Which PMS genes are most associated with Autism?

Figure 3
Genes disrupted in autism and schizophrenia.  Modified from Gandel et al. 2018 Science.  doi:10.1126/science.aad6469.

The previous blog looked at the relationship between SHANK3 and autism risk (Does SHANK3 cause autism?). Today’s blog looks at another new study.  This study is an analysis of which genes are dysregulated (“out of whack”) in major psychiatric disorders, including autism and schizophrenia (Gandel et al. 2018 Science. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap).  In the previous blog we learned that people generally have slightly different versions (variants) of each gene.  An unlucky person may have hundreds to thousands of gene variants that, added up, conspire to create a high risk of autism.  Thus, there are a lot of different combinations of genes that can lead to autism.

What the new study shows is, regardless how a person gets autism or schizophrenia, the same networks of genes become dysregulated.  Let’s first discuss what gene regulation means.  DNA is like a well-stocked bakery.  A good cook can prepare many different kinds of breads or desserts by choosing how much of each ingredient to use, and when.  Just about every cell in the body has the same DNA.  What makes one part of the body different from another is how much, and when, each gene is used. DNA cooking is called gene regulation.  In autism and schizophrenia, the proportions of ingredients have gone awry.

The green diagram at the top of this blog maps the results of the new study.  The researchers found certain critical “modules” (functional groups) of genes that are dysregulated in the brains of individuals with these two disorders.  Once, again, these genes are dysregulated regardless of how one acquires autism or schizophrenia.   The map identifies the 20 most dysregulated genes in each module (140 total) and how they interact in the brain.

What does this diagram tell us?  It says some things we already knew.  Autism (and schizophrenia) cause problems in neurons, the brain cells responsible for sensation, thinking and action.  Less obvious, autism seems to be related to two other cell types, astrocytes and microglia.  Astrocytes nourish neurons.  Microglia, which also come in contact with neurons, are known to regulate the formation and removal of synapses.  There are other important cell types, as well.

What is the news for PMS?  We learn that two PMS genes are core genes of the dysregulated neuron networks. I have circled these genes in RED.  There are about 20,000 genes in the human genome.  The paper identifies the top 140 dysregulated genes. Obviously, they are quite important for psychiatric disorders.  The two PMS genes are MAPK8IP2 and SULT4A1.  Not surprisingly, MAPK8IP2 and SULT4A1 have already been identified as two of the 18 most important genes of PMS (see Which PMS genes are most important?).

Which individuals with PMS are missing these genes?  Nearly all (over 95%) of people with PMS are missing MAPK8IP2.  About 30% of people with PMS are missing both MAPK8IP2 and SULT4A1.  If your child has a typical (terminal) deletion, you can look up which important PMS genes are missing in this blog:  Which PMS genes are most important?

At this point, it seems pretty likely that deletions of 22q13.3 do more than raise the risk of autism.  Deletions can directly impact MAPK8IP2 and SULT4A1, two core genes dysregulated in autism, schizophrenia and other neuropsychiatric disorders.  Perhaps the good news is that people who study autism and schizophrenia have a new impetus to study MAPK8IP2 and SULT4A1.  It is up to PMS parents to lobby, cajole and otherwise let everyone know that studying these genes is very important to us.

 

arm22q13

Previous blogs

Does SHANK3 cause Autism?
We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse modelsScience Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

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We need to study interstitial deletions to cure PMS

David Jan 2018
David has a terminal deletion, but he will benefit from studies of interstitial deletions.

Two very recent studies of Phelan McDermid syndrome (PMS) drew exactly the same conclusion: We need to recruit and study more PMS patients with interstitial deletions if we are going to understand the syndrome (see references 1 and 2, below).  This blog explains why that is a critical need.  In some ways, this blog is an update to an earlier blog (Why don’t we have better drugs for 22q13 deletion syndrome?).

