Epigenetics – Forgotten Perhaps, But Not Gone

Recently, an extremely interesting article about epigenetics appeared in Discover magazine titled “Grandma’s Experiences Leave a Mark on Your Genes.”  The tag line says that your ancestors’ lousy childhood or excellent adventures might change your personality, bequeathing anxiety or resilience by altering the epigenetic expression of genes in the brain.  Wow!

Those of us who work with genetics on a daily basis are used to looking at inheritance, pure and simple, DNA, STRs, SNPs, RNA and mitochondrial DNA.  Nothing more, nothing less.  All straightforward, right?

Epigenetics changes all that….or so we think…but how?

In 1992, two researchers, Moshe Szyf and Michael Meaney, one a molecular biologist and one a neurobiologist met at a conference, had a beer, and from there, epigenetic history has been made.

Epigenetics has to do with changes to molecular structure after the birth of a child – changes that can alter the function of DNA, which can alter you – many parts of you. It can make you susceptible to diseases and alter your personality, genetically.  This is in direct conflict with what we thought we knew.

Until epigenetics, the basic story line on how genes get transcribed in a cell was neat and simple. DNA is the master code, residing inside the nucleus of every cell; RNA transcribes the code to build whatever proteins the cell needs. Then epigenetic research showed that methyl groups could attach to cytosine, one of the chemical bases in DNA and RNA, much like a clinging vine.  Cytosine is one of the 4 nucleotides of DNA, the most basic building blocks.

epigenetic factors

The methyl groups could become married permanently to the DNA, getting replicated right along with the DNA through a hundred generations, but how?

The attachment of the methyl groups significantly altered the behavior of whichever gene they wed, inhibiting its transcription. It did so by tightening the thread of DNA as it wrapped around a molecular spool, called a histone, inside the nucleus. The tighter it is wrapped, the harder to produce proteins from the gene.

Think about what this means.  Without a mutation to the DNA code itself, the attached methyl groups cause long-term, inherited change in gene function. Other molecules, called acetyl groups, were found to play the opposite role, unwinding DNA around the histone spool, and so making it easier for RNA to transcribe a given gene.

It was found that this is particularly pronounced in the situation where mothers are either highly attentive or neglectful of their offspring.

Next came experiments on rats.  Szyf and Meaney began by selecting mother rats who were either highly attentive or highly inattentive. Once a pup had grown up into adulthood, the team examined its hippocampus, a brain region essential for regulating the stress response. In the pups of inattentive mothers, they found that genes regulating the production of glucocorticoid receptors, which regulate sensitivity to stress hormones, were highly methylated; in the pups of conscientious moms, the genes for the glucocorticoid receptors were rarely methylated.

Methylation just gums up the works. So the less the better when it comes to transcribing the affected gene. In this case, methylation associated with miserable mothering prevented the normal number of glucocorticoid receptors from being transcribed in the baby’s hippocampus. And so for want of sufficient glucocorticoid receptors, the rats grew up to be nervous wrecks.

Even more surprising, in subsequent experiments, when they infused their brains with trichostatin A, a drug that can remove methyl groups, these animals showed none of the behavioral deficits usually seen in such offspring, and their brains showed none of the epigenetic changes.  In effect, an eraser.

This information not only was revolutionary, it was highly resisted within the scientific community.  In the end, their landmark paper, “Epigenetic programming by maternal behavior,” was published in June 2004 in the journal Nature Neuroscience.

Meaney and Szyf had proved something incredible. Call it postnatal inheritance. With no changes to their genetic code, the baby rats nonetheless gained genetic attachments due solely to their upbringing — epigenetic additions of methyl groups sticking like umbrellas out the elevator doors of their histones, gumming up the works and altering the function of the brain.  Bad news.

Another scientist found that inattentive mothering in rodents causes methylation of the genes for estrogen receptors in the brain. When those babies grow up, the resulting decrease of estrogen receptors makes them less attentive to their babies.  Generational neglect.

Think about what this means for people, for you, for your ancestors.  Think about the potential effects of extreme stress, like the holocaust, for example, on the children born to those who survived.

Since the landmark, barrier-breaking 2004 paper, more than 2 dozen papers on this topic have been published.  And as you might guess, research on humans has begun as well.

In a 2008 paper, scientists compared the brains of people who had committed suicide with the brains of people who had died suddenly of factors other than suicide. They found excess methylation of genes in the suicide brains’ hippocampus, a region critical to memory acquisition and stress response. If the suicide victims had been abused as children, they found, their brains were more methylated.

What constitutes stress?  It turns out that economic stress factors can affect epigenetics too.  In 2011 Szyf reported on a genome-wide analysis of blood samples taken from 40 men who participated in a British study of people born in England in 1958.

All the men had been at a socioeconomic extreme, either very rich or very poor, at some point in their lives ranging from early childhood to mid-adulthood. In all, Szyf analyzed the methylation state of about 20,000 genes. Of these, 6,176 genes varied significantly based on poverty or wealth. Most striking, however, was the finding that genes were more than twice as likely to show methylation changes based on family income during early childhood versus economic status as adults.

Timing, in other words, matters. Your parents winning the lottery or going bankrupt when you’re 2 years old will likely affect the epigenome of your brain, and your resulting emotional tendencies, far more strongly than whatever fortune finds you in middle age.

The message here is that epigenetic changes seem to be more pronounced in the very young, infants of nonnurturing mothers, and children, as opposed to older adults.

Epigenetic changes seem to be inherited by children.  If this is true, then how does this happen and is it measureable?  In terms of genetic genealogy, these epigenetic changes might be able to be attributed to a particular ancestor, say, a Revolutionary War or Civil War solder, perhaps.

Would there be any way to tell where the epigenetic change came from, which ancestor?  Is this trackable genealogically, and would it be beneficial to ancestor identification?

And if it’s true that certain drugs, an epigenetic elixir of sorts, can remove methyl groups and effectively wipe the slate clean, would we want to do that?  Would it in effect erase the family curse of, say, serial alcoholism or mental illness. Are there benefits that we aren’t aware of or could too much be wiped out?  How would that affect memories, like Post Traumatic Stress Disorder?  Would a terrible memory be turned into something less terrible or at least manageable?  Would our perspective of what happened to us change?  Would our outlook on life change?  Would we become an optimist if we are a pessimist?  Could it cure depression?

This information also makes me wonder why we aren’t all blithering piles of goo?  None of us has escaped a lineage with a terrible event. In my own line, I have an alcoholic grandfather, a grandmother who abandoned her kids, a Civil War veteran who was a POW, a War of 1812 veteran, a Revolutionary War veteran who was with George Washington that terrible winter, and that’s just one quick glance up one line on my tree.  What protects us from the accumulated epigenetic tangle?  Something must be at play here, protecting us in some way, because we can still function.

Let’s look at the other side of that coin.  Until we figure out how to cure epigenetic trauma and its effects on our DNA, could we harvest the information from this new world of clinging vine DNA for genetic genealogy?

Please do take time to read the original Discovery article.  I have excerpted parts of it here, but it’s very detailed and describes the discovery process and subsequent proofs in much greater detail.  Epigenetics is likely the next frontier in genetics, and it has already arrived.  I have to wonder if it has a place in genetic genealogy as well.



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