recent support for the existence of transgenerational epigenetic inheritance in mammals suggests that the epigenetic state of the locus in the previous generation may also play a role. Over the next decade, many of these processes will be better understood, heralding a greater capacity for us to correlate measurable molecular marks with phenotype and providing the opportunity for improved diagnosis and presymptomatic healthcare.

Here’s a question that’s been bothering me: how could one demonstrate the extent of epigenetic inheritance in humans? Any “easy” look at heritability is confounded by genetic effects. Here’s my experiment: I’d need a number of genetically identical sperm with different epigenetic profiles and a number of genetically identical eggs with different epigenetic profiles (and assume I know these genome-wide profiles). I make me a bunch of twins, and determine their genome-wide epigenetic profile at some stage of development. Any correlation between the epigenetics of the children and the epigenetics of the parents would be most parsimoniously explained by epigenetic inheritance. This is probably both technically and ethically impossible, so is there any other way?

8 Comments

  1. Re: Demonstrating the extent of epigenetic inheritance in humans. 
     
    Once the molecular mechanisms of epigenetics are explored in animal models such as fruit flies and mice, similar molecular signatures could be identified in humans. A model relating epigenetic state to phenotype would then be built. The model could be tuned by testing large numbers of human adults for epigenetic state and phenotype. The phenotype traits of most interest would likely be tissue specific gene expression levels. Such low-level trait variation with epigenetic state would be more easily isolated than would more complex traits.

  2. Here’s a general question: For the non-technical discussion the social effects of nature vs. nurture in humans, is it terribly important to divide nature up into genetics and epigenetics?

  3. For the non-technical discussion the social effects of nature vs. nurture in humans, is it terribly important to divide nature up into genetics and epigenetics? 
     
    the latter is a subset of the former…but i think it is important because epigenetics is relevant to ‘phenotypic plasticity.’ but, if epigenetics is a small proportion of the variation, it might be best to not discuss it in detail since it is a ‘in progress’ area which we really don’t know that much about IMO (e.g., think of parental specific genomic imprinting, where mechanism of how it ‘remembers’ and ‘knows’ is still a mystery to my knowledge).

  4. epigenetics also provides a possible molecular mechanism for “nurture” to play a role in biology.

  5. A model relating epigenetic state to phenotype would then be built. The model could be tuned by testing large numbers of human adults for epigenetic state and phenotype 
     
    but what about genetics? inferring anything from a correlation between epigenetics and phenotype is questionable because of the possibility of genetics underlying the epigenetic signature.

  6. to elaborate: the methylation status at a given gene could be 1. inherited independent of genetic inheritance or 2. determined by the genetic status at another locus (either in cis or in trans). how do you distinguish between the two?

  7. JP: ?to elaborate: the methylation status at a given gene could be 1. inherited independent of genetic inheritance or 2. determined by the genetic status at another locus (either in cis or in trans). how do you distinguish between the two?? 
     
    The molecular mechanism of methylation status will be worked out in plant and animal models. (E.g., the mechanism by which siRNA in a mustard plant can cause specific DNA sequences to be methylated.) Once the molecular mechanisms of methylation are known, a scientist would look for evidence as to the specific source of the gene?s methylation state. For example, he might look for the developmental stage at which the methylation first occurred and then look at the genes that first became active at that stage. Or he might try to match the binding site of known methylation agents to the DNA sequence of the gene. Once the specific mechanism is known, the scientist should be able to determine whether the methylation status was inherited independent of genetic inheritance or was genetically determined by another locus.

  8. Sailer writes … 
     
    For the non-technical discussion the social effects of nature vs. nurture in humans, is it terribly important to divide nature up into genetics and epigenetics? 
     
    Razib replies … 
     
    the latter is a subset of the former … 
     
    I disagree. The former is a subset of the latter.  
     
    Epigenetics provides a mechanism by which the genome itself can be heavily conserved, yet allow for changes in an organism between generations. However, those changes are still within a stable framework provided by the genome, so this may be a distinction that is merely semantic.  
     
    Epigenetics is important both intergenerationally, and in the development of cell lines in the lifetime of the organism. There appear to be many intergenerational signals in the epigenome that mediate expression in the genome. As a mechanism in evolution, epigenetic signals may provide a hint about the environment an organism will live in.  
     
    These hints should be hugely important in mammals and especially humans, because humans invest so much in each reproductive outcome, and much of that investment comes before the child itself can take over and become responsible for its survival and reproductive success. Thus, epigenetic effects should reinforce environmental effects in most cases, and make it even harder to distinguish between nature and nurture.  
     
    In an environment of plenty, it is advantageous for an organism to be large in stature, because of competition with other individuals. But in an environment of scarcity, it is better to be smaller. Does this explain why, with each passing generation since the demographic transition and the Industrial Revolution, humans are growing taller and larger? 
     
    In humans, the most important development of the brain goes on early in life, including in utero, before the advantages that particular cognitive skills will provide in life can have an effect on survival.  
     
    Is there some way that the developing fetus knows whether it needs a brain that can master calculus and philosophy? Or would those metabolic resources be better devoted to another area?  
     
    Perhaps the father (and maybe the mother as well) have mastered calculus, philosophy, and linguistics. Is there a way that this high level of brain development gets passed on through epigenetic hints, such as by methylation of sites in the germ cells that control the expression of certain genes?  
     
    In this way, as Hamilton suggested, epigentic effects may be am explanation for the Flynn Effect (rising intelligence in modern socities). But there may also be perverse or negative effects such as the rising rates of autistic spectrum disorders.  
     
    It has been suggested recently that the rising rate of Type II diabetes is such a perverse or runaway epigenetic effect.

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