PMS can be broken down into a few obvious classes.  The original disorder, 22q13.3 deletion syndrome, has terminal deletions and interstitial deletions.  Later, SHANK3 variants (often called “mutations”) were added.  As I have discussed before (Gene deletion versus mutation: sometimes missing a gene is better), mutations are a mixed bag. Some mutations produce symptoms like 22q13.3 deletion syndrome, but other mutations produce other disorders (like ASD or Aspergers), or no disorder at all.

The overwhelming majority of 22q13.3 deletion syndrome / PMS cases are terminal deletions.  The smallest terminal deletions include the genes SHANK3, ARSA and RABL2B.  Of these, SHANK3 was identified as the most important gene for small deletions.  SHANK3 is not the only important gene (see Which PMS genes are most important?).  Early on, researchers were aware that interstitial deletions have the features of PMS (Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development).  Like other deletion syndromes (e.g., 16p11.2 deletion syndrome ), no one gene deletion explains all the cases of PMS.

PMS research started out with SHANK3, but somehow it got stuck there.  Being stuck has led to some serious deficiencies in our understanding of PMS.  First, very little is being done for the future of children with interstitial deletions.  Their SHANK3 gene is intact, so SHANK3 research does them no good.  Second, drug studies that use PMS patients to study SHANK3 are likely to fail without accounting for the important genes in each PMS patient.  This was discussed in the recent paper on PMS genes (reference 2). PMS patients have such a mix of deleted genes that the benefits of a drug for SHANK3 loss might not be detectable.  Third, certain serious problems seen in PMS are unlikely a result of SHANK3.  These issues, like poor thermoregulation (body temperature control), lymphedema, cerebellar malformation, mitochondrial problems, and certain developmental problems, impact a large proportion of children with PMS.  Every year children and adults with PMS die. We need to know which genes are associated with lethality. These issues will remain serious problems for people with PMS as long as SHANK3 remains the narrow focus of PMS research.  Even our understanding of SHANK3, itself, is incomplete without a much better understanding of the other important genes of PMS.  

The best way to understand the many genes of PMS is to study people with interstitial deletions.  They are the only PMS patients where we can safely say that SHANK3 deletion does not play a role. My last two blogs show that we actually know a lot about PMS genes that are most likely to cause problems.  However, we need to know much more about how each of these genes affect people.  That requires people with different size interstitial deletions.

There was one research study of people with interstitial deletions published in 2014 (Disciglio et al.).  It covered 12 patients.  Since that paper, there has been only one additional (single) case study  of an interstitial deletion.  By comparison, PubMed shows 164 papers with SHANK3 in the title.  Most PMS families are probably not aware that the current major studies of PMS specifically exclude interstitial patientsNatural History of Phelan McDermid Syndrome and the Electrophysiological Biomarkers of Phelan-McDermid Syndrome.  Some of the sites in these multisite studies have not excluded participants with interstitial deletions, recognizing the scientific importance of these cases.  Scientifically, excluding interstitial deletion patients makes no sense.  We should be seeking them out, recruiting them.  As a parent, excluding interstitial deletions seems unfair to both those families, and to the rest of us.  We need to get unstuck. We need the best science possible to help our children.

 

arm22q13

References

  1. A framework to identify contributing genes in patients with Phelan-McDermid syndrome. NPJ Genom Med 2017
  2. Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Gen 2018

 

Previous blogs

What do we know about PMS genes?
Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse modelsScience Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

 

Which PMS genes are most important?

David sitting up Dec 2017 - small
David hanging out on a Saturday morning

What makes a gene important?

Ask anyone who has read about 22q13.3 deletion syndrome (Phelan McDermid Syndrome) which genes are most important and they will start with SHANK3, even though some people who have 22q13.3 deletion syndrome are not missing SHANK3. SHANK3 is most important for two reasons. First, mutations or deletions of SHANK3 can (although not always) have a strong negative impact on individuals. Second, a large percentage of the PMS population are missing SHANK3. Thus, SHANK3 meets the criteria of 1) potentially large impact on an individual and 2) a large percentage of the population is missing SHANK3. This blog is a closer look at all the genes that meet these criteria.

