Wednesday, November 25, 2015

Epigenetics: what is it and what isn't it? Part II: How far can it take us?

Some people are heralding discoveries in epigenetics as a vindication of Lamarck's idea of the inheritance of acquired characteristics.  As we said yesterday, and in our previous posts on Lamarck, in a technical sense this may be so, if multigenerational transmission of epigenetic marking can be clearly demonstrated.  This is a big 'if' but in subtle ways.  DNA usage can be inherited, as epigenetic research shows.
Lamarck.  Any serious connection to epigenetics? Source: wikimedia commons
Let's assume it can be transgenerational--that is, not erased in the formation of sperm or egg cells so that a given gene's epigenetic marking can be transmitted across many generations.  In a way, this would subvert the adaptability of organisms by pre-programming, as if they had already been exposed to whatever environmental factor leads to the epigenetic marking.  That would be anti-evolutionary in the sense that organisms have, by and large, evolved to adapt to environments, not to predict them, so it would be better to re-set the genome so it doesn't express genes that it doesn't need to express, etc.

But let's assume current findings are basically supported by research that shows transgenerational inheritance.  This would be Lamarckian inheritance--the inheritance of acquired characteristics--but is it Lamarckian evolution?  That's a more subtle question.  If it is, say, useful to respond to some nutrient X, then passing a hyper-responsive gene usage pattern would be adaptive.  It would be based on experience and inherited, Lamarckian.

What sorts of traits are we talking about here?  We need to be careful in several ways.  First, the epigenetic effects that have been identified affect gene regulation (gene expression or not, expression levels), but not the structure of genes or their regulatory DNA sequences.  In itself, that's no big deal, as regulation is a part of function and hence evolution.  ln fact, if individuals who do better because they mark certain genes for (say) increased expression, and that is inherited, and if the modification increases survival, that's good--it's adaptive!  If then at some later time a DNA sequence change, a mutation, makes the cell respond in the same way without requiring the more temporary epigenetic marking, then the new cellular responsiveness would become built into the genome itself.  That has long been known as a potential evolutionary phenomenon (called either the 'Baldwin effect' or 'genetic assimilation').  It presents no challenge to evolutionary thinking and is still basically Darwinian.  It would mean that while evolution can occur by epigenetic means, it eventually goes the usual genome-based way of 20th century evolutionary theory.  No problem.  It can be called Lamarckian, but we shouldn't give Lamarck too much credit, because he had no knowledge of any of these mechanisms, and was (like Darwin after him) largely guessing about how to fit what is observed to some persuasive theory.

But what Lamarck was talking about were 'real' adaptations, like flight in bats, or whales in the sea, or the complex organs by which mammals execute special function, or the evolution of eyes. These are the 'real' adaptive changes that he, and Darwin and many others, were trying to account for in natural rather than theological terms.

Modification of expression levels of insulin or some metabolic trait, or even some skin pigment based on life-experience would seem so trivial relative to more complex 'real' adaptations, that we seemingly can keep Darwin on his pedestal of honor, and Lamarck in the laughing gallery.  Or can we?

Different sorts of 'adaptation'
The epigenetic examples that have been studied so far concern the usage of genes, that is their regulation.  They do not affect the structure of the genes themselves (that is, the protein or functional RNA that they code for).  In that sense, the standard anti-Lamarckian view of epigenetics would be that it doesn't really introduce anything new, but just adjusts what is already there.  Yet Darwin and even Lamarck were concerned with  how new traits arise.

We all know of the ridicule levied at Lamarck for arguing that giraffe ancestors became modern giraffes by striving to eat high leaves, which in essence stretched their necks and that change was then inherited.  Lamarck didn't require random mutation and natural selection, and in fact he only mentioned giraffes once in his book. There he noted that legs and other structures, not just necks, had to change in their evolution.  Laughter notwithstanding, Darwin would say that mutations variously giving longer necks and differently structured limbs etc., led their bearers to bear more baby giraffes and long-neck adaptation occurred that way.  But could such complex structures have evolved by epigenetic means, by quantitative changes in development later genetically assimilated?

