Monday, April 8, 2013

Epigenetics isn't everything but it is something

'Epigenetics' is the new 'gene for.'  A good way to tell if a field in biology is hot is if it's become an -ome, with a Wiki page, and epigenetics has.  The 'epigenome' will now explain everything from why identical twins aren't, to why we get the diseases we'll get and why we behave as we do, and science studies and gender studies and social critics are using epigenetics to reconfigure their approach to understanding how biology and society are intertwined.

There are a couple of issues here.  One is that some people use 'epigenetic' to refer to things like, say, obesity due to overeating because diet interacts with one's genetically based metabolism.  However, the current 'hot' meaning is that environmental factors directly affect gene expression, rather than just the result of normal gene expression.  So, a dietary component might lead to a gene being inactivated.

Now the fashionable aspect of this is, of course, that those in the area seem to want everything to be 'epigenetic' -- after all, one can get funded to do the epigenomics!  We mean not to disparage the field wholesale -- there is certainly something to it, but, like the human genome project, the epigenome can't possibly fill all the promises being made in its name.  It is, in this sense, a political ploy for funding and attention, as well as an enthusiasm for what seems new and possibly profound.

Still, epigenetic effects mean that DNA sequences alone do not determine what genes do, and the epigenetic modifications can have substantial effects, and be inherited.

The state of the art
A paper in the latest Trends in Genetics ("Bridging the transgenerational gap with epigenetic memory," Lim and Brunet) does an admirable job describing what's actually currently known about epigenetics, or 'non-Mendelian', non-genetic inheritance.  They point out that patterns of non-genetic inheritance have been described for almost 100 years, including Waddington's description of the inheritance of wing patterns influenced by heat shock in fruit flies in the 1940s -- it was Waddington who coined the term 'epigenetic', though his meaning was more general than ours today.

Parental imprinting, discovered during the 1980's, is another example of non-genetic inheritance.  This is when alleles from only one parent are inherited, the other set being silenced by DNA methylation and/or histone modification.  At the same time, Lim and Brunet point out, the discovery of transgenerational epigenetic inheritance (TEI) in mice was reported, in that case affecting coat color.  And many more instances have been reported since then, in many different organisms.  It became apparent as well that epigenetic modifications could last for at least several generations.

Lim and Brunet describe a recent experiment in which
mice with an insertion of LacZ into the Kit gene gave rise to genetically wild type offspring that still exhibited the tail and paw color phenotype characteristic of Kit mutants for at least two generations.  Genetically wild type descendants of ancestors that had the Kit mutant phenotype showed an altered pattern of Kit RNA expression, with RNA molecules of shorter size in brain and testis.  Microinjection of RNA from heterozygous mutant animals into one-cell embryos was sufficient to recapitulate the mutant phenotype in the following generation.
Our objections to the use of 'wild-type' and 'mutant' notwithstanding, the persistence of the traits from the altered mice into the next generations is of interest. The authors suggest that the transgene (the LacZ inserted into the Kit gene) disrupts a specific locus in the parental genome, which causes the production of abnormal RNA in sperm, which is then transmitted to at least the next two generations.  How this 'epigenetic memory' works is not yet clear but the apparent role of RNA in this process has been replicated in experiments with other traits.  One example is the injection of fertilized eggs with micro RNAs targeting specific enzymes that regulate cardiac growth, which had the capacity to slow the growth of the heart for several generations, though it seems that not all RNA has a similar capacity. 

Work has recently been done on transgenerational epigenetic inheritance in the model worm, C. elegans, as well, specifically on longevity and fertility.  The inheritance of sterility and longevity influenced by histone modifications -- demethylation -- has been documented, and observed to last for at least 5 generations. 

TEI and environmental stimuli
Another mode of TEI, which is perhaps more relevant to life as it's lived outside the lab, is that that might be induced by metabolic changes.  Over- or undernutrition of parents is the example we've heard most about, with respect, e.g., to the multi-generational consequences of widespread famine. 
Exposure to a chronic high-fat diet in rat fathers results in impaired insulin metabolism and pancreatic cell gene expression in female F1 offspring.  Female offspring from fathers fed a high fat diet mated with mothers fed a control diet exhibited an increase in blood glucose ... and a decrease in insulin secrettion compared with offspring with both parents fed a control diet.
Analysis of gene expression in islet cells showed differential levels of expression of various types, including signaling factors.  Other experiments have shown altered phenotypes and gene expression two generations after male mice were overfed, suggesting again that this is due to a TEI rather than genetic changes.  Some hypothesize that the epigenetic changes are to the contents of sperm and seminal fluid (which includes chromatin, RNA and metabolites).

The effects of undernutrition can also be inherited, including "increased expression of genes involved in fat and cholesterol biosynthesis" and genes involved in DNA replication.  Alterations in lipid metabolism and cell proliferation have been demonstrated in offspring of mice who've been deprived of food.  At least one study demonstrated epigenetic changes in the sperm of parental mice on restricted diets.

The effects of famine during World War II on a large family cohort in the Netherlands have been examined, and metabolic consequences shown to last for at least two generations.  A family cohort from 19th century Sweden shows much the same, as well as that food intake during adolescence of grandparents correlated with survival of grandchildren, suggesting that there may be a critical period for production of healthy gametes.

Further examples include the effects of heat shock in Drosophila, TEI of small RNAs from viruses in C. elegans with gene silencing consequences, TEI of behavior patterns such as depression, via exposure to psychological stress in utero, and olfactory imprinting behavior in C. elegans.