In a recent study, a group of researchers looked at genes that are highly likely to contribute to PMS and are missing in most people with PMS (Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome [full disclosure: this blog was written by an author on the paper]). That is, genes that appear to meet the same two criteria as SHANK3 for importance. What makes this study important is that it does not differentiate between genes that have been carefully studied and genes that have never been studied. We parents are not interested in gene popularity contests, we are interested in learning what is making our children sick.

I read that SHANK3 was the only important gene

Up until now, nearly all PMS research has been focused on one well-known gene, SHANK3. But, for the overwhelming majority of PMS sufferers, some 97% (see Understanding deletion size and How do I know which genes are missing), PMS is a polygenetic disorder. That is, many genes are involved. Is it possible, as a few SHANK3 scientists have suggested, that only the SHANK3 matters? Considering that people can have all the problems of PMS even with intact SHANK3 (called “interstitial deletions”), it does not seem possible that SHANK3 is the only gene that matters. (For the minority of parents whose child only has a SHANK3 variant or loss, SHANK3 is the only important PMS gene, but that strikes me as a rather selfish viewpoint.)

How can we find out which genes are most important?

There are 108 PMS genes and only 44 have been well studied. If there was no way to identify the important genes, we would be in serious trouble. Fortunately, the recent study of PMS genes was possible because of a recently compiled database of over 60,000 genomes of normal individuals (Exome Aggregation Consortium). Normal in this case means no developmental or neurological disorder. Why normal individuals? Because, this huge database lets you predict which genes can cause trouble.

Here is the trick to finding a likely gene troublemaker. Pick a gene. Look at 120,000 copies of that gene. (Each human has 2 copies, so 60,000 people = 120,000 copies of the gene.) Like anything else, some will be a little different than the others. In fact, you can estimate how many variants you would expect to occur by chance in a population of 60,000 normal people. So, for a given size gene, maybe you would expect 40 different variants of that gene in the population. What if you find only 5 variants? Something’s fishy if you find only 5. The best explanation is — here is the trick — that the other 35 possible variants of that gene cause serious problems. For one reason or another, those 35 variants removed the owners of that gene from the population of “normal individuals”. Those missing 35 variants are pathological. They cause a loss-of-function. The gene is called loss-of-function (LoF) intolerant, and those genes that are very LoF intolerant are the ones most likely to cause major health problems.

Wow! Which genes are most important?

So, which PMS genes are very LoF intolerant? That is an easy question to answer. You can go to the EaAC web site and look up any gene. Look for the row with LoF and get the “pLI” value. A value between 0.9 and 1.0 is a bad news gene. SHANK3 is 1.0 — no surprise there, but what about other genes? Let me save you some time. Below is a list of PMS genes that have a pLI value above 0.9.

Genes in this list are in the order of their position on the chromosome. The ones at the top of the list are more frequently lost in the population. If your child has a terminal deletion, look at all the genes with a Kb value smaller than your child’s deletion size. Those are the genes that most likely contribute to his/her disorder.

   Gene       Minimum deletion size (Kb) 
   SHANK3          85 
   MAPK8IP2       207 
   PLXNB2         540 
   TRABD          619 
   PIM3           854 
   ZBED4          928 
   BRD1           995 
   TBC1D22A     3,643 
   GRAMD4       4,181 
   CELSR1       4,281 
   SMC1B        5,405 
   PHF21B       5,809 
   PRR5         6,081 
   SULT4A1      6,956 
   SCUBE1       7,475 
   TCF20        8,603 
   SREBF2       8,911 
   XRCC6        9,154 

The first thing to notice is that what started out as 108 genes is now reduced to 18 genes. There are a few other genes with pLI below 0.9, but not far below 0.9. These may also be important. Regardless, the number of PMS genes has gone from intractable to something much more manageable. If your child has an average size deletion (around 4,500 kb), then there are 10 relevant genes. Note that some, although relatively few, children are missing only SHANK3.

