The Deeper Genome: New Research Findings in Genomics and Epigenomics

Brian Koehler, PhD
16
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Author’s note: UK Oxford University biologist John Parrington
was a significant influence on many of the ideas in the posting.

In our field, there is a significant “missing heritability” between rates of “schizophrenia” in monozygotic twins and the combined reduced influence of genetic variants identified in genome-wide association studies (GWAS). The 80% figure often given as a heritability factor is somewhat misleading for students in our field who do not know how the H2 statistic is derived and various ways of deriving it. Through extensive molecular biological research of the most recent studies on monozygotic twins I have derived a theory which will make a much stronger case for socioenvironmental influences on what was previously though of in classically genetic terms.

What may be happening in our new understanding of what a gene is may be analogous to what happened with the contrast between Newtonian physics and quantum mechanics (which defies common sense and yet is one of the most predictive, and practical, models we have). I thought it might be of interest to some  to learn of recent developments in our understanding of what a gene is, our discarding of classical doctrine of molecular biology (unidirectional flow of DNA to mRNA to protein), the discovery of transposons, etc.

In 1911, Ernest Rutherford proposed the initial model of the atom analogous to a miniature solar system with electrons, like planets, orbiting the nucleus (the Sun). Further research demonstrated this to be very simplistic. Some in the biological sciences and the popular press are still tethered to an outdated concept of the gene and genomics. The Human Genome Project estimated that we have only approximately 20,000 to 25,000 protein coding genes. Then we learned that about 98% of our genome is non-coding genes. ENCODE (ENCyclopedia of DNA elements) demonstrated that our genes make up only 2% of our genome. We then learned of all the different kinds of non-coding RNA (microRNAs, piRNAs, etc.) and that RNA can code for DNA.

Non-coding intronic DNA (non-protein making), the vast majority of DNA, are increasingly being understood.

The same gene (exonic regions) can produce hundreds of different proteins via splicing (rearrangements) due to non-coding RNA and other chemical cellular signals. So the same gene can produce very different proteins in different environments and therefore different disorders/diseases. The common genes found to  date usually account only for less than 5% of genetic influences in disease. Genetic epidemiologist at King’s College London and director of the largest twin registry in the world, physician Tim Spector, noted: “Most scientists agree that we simply aren’t yet smart enough to realize what we don’t know.”

Some of the important new emerging developments in our understanding of genes, is that far from simply being a linear code, the genome only makes sense as a three dimensional entity/process. The 3D entity we call a gene dynamically changes in response to signals originating both within and from outside of the cell. A second important research finding is the recognition that RNA plays a far more important role than previously thought. It is not simply a messenger between DNA and proteins (the building blocks of our bodies), RNA has multiple significant roles, on a much wider and expansive scale than imagined. DNA is by no means a fixed blueprint, the genome is a complex structure that includes proteins, and both DNA and proteins can be chemically modified in a far more rapid, and reversible way than previously assumed.

This allows the genome to be exquisitely sensitive to signals from the environment, and raises a serious challenge to the concept that life is a unidirectional flow of information from DNA to organism. RNA can code for DNA. This reversal of information requires an enzyme called reverse transcriptase (whenever you have a suffix with the letters “ase” you may very well be talking about an enzyme). The concept of the gene as a structurally stable unit is now being questioned, with emerging evidence that certain genomic elements have an ability to move about, transpose (“jumping genes” a “transposon”), at times to the detriment of cellular function, but also serving positive functions, as a novel genomic function. Transposons, mobile genomic elements, are thought to comprise approximately 45% of our human genome. The environment

Francis Crick, of the structure of DNA fame, thought we would be able to explain all of biology, by reducing complexities to their component parts, in terms of physics and chemistry (I highly doubt this will prove to be the case). Some research on the power of one gene to create a significant change bears this idea out. However, with “knockout mice,” in which a gene has been eliminated to observe its function, often, there is little effect on the organism, or an effect opposite to predictions. Gene action can only be understood as part of a wider whole.  We can now observe changes in the activity of the genome as a whole, when genes are expressed or turned off and this can be extended to the human brain.  Gene expression is on a continuum, as is gene suppression. It does not have to be an all or none process (and usually it isn’t). Some researchers involved with “gene knockout models” of “schizophrenia,” may be aware (hopefully) of the significant difficulties in modeling these states in animals, given the demonstrated significant role of social factors as well, but from a purely genetic perspective, these are crude approximations of the true genetic complexity of human disorders.