Giraffes by epigenetic evolution?  Source: wikimedia images
Regulatory modification doesn't seem able to produce new things, does it?  Is it possible to produce new structures by changing the expression patterns of currently existing structures?  If there is anything seriously 'Lamarckian' about epigenetics, perhaps this is where any really interesting issues arise (and, keep in mind that Lamarck's kinds of explanations were the sort of thing one might conjecture with what was known at the time, so one can, at most, use his name reservedly, as is the case with Darwin).

Mutations can occur in regulatory regions and affect the binding efficacy of regulatory proteins.  So changes in DNA sequence of these regions can affect the expression of genes they control.  In that sense mutations can in principle arise that do what epigenetic modification does: change gene expression.  If this occurs in situations where environmentally induced expression changes occur, then genetic assimilation can introduce expression changes more permanently in the genome.  There's no problem here.

Still, epigenetic changes don't directly change the structure of proteins, so can the latter be related to epigenetic responses to the environment?  In principle, certainly they can!  Gene structure clearly affects the dynamics of the protein's actions.  Mutations in the structure of a cell-surface receptor that responds to some environmental factor can affect its efficiency, and in that sense mimic the effect of epigenetic change that raises or lowers the sensitivity of genomic response to that same factor. Similarly, making more of something (say, collagen in skin and bone) could be similar in effect to making less but stronger material.  In that sense, genetic assimilation of structural changes can, in principle, mimic or be equivalent to epigenetic effects (here, by the way, we're ignoring whatever it is that enables a particular environmental factor to affect gene-specific epigenetic change--a major and highly relevant issue!).

In fact, it is not so trivial to ask what is a 'new' trait rather than a modification of something existing, especially if one thinks in terms of how development works.  Giraffe necks are complex structures, but are longer necks new or just quantitative changes in all the tissues involved?  If you think carefully, the very fact of evolutionary continuity--descent with modification to use Darwin's own phrase for it--raises the question as to what's actually new rather than quantitatively different from what came before.  The answer in our context here is not at all obvious.

In sum, one issue is that if gene structure changes can have similar effects to gene regulatory changes, then epigenetic mechanisms, that is, traits acquired by experience, can be related to adaptive evolution in the usual Darwinian sense of adaptive traits.  But this is not at all the same as the adaptive evolution of complex traits.  Could they, too, evolve via epigenetic mechanisms?

Could classical complex adaptive traits evolve through epigenetic means?
We now have extensive direct knowledge to show that tens, hundreds, or (typically) thousands of different genes are employed even in simple phenomena like the formation of basic tissue layers and lineages in embryos. The same is true for bones, eyes, organs and so on.  These causal elements all vary in and among individuals and species so that, within limits, many different combinations of genes and (importantly) the timing of their expression affects the traits that develop.  The differences are related to regulatory as well as structural sequence.  Genomewide mapping shows similarly complex causation of traits like behavior, or diseases like cancers, diabetes, and so on.

Similarly, we know that most of the traits we discuss in regard to adaptive evolution (and that were the objects of Darwin's and Lamarck's interest), evolved gradually, usually over countless thousands or even millions of generations.  That's hard to keep in mind, but to understand evolution properly we must try to do so.

An important fact is that the function of most genes is to affect the expression of other genes through various sorts of signaling or processing, indirectly as well as directly.  Signals, receptors, regulators, modifiers, and so on all are about quantitative effects, and an embryo is the result of a cascade of quantitative interactions, that end in physical structures and processes (like metabolism).  Even if final properties of adaptive traits are purely structural, they are the result of regulatory interactions.

