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4

Epigenetic Mechanisms, Quick &  Dirty

Jablonka & Raz (2009) show us this elegant illustration of broad and narrow epigenetic transmission.

Epigenetic inheritance in the broad sense is the inheritance of developmental variations that do not stem from differences in the sequence of DNA...information transference that can take place through developmental interactions between mother and offspring..., through social learning..., and through symbolic communication.

We...define cellular epigenetic inheritance as the transmission from mother cell to daughter cell of variations that are not the result of differences in DNA base sequence and/or the present environment.  Transmission can be through chromatin marks, through RNAs, through self-reconstructing three-dimensional structures, and through self-sustaining metabolic loops.

In the single-cell "bottleneck" variety of epigenetic inheritance (pathway a in the above diagram) Jablonka &  Raz focus on...

The environment may induce epigenetic variation by directly affecting the germline or by affecting germ cells through the mediation of the soma, but, in either case, subsequent transmission is through the germline.

Evolutionary Implications

According to Jablonka & Raz (2009), there are 5 effects of epigenetic mechanisms & inheritance vis-a-vis evolution:

(i) evolutionary change occurring through selection of epigenetic variants, without involvement of genetic variation; (ii) evolutionary change in which an initial epigenetic modification guides the selection of correlated genetic variations; (iii) evolutionary change stemming from the direct effects of epigenetic variations and epigenetic control mechanisms on the generation of local and systemic epigenomic variations; (iv) evolutionary change resulting from the constraints and affordances that epigenetic inheritance imposes on development; and (v) evolutionary change that leads to new modes of epigenetic inheritance.

Siberian Silver Fox Experiments

The Siberian silver fox experiments are so cool, & often cite them as an example of gene linkage.  Honestly, I was just BSing in suggesting that the curly tails, rounded nose, etc. were possibly linked on the same chromosome to tameness & recognized that there might be other factors involved.  Lo & behold, a citation in Jablonka & Raz (2009) pointed us toward epigenetic studies to come out of that body of research.

Cute & cuddly silver foxes
Cute & cuddly silver foxes

It turns out that the coat spotting & non-spotting variation that we associate with domestication occurs too quickly to be pure mutation, though it behaves like a dominant & semi-dominant trait, & couldn't be explained by inbreeding because the inbreeding coefficient was too low (0.03).  Instead, they believe

the stress of domestication and selection for tameness targeted genes with large effects in the neuro-hormonal system...and may have heritably reactivated some of them...This epigenetic interpretation, in terms of new epimutations rather than new mutations, explains the high rate of appearance and disappearance of some phenotypes, and support for this comes from the fact that at least two of the genes (Agouti and C-kit) that seem to be involved in the changes are known to have heritable epigenetic variants in mice...

One aspect of epigenetics that seems important here is the concept of canalization, introduced by Waddington several decades back (he also introduced the concept of epigenetics in general, which everyone rightly thought was Lamarkian & wrongly ignored--turns out he was on the money).  Roughly, canalization means that some environmental perturbation pushes a phenotype into a canal or valley, whereafter selection pressures prevent the phenotype from returning to its previous state because the "climb" up the sides of the canal or out of the valley are too steep.  Think of a marble on a tabletop that is essentially flat but has a valley to one side of it.  Stochastic chance dictates that the marble can roll any which way, but if it happens to roll toward the valley, it gets stuck there & can only roll further in the valley.  Or as this image illustrates, there are several possible environmental variations possible, but once a phenotype goes one way (plastically), it cannot go back.

So it seems to be with the silver foxes.  Once an environmental condition pushes silver foxes (or wolves before them) one way (luring tame ones to their yummy debris & handouts) or another (spooking the nervous ones to run away), a cascade of epigenetic mechanisms pushes them further along.  At that point, according to this model, tame ones cannot become anxious/aggressive & vice versa.

While cute silver foxes that you can cuddle with get all the press, the less publicized but equally fascinating is the aggressive foxes that want to rip your face off.