In my next blog I will discuss what these genes do and how they might impact your child.

arm22q13

Previous blogs

Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse modelsScience Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Splitting, Lumping and Clustering

David circa 2009
David happily watching his videos in the summer of 2009

If we want to find treatments for Phelan McDermid syndrome (PMS), first we need to figure out what is PMS.  That was spelled out in my blog: Why don’t we have better drugs for 22q13 deletion syndrome? My next blog addressed how to organize all the different genetic deletions and mutations so that we can define PMS (Defining Phelan McDermid syndrome).  Today’s blog addresses ways we can define different types of PMS.  If we don’t define different types, we are wasting our time experimenting with treatments.  For instance, some PMS kids talk fluently, some talk in short sentences, some can only say single words and many, like David, do not talk at all.  These and many other difference warrant different groups of kids when we test treatments.

Just as there is huge variation in abilities and behavioral characteristics, our kids have very diverse genetics.  Recent studies of rodents  show that not all with Shank3 mutations are alike.  In fact, drugs may work very differently on different Shank3 mutations. Anyone who has kept up with my blogs knows that deletions of different genes are likely to have very different effects on our children.  These difference are very important.

Useful drug testing is stuck right now until we develop a way to categorize people with PMS based on both phenotypic characteristics (symptoms and manifestations) and genotypes (deletions versus mutations and which genes are affected).

I have heard scientists who study Shank3 mice talk about “splitting” and “lumping”.  Splitting is breaking groups into subgroups.  Lumping is putting everyone/everything together into a single group.  Lumping has not worked and the growing consensus is that lumping will never work in our population. Splitting based on just one characteristic (e.g., deletion size) probably won’t work, either.  We need a more refined approach.  What we need is “clustering”.  Clustering is what mathematicians and scientists do when categorizing requires using many different characteristics at once.

Here is an example.  Let’s say you want to buy a car.  You might look at various cars and think about both price and gas milage.  You could make a graph something like this:

Car Clustering2Similar types of cars have similar prices versus gas milage tradeoffs.  Race cars are more expensive, but get poor gas milage. Clustering is when you identify meaningful subgroups on a graph because the individual points are close together.  Each group is a cluster.  Even if not every car fits neatly into a cluster, you still have an organizational scheme that can be very helpful.

PMS needs meaningful groups.  Clustering can get complicated when there are more and more features that divide up the population.  However, computer programs can take care of the complexities.  What we need first is to identify which characteristics are important for grouping.  As a practical matter, researchers go back and forth. They consider characteristics, run a program that automatically clusters the data based on those characteristics, and then look to see if the clusters make sense.  That is what we need to do.

When we took David to the PMS Foundation Family Conferences in 2008 and 2010, we met a handful of kids that were remarkably like David (see photo of David, above).  What was it about those kids?  As I recall, they walked the same way, loved watching music videos, asked for help the same way, were nonverbal and all have relatively larger deletions.  Are those meaningful characteristics?  Will they help us divide PMS into different groups for meaningful drug studies? We need to find out.

arm22q13

 

Previous blogs

Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

What do parents want to know?

david-dressed-up
David dressed up in his birthday best

One nice thing about writing a blog is getting feedback.  While I embrace and benefit from all kinds of feedback, I admit being partial to positive feedback.  I get some nice comments from friend on my Facebook page.  I love the encouraging comments that get posted here.  There is another kind of feedback that is neither positive nor negative, but very informative.  It is the kind of feedback that we should all pay attention to.  Visitors vote with their mouse (or touchscreen).  Every time someone clicks on a blog link, WordPress adds one to a blog page counter.   Now that it is 2017, let’s see what the numbers recorded in 2016 tell us.

stats-2016
Frequency of access for all English Language pages of this blog in 2016

The most requested page is at the bottom of the graph: How do I know which genes are missing?  That is the number one question on parents’ minds.  It makes sense.  If your car breaks down, you want to know what caused it, even if you don’t know much about cars.  At the very least, you have some idea of what needs fixing.

Three more questions are virtually tied for 2nd place. Have you ever met a child like mine? and How to fix SHANK3 are discussions of SHANK3 and its relationship to the other genes of 22q13 deletion syndrome.  Together, with the most requested blog page, over one-third (35%) of mouse clicks on this blog are from people who want to understand how all the genes of 22q13 deletion syndrome operate together to produce the disorder.  The other blog page that is tied for 2nd place addresses the same topic from the opposite direction: How can the same deletion have such different consequences?

