Pt. 1 - Epigenetics and Genetic Testing: Software vs. Hardware

Recently, I've become more and more interested in genetic testing and what it can tell us about our health as 23andMe, the Mountain View, California, based genetic testing company has received additional FDA approval for test interpretation.   I'm particularly interested in how these types of companies interpret the raw data, how reliable it is, and what are the actual factors determining the percentage chance of disease, life expectancy, etc. given in summary reports.  How can we as individuals, whether we actually consider ourselves "athletes" or participants in athletic events, use this information to personally better our health?

The Science

First of all, I think to better understand what exactly genetic testing is telling us, we should get a layman's understanding of what is going on behind the scenes.  Genetics is the study of heredity, or how the characteristics of living things are transmitted from one generation to the next.  We primarily associate this with DNA, the hardware of our genetic makeup.  On top, or perhaps around this is epigenetics, the study of heritable traits that are not dependent on the primary sequence of DNA, or put simply, the software that is running the show.  Epigenetics refers to processes that affect the way a gene works, or in scientific terms its expression. Genes work by transcription and translation, which is essentially the process of copying and then translating that gene into a usable protein. Epigenetics comes into play with substances that interact with the gene affecting when it’s turned on or off, the timing of the gene being turned on or off, and the amount of total protein end product that’s produced.  How does one affect the other, what control do we really have, what control did our parents have?

The actual explanation of what is going on between genes and their expression is quite complex and I'm sure biologists can add further insight.  One of the main methods include substances directly attaching to the DNA and switching how the DNA functions.  Another method involves substances that can trigger constriction or loosening of the DNA itself, shutting down or enabling transcription dependent on how packed the DNA is.  We're all stuck with our genetics, however, manipulation of those genes is possible.  Better yet, this explanation from the New Yorker Magazine article titled "Same But Different" published in May 2016.

"Two features of histone modifications are notable,” Allis said. “First, changing histones (basically, DNA packaging) can change the activity of a gene without affecting the sequence of the DNA.” It is, in short, formally epi-genetic, just as Waddington had imagined. “And, second, the histone modifications are passed from a parent cell to its daughter cells when cells divide. A cell can thus record ‘memory,’ and not just for itself but for all its daughter cells.  ”By 2000, Allis and his colleagues around the world had identified a gamut of proteins that could modify histones, and so modulate the activity of genes. Other systems, too, that could scratch different kinds of code on the genome were identified (some of these discoveries predating the identification of histone modifications). One involved the addition of a chemical side chain, called a methyl group, to DNA. The methyl groups hang off the DNA string like Christmas ornaments, and specific proteins add and remove the ornaments, in effect “decorating” the genome. The most heavily methylated parts of the genome tend to be dampened in their activity."

A good real life example is an ant colony.  The role a particular ant maintains is often determined not by genes but by signals from their physical and social environment.  Ants in their larval stage are separated into different types based on environmental signals.  The genomes are nearly identical, but the way the genes are expressed determine what the ant becomes, not their actual genetics.  Considering the different sizes, types, and behaviors of ants, that's a big difference with basically the same DNA.

So what’s the big deal?

It means that how the genes function can be changed based on environmental influences. Even more astounding is that these changes can be passed down to the next generation. So what you do, or what your parents did, can directly affects what happens to your kids and possibly theirs. You’re not what you eat. You’re what your parents ate, what your grandparents ate, and possibly what their parents ate.  An article from The Atlantic (Khazan 2015) titled "Why It Was Easier to Be Skinny in the 1980s" looks at relatively few reasons why this might be the case.  Besides the fact the article contains a couple of misplaced memes, it does pose an interesting question.  Is it really harder to be in good health in the present day versus the past?  The answers put forth in the article are limited to environmental chemical exposures, prescription drug use, and present day microbiome makeup of our gut bacteria.  I think a major factor can also be the epigenetic expression based on the changing lifestyles of our parents, grandparents, etc.