Aggressive domesticated silver fox Courtesy of Lyudmila Trut / Institute of Cytology andGenetics / The Siberian Division of the Russian Academy of Sciences (Source: Dugatkin 2003, http://www.dana.org/news/cerebrum/detail.aspx?id=2922)
Aggressive domesticated silver fox Courtesy of Lyudmila Trut / Institute of Cytology andGenetics / The Siberian Division of the Russian Academy of Sciences (Source: Dugatkin 2003, http://www.dana.org/news/cerebrum/detail.aspx?id=2922)

So what's going on with these aggressive foxes?  According to Popova (2006), there are at least 16 genes that influence aggression, but most aggression behavior is influenced by just a few of those.  A major player seems to be serotonin (5-HT).  The 5-HT pathway in the brain suppresses aggression.  5-HT is not a gene though, it is a hormone; & genes code for proteins.  So if there's a gene change, what is/are the gene(s)?  It could be any gene that produces an enzyme involved in the essential mechanisms of the 5-HT system, which include synthesis/degradation, reuptake in the synaptic cleft, & density/sensitivity of receptors (for more background on 5-HT, I've written on this before here).  As the figure below illustrates, there are enzymes that catalyze serotonin synthesis (TPH & decarboxylase of aromatic l-amino acids), two enzymes that help break serotonin down (MAO A & B), & an enzyme (SERT) that transports serotonin.

There are two TPH genes, & it is the 2nd one (TPH2), expressed in the brain & responsible for the central nervous system, that effects 5-HT & seems to be responsible for aggressive behavior.

Silver foxes displaying friendly responses to human contact were shown to have higher 5-HT and 5-HIAA levels, and higher TPH activity in the midbrain and hypothalamus in comparison to nonselected wild-type silver foxes bred in captivity. Importantly, the changes were found in the midbrain representing the area of main location of TPH2-synthesizing cell bodies.  These findings were interpreted as an indication of an increased activity of the brain 5-HT system in the tame animals and, subsequently, a decreased activity of this system in highly aggressive animals.

MAO A has a higher affinity for 5-HT & is considered the principle enzyme in breaking down serotonin.  When MAO A is disrupted in mice, they get more aggressive.  Deletion of SERT (the transporter that allows 5-HT molecules not taken up by post-synaptic receptors to be recycled & reused) in knockout mice also produces aggressive behavior.  Finally, there are 14 different subtypes of 5-HT post-synaptic receptors.  Genetically low aggression has been associated with increased expression of specific subtypes of these receptors in the midbrain & specific densities & function in specific regions of the brain.  These likely function to suppress aggressive behavior.

The figure below depicts this as essentially two pathways, which we can compare analogously to the Jablonka & Raz depiction of the narrow "bottleneck" pathway, albeit via two cells (or genes).  I think.

If any one of these mechanisms or either of these pathways influences aggression, they will interact with the environment to mutually reinforce themselves & push the marble down toward the other pathway too.  In other words, if the stress of domestication bumped the marble off the plane, having even only a slightly higher tendency of aggression relative to tameness will result in amplification of the entire aggression pathway, even if the environmental conditions of captivity are thereafter removed (i.e., the animal is released).  What still remains to be clarified is how the initial brain changes occur & the roles of other mechanisms in the system.

Zane Thayer & Chris Kuzawa review data that offer a clue.  They point out that "psychosocial stress contributes to the social gradient in health" (2011:799).  This is well-established by now, but the mechanisms are interesting.  In two studies particularly relevant to our question of how the stress of domestication may influence aggression in silver foxes, childhood abuse was associated w/ methylation differences at the GR (glucocorticoid) locus in the hippocampus & the serotonin transporter protein (SLC6A4) locus.  Another study found that maternal depression during pregnancy predicted stress reactivity & methylation of the GR locus in buccal cells of their infants 3 months after birth.  Methylation is the addition of a methyl group to a substrate or substitution of an atom by a methyl group.  This can take place in DNA or proteins.  In DNA, it can result in the change of an amino acid base, thus a change in the genetic code resulting in production of different or altered proteins.  In proteins, it results in regulatory changes in the protein functions, so methylation can have wide-ranging effects.  The methylation of the GR receptor locus may affect things like the binding of glucocorticoids to the receptor.  Glucocorticoids are best known for their role in stress response, but, relevant to this discussion, they are also operative in memory consolidation and learning, as contextual fear conditioning, among many other functions.  The SLC6A4 serotonin transporter protein terminates action of serotonin in the synapse & recycles it, which is a key function in mood stabilization.  Low serotonin is associated with high fear response.

