One Gene to Regulate Them All (or, at least many of them)

I have recently written about the complexities of the underlying genetics of autism, including issues of gene regulation. That particular article focused on RNA regulation through methylation. Now there is more evidence for the importance of RNA regulation in Nature. The CPEB-4 protein is involved in the addition of the poly-A tail to mRNAs, and there is a version that specifically regulates this in genes connected to autism.

Each mRNA–which allows the genes for proteins to be turned into those proteins–has a tail of adenosines (one of the nucleotides) added to it after it is transcribed from the DNA. This is important because when the mRNA is translated into a protein, a nucleotide is removed from the end of the RNA. The longer the tail, the more proteins can be made. If only short tails can be produced, there will not be enough proteins produced. CPEB-4 seems to be involved in regulating the length of the poly-A tail.

As already mentioned, things in the cell are complex. In learning more about this gene, I have learned that the protein, cytoplasmic polyadenylation element binding protein, is found in the dendrites and cell body of neurons, but that “treatment of neurons with ionotropic glutamate receptor agonists causes CPEB4 to accumulate in the nucleus. ” Here we again see a gene/protein related to autism connected to glutamate. Stress conditions in the brain–low oxygen or glucose, for example–cause CPEB4 to be sent from the cytoplasm to the nucleus, where they cannot do their job of regulating poly-A in the cytoplasm.

As noted, the CPEB4 gene seems to be central, but that doesn’t mean we should necessarily see mutations in it connected to autism. There could be mutations in the gene(s) for the ionotropic glutamate receptor, or in the gene(s) for glutamate production, or in some other regulator of CPEB4. So while you are bound to find popular articles out there crowing about the fact that there is a “central gene” connected to autism, don’t be mistaken: it’s still a complex situation.

RNA Methylation

People rarely understand just how complex molecular biology really is. People are out there looking for the “autism gene” or “genes,” but have only found a low percentage of people who can be connected to a specific genetic change in a particular protein-producing gene. For many people, that means that environment is likely to be the main cause. However, there are many other factors in molecular biology that will have an effect on cellular outcomes that won’t be connected to a mutation in a protein-producing gene.

There are a variety of other things active inside a cell that affect protein expression and function. DNA can be methylated such that certain genes are turned off. RNA can be methylated as well, which affects translation of mRNA into proteins. The benefits of methylating RNA over DNA is that the cell is able to respond to its environment much more quickly. As the linked article notes, this allows for proteins to be turned on at synapses very far from the neuron’s nucleus. Both forms of methylation are of course a result of a protein or protein complex, meaning there is a gene or set of genes involved in them as well. So it still ends up being genetic–the only thing is that we won’t be looking for direct proteins, but rather proteins involved in these regulatory processes.

Insofar as the numbers of certain proteins in synapses is connected to certain varieties of autism, one should definitely look at regulatory elements in the production of those proteins, the transport of those proteins, the folding of those proteins, and the insertion of those proteins into the membrane when relevant. Those will all involve completely different protein complexes and processes, meaning there are a large number of potential pathways to the same basic outcome.

I think it’s important to learn how the various forms of neurodiversity come about simply because I support any and all basic research. I do think, though, that we need to change people’s attitudes about autism in general as we make these discoveries. It may be–and it’s likely to be–the case that those with such severe autism that they are rendered severely disabled (autism 3) are genetically quite different from the rest (autism 1 and 2), and that there might be a very wide variety of things we’re placing under the “autism” umbrella.

At the same time, it’s clear that my autism 2 son inherited his autism from me, though I’m only autism 1. This suggests either an environmental factor also being in play, or combinations of genes , or both affecting degree. There may be gene combinations which result in autism, so that if for example, you have gene X and gene Y, and mutation x’ and mutation y’, then XY would be neurotypical, X’Y would be neurotypical, XY’ would be neurotypical, and X’Y’ would be autistic, for example. Or there could be certain benefits to X’Y or XY’ for those individuals, yet when they get together and make an X’Y’ autistic child. Or X’Y’ is more sensitive to environmental factors than are the other three combinations, such that in the right environment, even X’Y’ won’t result in autism.

As I said, these things are very complex. Anyone who tells you they have a simple answer to the cause of autism is selling snake oil.

Intelligence Genes and Autism

The article is a little vague, but I suppose if you’re talking about hundreds of genes, it’s hard not to be (especially in such a short article). Using new statistical methods, scientists have found 939 new genes associated with intelligence. The article notes:

Many variants of genes associated with higher intelligence turned up in people who also lived longer and did not have Alzheimer’s disease, attention-deficit hyperactivity disorder, or schizophrenia, the team reports today in Nature Genetics, suggesting that intelligence protects against these disorders. On the downside, genes associated with intelligence correlated with a higher risk for autism.