Expression not matching our environment

Why are there epigenetic changes anyway?  Scientists have posited that if we think of evolution or natural selection as being long term genetic adaptation to the environment, epigenetics provides for short term rapid adjustments to the environment.  The problem comes when that environment does not match the expectation or objective of the epigenetic change.  If a mother is malnourished or lacking certain nutrients, the body makes sure to tweak the gene expression so that if a newborn baby is on its way, it is prepared. For instance, you might see adaptations leading to increased fat storage, or decreased BMR as a hypothetical example. On the other hand, if a person experienced a catastrophic event that was a large stressor, then the body would make epigenetic changes to counteract this “stressful” environment. So you might get something like stress hormone suppression or fewer receptors in the next generation.  “Developmental plasticity attempts to “tune” gene expression to produce a phenotype best suited to the predicted later environment . When the resulting phenotype is matched to its environment, the organism will remain healthy. When there is a mismatch, the individual’s ability to respond to environmental challenges may be inadequate and risk of disease increases” (Godfrey, Epigenetic Mechanisms and the Mismatch Concept of the Developmental Origins of Health and Disease).  I.e. If we are born into an environment where, based on our parents experience, we would be on our feet all day but instead sit at a desk working, mismatch ensues.

So what can we do about it as an Athlete?

The above discussion can lead us into research where epigenetic changes due to diet, exercise, stress, etc. can lead to positive changes.  For example, a study by Craig Sharp (2008) titled "The Human Genome and Sport" fed a pregnant rat B12, folic acid, and choline resulting in lean mice compared to fat mice in the control study.  The ingested substances changed the gene expression of a specific gene, turning it off, and creating the leaner mice.  New research has been conducted on PGC-1alpha, a protein that regulates the genes involved in energy metabolism, which is involved in the formation of EPO (erythropoietin).  EPO increases red blood cells and mitochondria.  It is a banned substance in most sports when taken exogenously.  In babies, they’ve found that PGC-1a manipulation via epigenetic changes could play a role in the subsequent metabolic programming of the baby. While the link hasn’t been established, there’s potential that this could explain why smaller than average and larger than average babies tend to have lower mitochondria numbers than average sized babies.

How about muscle fiber types?  Research has begun to indicate epigenetic changes can influence the muscle fiber (type I, type IIa, IIx, etc.) breakdown in individuals.  With training, you can shift slightly left or right on the fiber type continuum.  In a study by Pandorf et al. (2009) they found that unloading or loading a muscle resulted in epigenetic changes that altered expression of the taking rats and suspending them so that their hind legs were unloaded (they simply used their front legs) resulting in an epigenetic change that shifted the expression of various Myosin Heavy Chain (MHC) protein forms. What this tells us is that epigenetic factors are another regulator in what MHC is expressed. They play a role in your development of Fast Twitch or Slow Twitch muscle fibers.

Training/cellular stress increases phenotypic plasticity. This refers to the degree that an organism can change its phenotype in response to the environment. In plain English, training increases the body’s ability to adapt to environment. The stress influences what’s changed and when it is changed. Epigenetic switches try and match to the stress.

A recent study by McGee et al. (2009) seems to confirm this hypothesis. They had subjects cycle for an hour before taking muscle biopsies to look for evidence of epigenetic changes. They found that epigenetic changes were in fact taking place via a mechanism that enhances the process of transcription. This opens up the door for transcription factors like the aforementioned PGC-1alpha to come in and produce a result specific to the exercise stress (i.e. mitochondria creation). This would seem to lend credence to the possibility that stress, or training, increases epigenetic factors. Whether this is transgenerational (gets transmitted to the next generation) is unknown. It’s doubtful that a single workout is, but perhaps an accumulation or a very high level of cellular stress might induce transgenerational epigenetic changes.

In conclusion, training and nutrition make changes to the epigenome, essentially impacting how your genes function.  What that all means?  I don't think we are quite sure yet, but it does make a profound case for how actions can affect familial generations to come.

Part 2 will discuss how to look at a genetic test and ascertain its usefulness, and what we can personally do for our health based on those findings.

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