So the psychosocial stress of domestication in some silver foxes could result in methylation of glucocorticoid & serotonin receptors, directly influences fear/aggression response in pups, that persists throughout their lives.  It can also influence depression in mothers that is passed on in the receptor activity of their pups.  We can link this with Larry Schell's model of risk-focusing.  Replace "SES" with "personality."  Fear/aggression in mothers increases the risk for fear/aggression in descendants, as tameness in mothers increases the risk of tameness in descendants.

Larry Schell's risk-focusing modelAlthough the model above suggests gene line changes, the broad epigenetic view suggests that some of these influences may not influence the germ yet still persist over multiple generations because of the influence that maternal disposition has on offspring gene expression.  Or, as Thayer & Kuzawa note

...Genes are regulated by biological "memories" of experiences acquired earlier in our own lives, and even by recent predecessors... (2011:801)

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Mechanisms of Cellular Epigenetic Inheritance

Epigenetic inheritance is basically the observation that offspring may inherit altered traits due to its parents past experiences. So a parents experiences, in the form of epigenetic tags, can be passed down to future generations. Epigenetic inheritance systems are  the processes and mechanisms that underlie cellular inheritance.  There are four types of EISs recognized today and they are....

  1. EIS based on self sustaining regulatory loops
  2. EIS based on three-dimensional templating
  3. Chromatin marking EIS
  4. RNA mediated EIS

All of these can contribute to between-generation epigenetic inheritance.

SELF SUSTAINING LOOPS: These are metabolic circuits through which different patterns of activity can be maintained resulting in alternative heritable phenotypes. The early studies of the loops involved the bistability of the lac operon of Escherchia coli and this system has been analyzed at molecular and theoretical levels. The studies showed that when inducer concentrations are low, genetically identical cells can generate two alternative, true breeding, stable phenotypes. These loops have been described in bacteria and other taxa.

Three-Dimensional Templating: Structural inheritance refers to the inheritance of alternative three dimensional structures through spatial templating: a variant 3-D structure in a mother cell guides the formation of a similar structure for a daughter cell, leading to the transmission of the architectural variant. - This all started from the investigation of cortical variations in ciliates. A modified organization of the cilia on Paramecium can be inherited through many asexual and sexual generations. Another form of this structural inheritance is the propagation of prions. A single protein can misfold into several different conformations that have specific growth dynamics, stabilities, pathologies, and cross species infectivity. Many prions can interact which could lead to the formation of different transmissible phenotypes. SO unicellular organisms which have the same genotype and live in the same enviroment can exhibit heritably different morphologies and physiologies.

CHROMATIN MARKING EIS:  Chromatin is what is inside chromosomes and includes DNA and everything in it. The organization and location of chromatin and chromosomes determine everything concerning how genes are transcribed, how DNA repair works, how different chromosomal domains are organized, and how chromosomes behave during the cell cycle. There is evidence that chromatin variations can be transmitted through generations of people. Therefor the study of the chromatin marking EIS is crucial for the understanding of development and heredity.

RNA MEDIATED EIS: RNA is central to the regulation of cellular dynamics in the eukaryotes and is also involved in cell and organism heredity. RNA interference has been located in all eukaryote phyla from yeast to man. In RNA pathways, double stranded RNA molecules are chopped into shorter dsRNAs by the enzyme dicer. The resulting siRNA is loaded onto a complex of proteins, one strand of the duplex is removed and the other directs silencing. RNA can affect cell and organism heredity in several different ways, one example being the result of replication of siRNA through RNA dependent RNA polymerase.