ENCODE has shown us that a significant amount of biochemical activity in the genome appeared to be specific to humans. It is our self-conscious awareness and capacity to shape  and give meanings to our experiences that are our most distinctive aspects of our species. Our human brain has approximately 86-87 billion neurons (not counting the at least equal number of complicated varieties of glial cells) and 100 trillion nerve connections (synapses). The latter is called our “connectome.” As Sebastian Seung of MIT noted: our connectome has a million times more connections than our genome has nucleotides (letters). Thus, there is much more information contained in the circuitry, e.g., experience-dependent neuroplasticity, than in our genome. As molecular cell biologist John Parrington at Oxford University noted: “ Genomes are child’s play compared with connectomes (p. 203, in his 2015 volume “The Deeper Genome:Why there is more to the human genome than meets the eye” published by Oxford University Press).

Back to transposons. They are co-opted in regulatory roles and they already come equipped with DNA sequences involved in gene expression. They may be significantly influenced by environmental factors which lead to hormonal alterations in the organism. Environmental stressors can increase transposon activity. This has been shown in plant studies and there is increasing evidence that stress can lead to transposition-led changes in the genomes of mammals. Stress can induce transposon activity in the mammalian brain. PTSD symptoms such as lack of habituation, i.e., feeling unsafe when the danger situation has been ostensibly eliminated, in rats were associated with increased transposon activity in the amygdala, a neural structure known for its significant role in fear acquisition.

Recent research has suggested that the genomes of different cells in our body (roughly 100 trillion) may be far more different than previously thought. Such diversity may be caused by errors in the DNA copying process that occurs every time a cell divides or by mutations from such things as radiation or toxic chemicals in our environments. Some of the cellular genomic diversity seems to be caused by transposon activity.  Recent studies in the human brain reveal much more active transposition than previously thought. Just as our immune systems create genetically different antibody-producing cells to fight off non-self antigens, genomic diversity in our neuronal cells  may allow us to respond to the many stressors and challenges life presents to us.

Cortisol, a primary stress hormone in us, combines with its receptors inside the cell’s cytoplasm. Cortisol and its receptors become transcription factors that enter the neuronal nucleus and activates target genes. Stress, we now know, can have long-lasting epigenetic changes in our genomes. Mammalian pups exposed to low levels of nurturance have higher levels of DNA methylation of the regulatory region of genes coding for the cortisol receptor, e.g., in the hippocampus (parenthetically, it is estimated that at least 800 genes are maternally regulated in this important structure involved in learning, memory and stress monitoring/regulation). These pups are much more stress reactive, reluctant to deal with novelty (e.g., a possible neural basis/correlate of racism, homophobia, etc. downstream to insecure attachments?). Human suicide victims with a history of childhood abuse were shown to have higher levels of DNA methylation of cortisol receptor genes. DNA methylation has an inverse correlation with gene expression. These highly methylated genes are suppressed (on a continuum) and this results in impaired negative homeostatic control of the neuroendocrine stress pathways from the amygdala to the hypothalamus, pituitary and adrenal cortex (LHPAAxis).

Recently, the effects of stress on the human genome has been shown to be more dramatic than previously imagined. The ends of chromosomes are protected by DNA sequences called telomeres that shorten every time a cell divides, and is thus a marker of cellular aging. Recent studies have shown both adults and children to have increased telomere shortening when exposed to environmental, psychological stress. In one study with stressed children, they had a staggering 40% shrinkage of their telomeres compared to controls. This was found in boys, and they also demonstrated differences in the genes coding for serotonin (5-HT) and dopamine (DA). These neurotransmitters are implicated in such syndromes as depression, bipolar disorder, anxiety disorders and “schizophrenia.”

Epigenetic research has demonstrated that pregnant mice exposed to different diets and environmental  toxins can pass on these epigenetic changes to first, second and third generations. Recently, we discovered that some non-coding RNAs can be transmitted to the next generation via the sperm. Male mice subjected to stress as infants, produced offspring in the first and second generation with a phenotype resembling depression. These offspring had abnormally high expression of five micrRNAs (miRNAs) in their blood and in their hippocampus. The researchers put in controls to rule out social transmission of stress by isolating sperm from the stressed mice and injecting it directly into fertilized eggs from unstressed parents. For me, this (sperm microRNAs) is only one piece of the complexity that underlies what attachment-oriented psychoanalysts have called transgenerational transmission of traumas. We now know epigenetics is intimately involved in this across multiple generations. Nature seems to make an environmental forecast for offspring that the first, second and third generations will confront similar environmental threats as the parent. Inducible defences against threats to survival (including threats to the survival of the self in humans?) are particularly likely to be transgenerationally transmitted according to some research.

I would like to just briefly and simply review several previous genetic assumptions which scientists no longer hold (although the general public and pop science media still seem to be incorrectly holding onto). These are as follows:

  1. Genes are the blueprint and code of life, e.g., Dawkins assumption of self-replicating “selfish genes.” No doubt genes are very important, but the key cellular processes that turn genes on and off are important-from the longer term epigenetics of DNA methylation to the shorter term fine-tuning of microRNAs (e.g., non protein-coding RNA affecting and influencing gene expression). The rules that govern these interactive networks (e.g., cells, genome, epigenome, proteome, etc.) are far from rigid and predetermined. In psychiatry, we are usually dealing with probabilities not deterministic relationships. As Leon Eisenberg noted: genes set the boundaries for the possible, environments parse out the actual. The epigenome is one dynamic bridge between the  fixed genome and the dynamic social/physical environment.
  2. The assumption that genes and heritability can’t be changed is incorrect. This is the exception rather than the rule. Predictable deterministic relationships occur in monogenic illnesses (single gene mutation) like Huntington’s disease (HD), but even in this disorder, epigenetics play a role. For example, clinical trials are ongoing to investigate the modification of the Huntington gene using a histone-modifying drug (SAHA), which is used in cancer treatment. In the Agouti mouse, adding methyl supplementation to the pregnant dam’s diet results in offspring which are thinner and have a different fur color (all in one generation).
  3. Environmental events can result in lifelong memories within cells which can be transmitted across generations through epigenetic channels. These epigenetic messages can exist in replicated daughter cells long after the events have passed. The environmental exposures of your parents and grandparents, e.g., diet (the “soft inheritance of Lamarck?) can have a significant influence on offspring across three generations. Psychoanalysts referred to this as transgenerational transmission of trauma without knowing the cellular and epigenetic processes involved, e.g., DNA methylation and histone modifications.

* * * * *

Some excellent references on the new genomics:

Glossary:

Epigenetic: The study of heritable changes not caused by changes in the DNA sequence, but changes in gene expression that can potentially be heritable and reversible.

miRNA: MicroRNA, a small non-coding RNA molecule found in plants and mammals, and in some viruses, which functions in RNA silencing and regulation of gene expression.

mRNA: Messenger RNA specifies the amino acid sequence of a protein. It is translated into a protein in a process catalyzed by ribosomes, residing outside the cell nucleus.

Transposition: The movement of a mobile DNA element into or out of a chromosome.

16 COMMENTS

  1. It’s nice when people listen to your suggestions 🙂

    Thanks for sharing this here Brian.

    This is a great article which helps us look beyond the simplistic notions of “schizophrenia is an illness primarily caused by genetic factors”… things aren’t nearly that simple. Not only is schizophrenia as a unitary illness invalid and nonexistent, but vulnerability toward psychosis can be transmitted by environmental factors over generations, as this article discusses. And the way in which genes dynamically express themselves in concert with environmental input can be modified and repaired by environmental experience after birth (I think this is what Brian is saying, some of which is a bit beyond me).

    To me this type of non-static dynamic thinking supports my contention that “schizophrenia” – or repeated chronic psychotic experience – can be modified and potentially reversed/healed fully.

    The importance of Brian’s type of approach is that it allows a lot more hope and optimism for people with “mental disorders”, because it implies there is so much relationally that can be done to change how people experience their world, i.e. that genes are not destiny. We desperately need this type of thinking to replace the type of interaction where young people are told, “You have a chronic incurable brain disease, schizophrenia, and need to be on these drugs for life.” What a bunch of bullshit that is!

    This article ties in with recent articles by William Schultz and Jay Joseph which taken together represent anti-deterministic thinking showing that human experience is modifiable in a quantum mechanics/relativistic kind of way, rather than being set in stone in a deterministic Newtonian way.

  2. I read a book by Bruce Lipton sometime back (title: ‘Biology of belief’), and he says “the notion that genes control biology has been so frequently repeated for such a long period of time that scientists have forgotten it is a hypothesis, not a truth.” He also says that “Unfortunately, scientists most often deny rather than embrace exceptions” just like ‘germ theory’ that was rejected when it was first proposed.
    I hope they teach epigenetics in schools, otherwise the future generations would also be just as ‘deluded,’ clinging to/defending their views.

  3. Much of this is beyond my personal scope of knowledge or research, however, I’d like to point out that it is highly likely most so called “schizophrenia” today is a result of doctors misdiagnosing symptoms of child abuse or adverse childhood experiences as psychosis, likely because they would prefer to profit off of child abuse, rather than deal with all the legal ramifications of actually helping a child abuse victim.

    http://psychcentral.com/news/2006/06/13/child-abuse-can-cause-schizophrenia/18.html

    And, of course, when one gives a non-psychotic child abuse victim an antipsychotic, Read’s other research does show you get extremely bad outcomes. Which would be logically expected, since the child abuse victim is in reality dealing with a crime cover up, not a “mental illness.”

    And the “gold standard” treatment for psychosis, the neuroleptic drugs, are known to create both the negative and positive symptoms of “schizophrenia” all by themselves. Improperly given antipsychotics (like those given to child abuse victims) can result in Neuroleptic Induced Deficit Disorder, which is likely almost alway misdiagnosed by greed inspired psychiatrists who harbor delusions their neuroleptic drugs are “wonder drugs.”

    “Neuroleptic induced deficit syndrome is principally characterized by the same symptoms that constitute the negative symptoms of schizophrenia—emotional blunting, apathy, hypobulia, difficulty in thinking, difficulty or total inability in concentrating, attention deficits, and desocialization. This can easily lead to misdiagnosis and mistreatment. Instead of decreasing the antipsychotic, the doctor may increase their dose to try to ‘improve’ what he perceives to be negative symptoms of schizophrenia, rather than antipsychotic side effects.”

    And inappropriately increasing the neuroleptics, or adding other psychiatric drug classes, especially those recommended to cure “bipolar” disorder today, can result in anticholinergic intoxication syndrome, aka anticholinergic toxidrome. The central symptoms of which are indistinguishable from the positive symptoms of “schizophrenia.”

    “Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.”

    “Substances that may cause this toxidrome include the four ‘anti’s of antihistamines, antipsychotics, antidepressants, and antiparkinsonian drugs[3] as well as atropine, benztropine, datura, and scopolamine.”

    It is highly likely 2/3’s of all “schizophrenia” today may in fact be the result of psychiatrists covering up child abuse by turning child abuse victims into “schizophrenics” with the neuroleptic drugs. And most, if not all, “bipolar” may actually be poly-pharmacy induced anticholinergic intoxication syndrome as well.

    It was confessed to me by an ethical pastor that the “dirty little secret of the two original educated professions” (the medical and religious industries) is that the function of the psychiatric industry is discrediting and torturing child abuse victims for the religions and covering up easily recognized iatrogenesis for the incompetent doctors who are paranoid of potential malpractice suits.

    And this “dirty little secret” does appear to be the likely cause of 2/3’s of all “schizophrenia” today. Sometimes the truth is not all that complicated.

    And I’m certain if this reality is confessed to, it would go a very long way in de-stigmatizing the so called “schizophrenia” diagnosis. Most “schizophrenics” today are child abuse victims, not dangerous criminals, as the psychiatric industry and our politicians propagate. Shame about our former speaker of the House’s current child abuse scandal. Not to mention the Catholic religions child abuse cover up scandals. And the unconfessed child abuse scandals of the Protestant religions as well:

    https://books.google.com/books?id=xI01AlxH1uAC&printsec=frontcover#v=onepage&q&f=false

    I hope to see an end to the psychiatric industry’s long standing role in society as child abuse profiteers.

    • Regarding “Someone Else”:” most so called “schizophrenia” today is a result of doctors misdiagnosing symptoms… ”
      I agree totally with you. “Schizophrenia” was invented before antibiotics were discovered, invented before science found many physical explanations for irrational behavior. The subject being trough emotional trauma explains the non-physical causes of weird behavior.

    • I agree with both of you, it is past time to get rid of all the scientifically invalid and unreliable DSM disorders, including “schizophrenia.” And I believe it’s highly likely trauma can cause “psychosis,” but also know from reading my medical records that I had doctors who claimed a dream query was “psychosis,” which is ridiculous. If dreams are “psychosis,” then everyone is a psychotic.

      But I also know the antipsychotics given to a previously healthy, non-psychotic person do, indeed, cause psychosis, too. In my case, it was due to combining the “bipolar” drugs, which are known to cause psychosis, via anticholinergic toxidrome (which is not bipolar). The drug induced psychosis resulted in my having the incessant voices of my children’s abusers bragging about raping my child, denying my other child a baptism on the morning of 9.11.2001, and getting away with murdering their own first born, in my head, which was really gross. And once weaned off the “bipolar” drugs, one also suffers from a drug withdrawal induced super sensitivity manic psychosis.

      I was luckier with this so called psychosis, my drug withdrawal induced “manic psychosis” / awakening just took the form of a lyrical libretto love story / spiritual journey where I supposedly obtained eternal life via some sort of seemingly Hermeticism inspired seventh heaven ceremony, because I had supposedly helped to get everyone else within the collective unconscious for God, with love. Not all so called “psychoses” are even bad – mine was a spiritual story, and awakening to my dreams. And I’m fine believing there may be a collective unconscious, many others believe this may be true also, and my spiritual journey was basically a born again in the Spirit tale, leaving me as the one of the blessed within “the bride,” which is exactly what a Christian is actually supposed to strive to be.

      But psychiatrists are apparently drug obsessed lunatics who want to massively drug (“snow”) Christians for belief in God and the Spirit, according to my medical records. I’m quite certain they need to be reminded that we have laws in the US which allow Americans to have freedom of religion, and thus it is not the legal right of psychiatrists to tranquilize and try to murder all those who believe in God, rather than buying into their DSM “bible” of stigmatizations and it’s psychopathic, disempowering, drugs forever, “life long, incurable, genetic mental illness” theology. What a bunch of disrespectful, delusions of grandeur filled loons my psychiatrists were! I’ve never met crazier and more deluded people than psychiatrists.

      • Regarding “antipsychotics given to a previously healthy, non-psychotic person do, indeed, cause psychosis” by Someone Else. Yes, I agree.

        I would also like to add , my experience of confinement , I call jail, others would call hospitalization probably made me crazy as well. To survive the jail , I had to become a dog for my masters.
        Everyone else there in the jail/hospital is conditioned or brainwashed like Pavlov’s dog experiment.
        I find my left hand doing things my right hand doesn’t know about, unconscious movement. I don’t think I had this before my jail time, but there is no way to prove where it came from.
        First they said I was crazy, then they made me crazy.

        • “First they said I was crazy, then they made me crazy.” That is what psychiatry is all about, apparently. It’s a gas lighting industry, and the psychiatrists are the kings and queens of “the staging of bizarre events by the abuser with the intention of disorienting the victim.”

          And my forced hospitalization was truly a criminal endeavor, too. One of my doctors was even eventually arrested by the FBI, due to his similar medically unnecessary “snowings” of lots of patients, for profit.

          Sorry about what happened to you, markps2. But you can prove where the uncontrolled movements are from, they’re a known adverse effect of both the neuroleptic drugs alone, and the proven drug interaction poisoning method which results in the central symptoms of poly pharmacy induced anticholinergic intoxication syndrome. It’s called tardive dyskinesia.

          I have the same problem with my left foot in the mornings. But I impressed the student who was practicing on me at my last physical by medically explaining the cause of my shaky morning foot. Now you can impress your doctor with your knowledge of medical terminology and your knowledge of the common adverse effects of the neuroleptics, too.

  4. Hi,

    This study concerns a ” discovery” in genetic research into Schizophrenia by Professor Sanbing Shen at NUIG (Ireland).

    http://www.irishtimes.com/news/science/risk-factor-linked-to-schizophrenia-identified-by-nui-galway-scientist-1.1674148

    “Schizophrenia” meant very little to me once I sorted out a responsible drug taper, and practical psychotherapy.

    I can only think that Professor Shen is barking up the wrong tree and obstructing genuine recovery.

      • Hi bpd,

        Thanks for commenting – I did try both models and the non medical solution was what worked for me. I can only think the genetic /bio model is a complete fraud.

        The problem with “schizophrenia” diagnosis (as I think you’ve implied) is that it can be used as an excuse for hijacking people.

        Anyway, non drug recovery doesn’t have to be traumatic – the drugs can be reduced very gradually and safely.

        Long term Recovery saves lots of money as well.

  5. I very much appreciate this article, although I do not fully understand it.

    Does the epigenetic model imply that schizophrenia and other mental disorders are indeed genetically related, not in the classical sense, but instead epigenetically? If this is correct, than drugs can be developed to function epigenetically, and essentially, the medical model is correct.

    • Don, I’ll take a crack at this. No, I don’t think the epigenetic model implies that the medical model is correct; in fact, it is another weapon against it. The epigenetic model doesn’t support the existence of separable discrete mental disorders, if I understand it right. The nature of the back-and-forth interplay between genes and environment is so complex and so individual that it supports the ideas of continuums or spectrums of problems without clear cutoffs, rather than discrete mental illnesses. Also, as Brian writes about, the level of complexity is truly stunning, with billions of changes to genes occurring daily. The likelihood of an little pill being developed that can essentially function as if it were a curative environment (because that is what genes are changed by in the epigenetic sense) seems to me to be very low. That would be true magic, and it ain’t gonna happen. It would be like inventing sudden alien technology that can create wormholes; it’s science fiction.

      I think the diagnostic medical model implies clearly separable discrete categories, and the theory of environment modifying genes and genes being like a script that interfaces differently with different environmental scenarios… again the epigenetic theory just doesn’t work in terms of separable mental illnesses. This is where the DSM fails as a Newtonian reductionist simplistic document in a reality that is relativistic, complex, dynamic, and full of uncertainty and shifts in viewpoint.

      I hope some of this made sense. It is hard to understand this new paradigm of neuroplasticity and epigenetics.

  6. I do not fully understand or appreciate this article and its implications for psychiatry with respect to the medical model and treatment with medications. Could epigenetic types of medicine be invented that fulfill the dreams of a quick and easy treatment for mental disorders?

    I have no scientific evidence for my theory of mental disorder transmission, which I call a cultural model.

    I attribute a part of the cause of my schizophrenia to my upbringing. My dad’s religion was work. He was a workaholic and had no time for me. His emotional unavialability was undoubtedly the result of receiving the same from his father. This type of behavior could have gone back many generations and its transmission, I believe, has nothing to do with genetics or epigenetics.

    I think that reductionist models of behavior and mental disorders are incorrect and distract from gaining treatment that is corrective. Its a disease of our times to want a quick and simple answer to all problems.

    Please let me know where I might be wrong in my thinking.

    • Very unlikely that epigenetic medicines would be invented, because they would have to act on genes as if they (the pills) were an environment, or rather a virtual reality version of the environment causing changes to the genes that a whole external world would over time (does that make sense?). I think this is about as likely as traveling into the past, teleporting to another galaxy, or Jeffrey Lieberman admitting that Robert Whitaker is right about everything.