A central question, perhaps the central question, has to do with the fact that for the above scenario to be plausible, epigenetic effects based on life-experience in the environment must affect relevant gene usage, and it is far from automatic that all of these factors involved in complex adaptive traits could be induced in that way. It's a lot easier to account for minor metabolic effects like this than for other traits, even bit by bit.  Still, some of them might, and they all would, in principle, be legitimate subjects for an epigenetic evolutionary role.  This will likely be an important area of investigation.

Could major adaptations such as Lamarck and Darwin were mainly concerned with evolve through epigenetic stages?  Clearly, with such hypercomplex systems as we're made of, and their very gradual evolution, there is no way to argue that epigenetic changes, aided by various forms of genetic assimilation, could not account for the evolution of complex adaptive traits.  At least some of organisms' life experience exposures (what Lamarck called habits or striving) can affect their gene usage and, ultimately over such incomprehensibly complex genetic and temporal landscapes, lead to the origin and evolution of complex adaptive traits.

Could some lifestyle activities in Africa have led for whatever reason to growth changes in giraffe-ancestors' necks, slowly and bit by bit, that led them to notice and eat higher leaves, which then led to genetic assimilation (which is a form of natural selection)?

Could doesn't mean did, obviously, nor even if these ideas applied to some traits there's no reason they would have to apply to all traits.  We know evolution takes many paths.  But the discovery of environmentally induced regulatory changes by epigenetic marking could in principle lead to complex trait evolution.  Even at best the onion-like multilayering of how an environmental experience comes to affect the expression of only some specifically relevant genes in the first place, will have to be understood.

Evolution, and evolutionary theory, carry on
Even if all of this epigenetic driving of aspects of evolution were found to occur, that would not be a threat to the general notion of adaptive Darwinian evolution--it just adds another aspect of the mechanisms involved, which often would involve a component of natural selection.  And indeed Darwinian concepts, especially of strong natural selection, are themselves very oversimplified relative to a far more nuanced reality.

If epigenetics turns out to be more broadly and evolutionarily important than we currently know from solid facts, Lamarck would in that limited sense be right, but it would not be for anything other than the idea that adaptive traits can appear to have evolved through gradually accumulated life experience.  Lamarck was quite aware of the complexity and, importantly, slowness of evolution. But he can't be credited with more than that.  He had no specific information about mechanism and in that sense no anticipatory insight.  In essence the same was true of Darwin: he was observing variation in life and accounting for its arrival via natural historical rather than theological or other non-material means. On present understanding, Darwin's ideas, flawed or incomplete (or pure guesswork) though they often were, seem closer to the mark of our current understanding in many ways, epigenetics notwithstanding, than Lamarck's (not to mention various others who at the same general time speculated about evolution).

Truly transgenerational phenotypic effects may be real or even widespread.  They may be built into genomes or might, in principle, last indefinitely many generations.  They could be more flexible relative to changing environments, via epigenetic routes than having to be hard-wired in the genome. But even if so, this would mainly add details to the generally understood means of evolution of traits, simple or complex.  Every such discovery, if true, would improve our understanding of life.  The jury is clearly still out in this case, and jurors are still properly doubtful, about whether or not it is a fact.


Carl Churchill said...

Don't neglect to mention how heritable DNA methylation is

Ken Weiss said...

Your comment seems perplexing to me. Unless I'm misinterpreting you or the article, the latter seems to say that epigenetics isn't very useful in criminology. There are many interesting, and many more over-sold, aspects of epigenetics these days, and whether or how it could be of greater importance isn't yet clear. It's obviously an important aspects of our biology, but just how is far from understood at present. Even twin studies, regardless of causal reasons, have substantial limitations, but that's a serious subject that's too large for a comment or reply.

Carl Churchill said...

Twin studies's so called "limitations" seem to be an obfuscation of the fact that they've been supremely useful in understanding the etiology of psychological traits, and differential psychology is a robust field.

On the other hand, it seems foolish to be singing the praised of Lamarckian epigenetics.