Taken together, nearly half (46%) of the information people want from this blog is to understand what genes are missing and why those genes matter.

Most visitors in 2016 already knew about 22q13 deletion syndrome.  Only about 4% of all clicks went to 22q13 deletion syndrome – an introduction. Fewer clicks went to learning about the author. (I can live with that!)  But, I think there are a other links that deserve attention.  Here is a suggestion for the new year:

Gene deletion versus mutation: sometimes missing a gene is better.
SHANK3 is not the only gene of 22q13 that can have serious consequences when mutated (modified, but not lost altogether).  Much is said about SHANK3 mutations, but 98% of people with 22q13 deletion syndrome are missing SHANK3 altogether. Understanding the difference may be crucial to finding cures.

I have dedicated the past few months to formal writing about 22q13 genes aimed at the scientific community.  That work has taken me away from this blog, but, hopefully, taken us all closer to effective treatments for our children.   That work is done for the moment and I hope to get back to this blog on a more regular basis.

arm22q13

 

Previous blogs

Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
Science Leadership
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction

Understanding translocations in 22q13 deletion syndrome: genetics and evolution

Mitz family circa 1922

My dad

That’s my dad.  No, not the dapper gentleman standing in the back.  He is the diapered baby sitting in front.  One interesting thing about this circa 1924 photograph, I can tell  you unequivocally, is that both males in the photograph are carriers of 22q13 deletion syndrome.  I can say this even though neither man was ever genetically tested and neither ever had children with a known diagnosis of 22q13 deletion syndrome.  How can I be so sure? I spent several years contacting relative and having them tested.  It was an interesting and often challenging undertaking.  My motivation was to warn family members and at least prepare them for the possibility of having to raise a son or daughter with 22q13 deletion syndrome.  Along the way I received “thank you” from some family members and angry words from others.  Some family members simply did not want to know.  It is a story for some future blog, I suppose.

From this family research I was able to deduce that Joe, my dapper grandfather, was a carrier of 22q13 deletion syndrome with a “balanced translocation” of genetic material between chromosome 22 and chromosome 19.  Some of my grandfather’s siblings were carriers and at least two of Joe’s sons were carriers.  My dad was one of the carriers.  He had four sons, including me, and I am a carrier.  My dad did not have children with 22q13 deletion syndrome, but I had two.

The power of genetic principles

I know my dad was the carrier (not my mom) because a few of dad’s relatives are carriers. (See the line chart on my page “Who is arm 22q13?“.)   I was able show that my grandfather was a carrier using similar family evidence.  Genetics and inheritance follow certain rules and those rules can be used to peer into the past.  Genetics and evolution are two different aspects of the same rules, and understanding them can be very powerful tools for understanding where we come from and where we might be going.

Somewhere between 15% and 24% of all children with terminal deletions inherit that deletion from a carrier parent.  If your family has carriers, nature has provided a curious way to remove carriers from future generations: have small families.  This graph shows why.

(right click on graph to enlarge in a new window)

disappear3The main graph has three colored lines. (Ignore the small “inset” graph with bars; it provides details some researchers might want to see.)  The green line on the main graph represents what happens when people in the extended family have relatively large families (4.4 children, on average).  The black line shows the same process when the average family size is less (3.6 children per family).  The red line shows the impact of small families (1.5 children per family, on average).  What impact are we talking about?  The beginning of the graph starts today.  The end of the graph shows what happens after 10 to 50 generations from today.  Since most people assume 25 years for each generation to pass, the first 10 generations will take 250 years.  Here is the point.  If people have only small families, we can expect carriers to disappear (reach 0.0 on the scale) from the population in fewer than 10 generations.  However, if people choose to have large families (green line), carriers are unlikely to ever disappear (green line never reaches zero).