Transgenerational epigenetic inheritance can be via DNA methylation, histone modifications, noncoding RNAs, short RNAs and other aspects of RNA function.  Lim and Brunet point out that the mechanism or mechanisms behind these modes of inheritance are not yet well understood.  They list questions that remain to be answered, including how the signals are eventually erased, how the changes are maintained, and whether the strength of the environmental stimulus affects the number of generations the effect is maintained.

TEI and evolution
Finally, they suggest that because transgenerational epigenetic inheritance is known to occur in many organisms, it must have been selected.  They postulate that perhaps it was advantageous to pass on information about the environment -- but environments change so quickly that it seems more likely to us that the ability to adapt would have been what was selected for, rather than the ability to stay the same, and TEI is certainly one adaptive ability.

Or, they suggest, TEI might increase the evolvability or rate of evolution of an organism.  Perhaps it affects the accessibility of chromatin to DNA repair enzymes, thus making certain loci more and less mutable.

An active mechanism that can obscure
There are active genetically encoded mechanisms for applying and removing epigenetic changes such as methylation.  These can be very specific and differ between males and females.  Much of the genome is 'set' differently in the generation of sperm or egg cells.  But once modified, unless it is re-set each generation, the effect can appear to be DNA-encoded in epidemiological studies but non 'Mendelian': family members share the trait, but not because of specific DNA variants, since some may have inherited modified, and others unmodified copies of the same variant. This is one major reason why epigenetic factors can obscure studies, like genomewide scans, to find genes that contribute to important traits like disease.

Not non-Mendelian!
Note that the phrase 'non-Mendelian inheritance' is thoroughly wrong, but probably ineradicable from the current jargon.  Genes are inherited in a Mendelian way.  Each of us carries two instances of human genomes, and we more or less randomly transmit a copy of one of them to each sperm or egg cell.  This random transmission is what is Mendelian:  Mendel didn't know about genes, but used traits to signal the inheritance of these 'elements' or 'factors'.

But the traits are not--that is not--inherited!  Only the genes are inherited.  It is only if traits are tightly tied to specific genetic variants that the appeance of the trait is highly correlated with the genetic variant that was inherited that the trait seems to be 'Mendelian'.  Therefore epigenetic patterns of occurrence in families that are not 'Mendelian' refer to alleles that were inherited but that, because of epigenetic modification, their effect is not manifest.  The inheritance itself is in these instances not affected.

It is very sloppy to speak of Mendelian inheritance in regard to any phenotype, and we can lead ourselves into trouble if we aren't careful.  There is, in fact, a phenomenon of non-Mendelian inheritance (called segregation distortion) in which the two alleles a person carries are not transmitted with equal probability.

We also noted more verbal sloppiness in the literature, by terms such as 'non-genetic inheritance' and 'wild type'.  So, we quoted this earlier: "an insertion of LacZ into the Kit gene gave rise to genetically wild type offspring."  If the mouse is genetically altered, how can it have the wild type genotype?  What was meant, we think, was that the genetically modified animal had the phenotype of the unmodified animals.  But it inherited the modified not the wild type genome.

But we've probably said enough already about how self- as well as other-misleading such loaded terminology can be.


rich lawler said...

This is a great post. I've been skeptical of some of the claims of epigenetics, solely because the folks who tout the powers of epigenetics are so quasi-religious about it. I like to be sold on evidence not promise. But these recent papers on epigenetic inheritance are fascinating and likely evolutionarily relevant.

One thing about the transgenerational aspect that you mention is the uniform environment posed by captive settings. I could see the "inheritance" of epigenetic patterns to be driven by a consistent environment from generation to generation in a lab setting, though the mouse experiment tries to change the dietary environment across generations (the uniform environment seems roughly analogous to quantitative genetic estimates of parent-offspring heritability where the parent-offspring environmental covariance term = 1, rather than assuming it is zero).

But perhaps TEI allows one to escape the Red Queen.

Ken Weiss said...

There are experimental data on lab animals (mice, C. elegans, and probably many others I don't know about), and they involve stochastic as well as (I think, in the case of C. elegans) experimentally imposed environmental changes that lead to imprinting.

In humans blood pressure and other variables, perhaps satiety or obesity-related traits, in which there seems to be imprinting in the phenotypes, at least. I don't know of human examples where the specific cause or mechanism, nor the number of persistent generations is known.

I agree about the epigenetics 'religion' which is a kind of fad like so much else. The more thoughtful people, of which I think Art Petronis is one of the best. You might like Art's paper in Nature in 2010 or 2011 (a review). And he had an interesting paper on intra-individual variation in the Am J Hum Genetics a few years back (you can find it easily by Googling or searching the journal website).

In humans, the idea would be that it is NOT uniform environments that raise the problem, but that some people are exposed to 'methyating' environments (if I may use such a phrase) that modify specific genes either in parents where they stay in the gamete, or in utero, and where the effect may be transmitted to the grand-generation.

I think the Red Queen is a very unfortunate and inaccurate simile, so I can't really respond to your last line. But if you mean that you can habituate to your environment and survive, and hence not have to await favorable mutations, then that like other adaptabilities would serve the purpose, I guess.

rich lawler said...

Thanks for the reference to Petronis, and for your other comments as well. I'm going to chase up Petronis's papers.