I have talked about genes and other features associated with high intelligence and autism on this blog before. While they say the connection between genes associated with intelligence and autism is “unfortunate,” I think scientists need to start wondering if this connection is more of a feature than a bug. In some forms of autism at least it may be a problem of too much of a good thing.

NOTCH2NL–The Human Gene?

There is a gene–NOTCH2NL–that is found only in humans (and Denisovans and Neanderthals, once upon a time). It’s actually part of an ancient family of genes, but this particular version is only found in humans–and, more, we have multiple copies of it.

What this gene does is slow down the development of stem cells into neurons. Why does this matter? This delay actually causes more stem cells to turn into neurons, meaning without NOTCH2NL, our brains wouldn’t have anywhere near as many neurons and thus wouldn’t be anywhere near as big.

This gene is found on chromosome 1, in the location 1q21.1. As the original article in Cell notes, additional copies of this region have been found in people with autism. In other words, it’s possible that at least some autistics have even more copies of NOTCH2NL, resulting in even more neurogenesis. More neurons could push the brain toward greater positive feedback, which seems to be a main feature of autism regardless of various potential causes.

What this implies is that the very process that made us humans–the proliferation of NOTCH2NL (after it evolved)–could be behind the emergence of autism. In other words, some autistics may be more human than human.

Autism and the Neanderthal (and Denisovan and other apes) Connection

There is a cluster of genes that is found in Homo sapiens, but which is not found in any other ape, including Neanderthals. It turns out that the deletion of this segment (essentially, reversion of the genome to pre-Homo sapiens, at least in this section) can result in autism. They point out that

researchers determined that this structure, located at a region on chromosome 16 designated 16p11.2, first appeared in our ancestral genome about 280,000 years ago, shortly before modern humans, Homo sapiens, emerged. This organization is not seen in any other primate – not chimps, gorillas, orangutans nor the genomes of our closest relatives, the Neanderthals and Denisovans.

This certainly seems to support my contention that autism is in a real sense neotenous, at least if we consider retention “earlier traits” to be a form of neoteny. And given that it seems to result in a brain that is structurally more similar to a young child’s (2-4), it may be neotenous in the more traditional sense as well (especially if the cluster of genes in question are turned on during childhood development). While there is a great deal they do not know about this gene cluster, they determined that one gene produces a protein binds with another protein that “allows the cells to capture iron more efficiently and make it available to proteins that require it.”

“This ability to help humans to acquire and use this essential element early in life might confer a significant enough benefit to outweigh the risk of having some offspring with autism,” Eichler said.

As I’ve pointed out here and here calling autism a “risk” is shortchanging all of the positive contributions autistic people (and perhaps only autistic people could have) made to the human race.

A Variety of Genetic Pathways to Intense World Autism

Recent research into the gender bias of autism (4:1 in favor of males), has shown there are sets of genes that are expressed more by males than females which express certain sets of autism genes. In this research it was found that

Many of the shared genes in these sets are related to microglia, immune cells in the brain that trim away excess neuronal connections, or synapses, in the developing brain and that may be dysfunctional in people with autism. One of the sets also contains genes related to star-shaped cells called astrocytes, which may be involved in learning and memory; these cells are thought to be both smaller and denser in autism brains than in controls.

Failure to trim away extra neurons is a recurring theme when it comes to autism.

If microglia cannot work properly, we would expect less synaptic trimming to take place. Which means a hyper-connected/hyper-active network.

Astrocytes are involved in clearing away neurotransmitters, and if they cannot work properly, we would expect buildup of certain neuotransmitters. Surely some of those neurotransmitters would be glutamate, which acts as a positive feedback neurotransmitter. Which means a hyper-active network.

Genes involved in the glutamate-glutamine-GABA cycle would contribute to imbalances in these neurotransmitters. Imbalances in favor of glutamate would result in a hyper-active network.

Genes involved in serotonin production can affect synaptic trimming, since serotonin is needed to trim synapses. Low serotonin would result in less trimming, meaning a hyper-connected/hyper-active network.

Vitamin D is involved in serotonin production, and vitamin D deficiency has been connected to autism:

vitamin D hormone activates the gene that makes the enzyme tryptophan hydroxylase 2 (TPH2), that converts the essential amino acid tryptophan, to serotonin in the brain. This suggests that adequate levels of vitamin D may be required to produce serotonin in the brain where it shapes the structure and wiring of the brain, acts as a neurotransmitter, and affects social behavior. They also found evidence that the gene that makes the enzyme tryptophan hydroxylase 1 (TPH1) is inhibited by vitamin D hormone, which subsequently halts the production of serotonin in the gut and other tissues, where when found in excess it promotes inflammation.

As noted before, vitamin D absorption is affected by glutamine/glutamate levels.