Let me be clear.  I am not advocating for any specific choice.  This is not about ethics.  In a sense, these are God’s rules.  They are inferred from the statistics of inheritance in the same way quantum tunneling is inferred from the statistics of nuclear emission.  I worked with a member of my family to generate this graph using a mathematical simulation.  I wanted to know how long 22q13 deletion syndrome has been in our family.  The answer comes from the green line.  Historically, my European ancestors had large families.  My great-grandfather had six children.  His children had an average of 4.8 children each.  These numbers suggest that the translocation could have existed in our family for tens of generations.

Promise

In my prior posting (“Understanding deletion size“) I promised to discuss a brain gene that is missing in 100% of the cases of terminal deletions.  I realize that explaining its importance will first require explaining a bit about evolution.  So, the rest of this blog will set the stage for judging the importance of a brain gene.

~~~~~ INTERMISSION ~~~~~
There is a lot of material here, so you are welcome to take a break before reading the second part.


Evolution:  There ain’t no missing link

Earlier I noted that genetics and evolution are closely related.  Describing evolution is simple in the same way that describing police work is simple. The task seems like it should be easy to explain, but the devil is in the details.  Many of the principles are not obvious at first, and both requires a lot of study.

Consider this make-believe story. A farmer has two children.  The son grows up to be a christian missionary in Africa and the daughter becomes an international arms dealer.  Their divergent lives lead to divergent branches of the family.  Years after dad passes away, two great-grandchildren meet.  One lives in a hut, is very religious and dresses modestly.  The other shows up on a yacht.  They are very different, but connected through a common ancestor (the farmer).  Evolution works the same way. The Chimpanzee is our closest living relative species. However, there was never a species halfway between Chimpanzee and Homo sapiens.  We share a common ancestor.  Some primate, extinct now, had members that experienced very different genetic and environmental events and each evolved into a different species.  These two offshoot species each underwent their own evolutionary history.

Primates (e.g., monkeys, apes, chimpanzees, humans) are special for a lot of reasons, but most notably for the development of higher brain function through the evolution of a new type of prefrontal cortex.  The new cortical areas help manage uncertainty, understand complexity and better imagine the future (Wise, 2008).  Rodents do not have an equivalent to the granular prefrontal cortex of primates.  Importantly, this area has undergone its greatest expansion in humans.  Two genetic features drive this type of dramatic specialization of brain function in humans: changes in the genes (either new ones or altered ones) and changes in when, where and how the genes are expressed.

Paralogs and gene expression

Here is a hypothetical example.  Let’s say a very early microorganism has a gene that we will call gene L.  Gene L is required for movement through its water environment.  Gene L is needed for “swimming”.   It is so important that the organism cannot survive any mutation of the gene. However, one day there is a genetic error during cell division and an offspring ends up with 2 copies of gene L (duplication event).  The new copy of gene L is somewhat “liberated”.  It can mutate and change without interfering with swimming, since the old copy of gene L is still available to do its job.  We name the two genes L1 and L2.  They are “paralogs” of the original gene L.  In our hypothetical case, gene L1 allows the organism to swim, and L2 is “free” to mutate and change.   One thousand years later, an L2 mutation event allows the organism to detect light in the environment.  The evolution of vision has just begun!  Thus, “duplication events” are crucial to evolution.  They copy important genes so that one copy can continue its original job and the other can do something new.  Sometimes, the two paralogs are very similar to each other, but are used differently in some crucial way.  L1 and L2 don’t have to be very different as long as having two different versions opens the door to new evolutionary opportunities.

Primate paralogs

The gene I will discuss next time is a paralog that only exists in ourselves and our very closest primate relatives.  That is, you and I carry a pair of genes that were duplicated and then evolved for specialized use in only the largest and most developed brains.  Moreover, humans have the most specialized use of the gene, and its specialization takes place in our brain. From an evolutionary point of view, this is a very special gene.  This gene is missing from every child with a terminal deletion, 98% of all known cases of 22q13 deletion syndrome. What critical functional role does it play in the human brain and how does that impact our children?

 

arm

Previous posts:
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction