Genes Change in Your Brain. Do They Change You?

A startling discovery of enormous implication has just been reported in the premier research journal, Science. Despite the accepted dogma that all of a person's cells have the same genetic coding, it turns out that this is not true, especially in neurons. The DNA in each nerve cell (we don't know about sex cells) has hundreds of mutations of the A-T, C-G nucleotides that constitute the genetic code for the neuron. Thus, no two neurons are alike. The study was conducted by 18 research teams at 15 U.S. institutions, formed as a consortium by the National Institute of Mental Health to examine neural genetic coding, using repositories of postmortem brain tissue taken from both healthy people and those with various mental diseases.

The scientists have no explanation at present for what is causing so many mutations and why each neuron has a different genetic profile. The most obvious possibility might seem to be that the mutations occurred as transcription errors during cell division. But there is a major problem with this explanation. We don't know when these mutations occurred. Except for granule cells in the hippocampus and cerebellum, neurons generally do not divide after the first few days after birth. So, if cell division is the cause of mutations, it must be due to what happens during the early post-natal period.

If the mutations occurred sporadically throughout a lifetime, a likely cause for mutation might be DNA damage caused by the free radicals that are generated in ordinary metabolism. Environmental toxins are another possible cause. The point is that the DNA changes are likely to affect how a neuron functions, and that change can last a lifetime.

We know that mutations can cause brain cancer and even certain other brain diseases. The research consortium was commissioned to see if the genetic variants predisposed to neuropsychiatric disease. Obviously, the vast majority of people have these diverse genetic codes in their neurons that do not cause disease. What do they cause? Can the mutations affect which neurons participate in which circuits? Can mutations affect how well you reason, or memorize, or your emotional responsivity? Nobody knows.

A whole new field of research has now been opened. Scientists need to examine different neuronal cell types to see if they are equally affected by mutation. Obvious comparisons needed are between granule cells and all the other neuron types that do not divide.

There is a related aspect that is not considered in this context. That is the likelihood that each neuron differs not only in its genetic code, but also in which genes are expressed. The new field of "epigenetics" has revealed that environmental influences, ranging from drugs, toxins, metabolites, and perhaps even lifestyles can affect the expression of genes, even when there is no mutation. In the case of brain, there is the distinct possibility that one's mental life can affect gene expression. This needs to be studied.

So far, what I have said about gene change and expression refers to single individuals. But what if some of these gene mutations or epigenetic effects that occur in neurons also occur in sex cells? That would mean that traits acquired during one's lifetime could be passed on to future generations. I would hope that the research consortium that has made this monumental discovery about brain cells will extend its charter to also examine sperm and ova.

Recent research on the genetics of the classic animal model of brain function, C. elegans, reveals that epigenetic inheritance of neuronal traits does occur. Gene expression was modified by exposing the animals to high temperatures, and the genetic change was conveyed via both ova and sperm to offspring that had no exposure to high temperature. The epigenetic change was still present some 5-14 generations later.

To the extent that the findings of both of these studies can be extrapolated to humans, we must now consider the possibility that personal lifestyle, environmental, and cultural influences on people may be propagated to successive generations of their children. Bad environments and lifestyle choices may extend well into the future, magnifying the deleterious consequences through multiple generations. We now have to consider that medical and behavioral problems, poverty, and degenerate cultures can arise not only when people make poor choices but that the effects can be genetically propagated to subsequent generations.

These issues may seem to present a challenge to the notion that humans have free will. We are programmed by things that happen to us. But do we not have a choice in deciding much of what we expose ourselves to? The issues are explored in my recent book, Making a Scientific Case for Conscious Agency and Free Will (Academic Press).

Sources:

McConnell, M. J. et al. (2017).Intersection of diverse neuronal genomes and neuropsychiatric diseases: The brain somatic mosaicism network. Science.  356(6336), 395. doi: 10.1126/scienceaa1641.

Klosin, Adam et al. (2017). Transgenerational transmission of environmental information in C. elegans. Science. 356 (6335), 320-323.

Brave New World of Gene Change in Brain

In recent years scientists have discovered mobile pieces of genetic material that move around inside cells. These pieces are called retrotransposons. They can copy themselves and insert near and into DNA and thus induce mutations. Australian research recently reported in the journal Nature reveals that retrotransposons can alter the genome of human brain cells. In fact, retrotransposons more effectively penetrate neuron genes than those in blood cells that were used for comparison. Thousands of retrotransposon mutations were seen in two of the five areas examined from brains of human post-mortem donors.

Though these pieces of DNA are not genes, they interact with genes that hop around to different sites within a chromosome (perhaps you heard about Barbara McClintok’s 1983 Nobel Prize winning discovery of “jumping genes”). All cells have enzymes that cut transposons out of a string of DNA, which then insert back in at other locations in the DNA. Sometimes the cut includes an adjacent gene along with the transposon, and thus when reinsertion occurs the gene hitchhikes along to the new location. The jumping around is not random; it occurs preferentially into active protein-coding regions, even sometimes in a different chromosome. The potential for changing function is enormous, yet we don’t know just what functional consequences occur. We do know that the process is most common in humans and higher primates.

We have known for some time that all cells are influenced by epigenetic effects; that is, events in the environment can alter the genome. The mechanism may well involve retrotransposons. Gene manipulation may be especially robust for altering learning and memory. It may be no accident that retrotransposon mutations were seen in human hippocampus, the brain region most directly involved in forming memories and the one part of the brain where new cells are continuously born in adults. Memory of learned events results from more or less lasting changes in the junctions (synapses) among cells in the circuits that processed the learning. These lasting changes are enabled by new protein production in those synapses. That protein is under genetic control (thus a memory can be sustained because the genes can replace any protein that degrades over time). 

Aldous Huxley, 1894-1963

The implications of this discovery for learning and memory―and brain function in general―are inestimable. More importantly, and here is where the “Brave New World” comes in, there should be the potential for manipulating gene functions in predictable and lasting ways by using synthetic transposons (which should be easy to manufacture).  Transport of synthetic retrotransposons into neurons might be accomplished by packaging them with a harmless virus; the basics of “transfection” technology are already well established. The hard part will be in discovering what transposons produce desired changes in brain function. But it seems reasonable to test various retrotransposons in the hope that some can be found that will help to cement or magnify memories and perhaps others that erase unwanted memories, as occur in post-traumatic stress syndrome. There is a potential down-side, however. Some retrotransposons may be a cause of cancer.

Source:

Baillie, J. K., et al. (2011) Somatic retrotransposition alters the genetic  landscape of the human brain. Nature. 479: 534-537.

NOTE: My new book on practical ways to improve memory will be released on August 1. You can order now at http://www.skyhorsepublishing.com/book/?GCOI=60239100060310