In other words, mutations affecting microglia, macroglia, glutamate-glutamine-GABA production, serotonin production, and vitamin D levels can all have pretty much the same effect in having hyper-connected/hyper-active neurons. Those are a large number of causes resulting in essentially the same effect.

Shank Genes and Various Autisms

MIT reports they have discovered the role of a gene linked to autism. The Shank gene is involved in the maturation of synapses, and mutations in one of the Shank genes (there are three in humans) accounts for 0.5% of all known cases of autism–the largest known genetic cause. In their research, they have also found that Shank proteins are involved with another protein whose gene has also been linked to autism.

There are no doubt a large number of ways the brain can wire itself, from synapses not forming correctly to more synapses than usual (which can interfere with each other and thus result in the synapses not forming correctly), more or fewer dendritic spines, etc.

I am willing to bet that we will find a variety of autisms caused by certain families of relations. The autism caused by mutations that affect the Shank-Wnt interactions are likely to be quite different from those caused by imbalances in neurotransmitters that likely cause intense world autism. In each case, a variety of mutations can lead us down the same pathways. In the Shank-Wnt interactions, we can have mutations in any of the Shank genes or in the Wnt gene and get the same outcome. In intense world autism, mutations that cause overproduction of glutamate, the underproduction of glutamine, affect the production of serotonin, or affect the binding of vitamin D so the body can use serotonin, or affect the production or absorption of vitamin D can all create the same or similar conditions. Various causes can result in the same effect.

On this blog I mostly focus on what appear to be the causes of my and my son’s autism, but of course any of the causes of any of the autisms are worth looking into and understanding. But of course I say that as an information junky–which is practically the same thing as saying, as someone with autism.

16p11.2

Autism is probably not a single thing, but is likely rather a variety of syndromes. This is possible because in complex systems like the developing brain, a variety of causes can have the same effects, and the same cause can result in different effects in its interactions with other causes.

Alterations in 16p11.2 have been identified with autism and most recently with specific neuroanatomic differences. Note, though, in their descriptions, that they identify low IQ and poor language skills. If this is typical of 16p11.2 variants, it can hardly explain those of us who are identified as being on the spectrum and yet having high IQs and even a degree of language mastery. The Intense World Theory version of autism probably does better with people such as my son and I, as well as many of the more gifted autistics. But that would imply at least two major divisions within autism that it may be a good idea to completely separate from each other.

Autistic Bees

Yes, you read that title right. Researchers looking to prove the sociobiological theories of E. O. Wilson that social behaviors have a deep genetic source have found that socially unresponsive bees have genetic similarities to autistic human beings. Most notably, there were similarities in GABA receptors, voltage-gated ion channels, and heat-shock proteinsheat-shock proteins.

Variations in voltage-gated ion channels are going to affect the speed at which neurons work. This can result in hyperactivation (intense world) or hypoactivation, or even inactivation, if altered.

Heat-shock proteins specifically react to stressful conditions, and many are chaperone proteins (which help guide protein folding and, thus protein function). They are up-regulated during stressful conditions, and given their roles in gene regulation and protein stabilization, it’s not hard to imagine the kinds of detrimental effects changes in these proteins could cause.

The fact that similar differences in similar genes in bees and humans strongly suggests that animal social behavior is deeply conserved. And that means that autistic traits can also emerge in a variety of species when parallel mutations take place.

Link Between Autism Genes and High Intelligence

It is not even remotely surprising to me that there has now been demonstrated a link between autism genes and higher intelligence. The linked study demonstrates that those who have some autism genes have higher intelligence. Autism may, thus, be an extreme expression of these genes such that it becomes disabling. In this sense, autism is similar to Tay-Sach’s disease, in which those who are heterogeneous for the gene have very high intelligence, while those homogeneous for it have the disease (and, in almost every case, a doctorate). Slight expression creates high intelligence alone, while more expression gets you autism.

This drives home the fact that autism is genetic. It also drives home that the last thing on earth we want to do is get rid of it. At the population level, there may be a strong benefit to having these genes in the gene pool. In exchange for a few severely autistic individuals, you get many highly intelligent people. Some of those people have varying degrees of social awkwardness as part of that expression, of course, but some of that comes from the fear people have for highly intelligent people and for people who think or act differently from them.

This also drives home the degree to which there is a spectrum that extends beyond the “autism spectrum.” I suspect that people with ADD/ADHD are also on the spectrum, on the other side of Asperger’s. Not coincidentally, those with ADD/ADHD tend to have high intelligence as well. The inability of schools to deal with the gifted, ADD/ADHD, Asperger’s, and autism are all part of the same problem. And the same is true of the fact that contemporary culture is equally incompetent in dealing with the existence of those who are most likely the smartest among us.