The Deeper Genome: New Research Findings in Genomics and Epigenomics

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 Some in the biological sciences and the popular press are still tethered to an outdated concept of the gene and genomics.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.

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Some excellent references on the new genomics:

• Nessa Carey (2015). Junk DNA: A Journey Through the Dark Matter of the Genome. NY; Columbia University Press.
• Why your DNA is not your destiny. Molecular biologist Nessa Carey presents an introduction to epigenetics and explains how it shapes life (39.25 minutes).
• John Parrington (2015). The Deeper Genome: Why there is more to the human genome than meets the eye. Oxford, UK: Oxford University Press.
• The Deeper Genome: Why there’s more to the human genome than meets the eye – Presentation by John Parrington (1.09.15 minutes):

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.