Originally posted 14 July 2015
Updated 28 March 2021
Available in Portuguese https://pmsbrasil.org.br/entendendo-o-tamanho-de-um-gene/
David has a terminal deletion of chromosome 22 caused by a balanced translocation. Like nearly everyone with 22q13 deletion syndrome (Phelan-McDermid syndrome), he is missing a lot more than one gene. What, exactly, does that mean?
DNA and genes
Each gene is made up of many “bases”. DNA has two strands (strings) that grip each other tightly. Imagine a bunch of bar magnets threaded onto a string like pearls. Now, in your mind, take two of these strings and hold them near each other. Slowly bring them close together. When they get near, the north poles of magnets from one string will start to find the south poles from the other string. When the magnets come together, opposite poles will grab each other. Anywhere north faces north, or south faces south, that pair will repel each other until one flips around and the opposites unite. DNA is made of chemical strings that have opposite poles. These opposites find their mate and the two DNA strands lock together. Each time a north meets a south you get a “base pair”.
Magnets can only make one type of partnership (north attracted to south). DNA actually has two kinds of partnerships from four chemical bases. The bases are abbreviate T, A, G and C. T and A attract each other. G and C attract each other. If you make a string like this: -T-A-G-G-C-A-, the matching string will always look like this: -A-T-C-C-G-. That is, the strings stick to each other in this way:
Voilà! You have a small strand of DNA. This miniature DNA has 6 base pairs. The order of the base pairs describe the protein that this segment of DNA makes. The lower strand is kind of mirror of the upper strand. If you know what is on one strand you can always figure out the other strand. Thus, we now know a bunch of properties of DNA: 1) The sequence of base pairs describes how to make a protein, 2) DNA is strongly stuck to itself, 3) DNA keeps a mirror copy of itself available at all times, and 4) the length of the DNA can be measured by counting the number of base pairs. There is a lot more to learn about DNA, but this is enough to discuss gene size.
Big genes are easier to find
In a previous posting I explained that 95% of all people with 22q13 deletion syndrome are missing at least 1 megabase (Mb) from their chromosome (see Understanding deletion size). 1 Mb means 1,000,000 (1 million) base pairs along the two parallel strands of DNA. Genes are segments of the long strings, like chapters in a book. And, like many books, some chapters are long and some are short. There are 32 genes in the distal 1 Mb of 22q13, many of which influence brain function. Chromosome deletion syndromes are inherently difficult to study because so many genes are involved. It is hard enough to study and understand the impact of losing a single gene. It is much harder to study and understand 22q13 deletion syndrome, where many genes are missing.
This problem with studying multiple genes is not unique to 22q13 deletion syndrome. It shows up in neuropsychiatric disorders like autism and schizophrenia, each of which have hundreds of associated “risk factor” genes. Autism, for example, results from various combinations of these many genes (see review by Gratten et al., 2014). Chromosomal deletions are known to operate in a similar way (see contiguous gene syndrome). Each missing gene weakens the normal operation of the brain. No one gene needs to be “dominant” for the combined loss to be devastating, especially when so many brain-related genes are missing at once.
Not everyone thinks of 22q13 deletion syndrome this way. Much of the current thinking about the genes lost in 22q13 deletion syndrome focuses on one or two genes that code for synaptic proteins. The term “synaptopathy” has been used a lot recently, but that word originates from the study of the inner ear where they are able to clearly demonstrate the relationship between synaptic function and hearing loss (Sergeyenko et al., 2013). The relationship between genes and function is not nearly as clear in 22q13 deletion syndrome. Synapses are involved, but the synapse may be only one site of dysfunction (see Is 22q13 deletion syndrome a ciliopathy?). For many years no one thought primary cilia were important. Now, ciliopathies are a recognized type of brain dysfunction despite the fact that synapses are also involved. Science often goes off in a wrong direction; it is part of the process. The other thing to remember about 22q13 deletion syndrome is that it is a neurodevelopmental disorder. Something goes wrong during the growth and maturation of the brain. There are so many things that can go wrong with too few or too many neurons connecting between two sites in the brain, neurons connecting to wrong places, wrong proportions of excitatory and inhibitory neurons, etc. Human neural development is one of the most complex processes in the animal kingdom. Errors in neurodevelopment are not just problems with synapses.
There is another reason that synaptic genes have taken the spotlight. The synaptic genes of 22q13 are relatively large genes. This is the theme of our blog.
In general, large defects are easier to notice than small ones. If we look at the history of 22q13 deletion syndrome, the first cases were discovered in people with very large deletions and with the most “severe” phenotype (symptoms). As research in 22q13 deletion syndrome advanced, smaller and smaller deletions were identified and studied. The gene that gets most attention is a large gene that has a large effect when disrupted. So, why does size matter?
The pie chart shows the 32 genes that are missing from about 95% of patients with 22q13 deletion syndrome. The genes are sorted in order of size. The largest gene is SBF1 and the second largest is SHANK3. The genes continue in descending order of size in a counter-clockwise direction. Although the reality is a bit more complex, it is generally true that the likelihood of a gene getting accidently modified, or otherwise disrupted, depends on the gene’s size. This pie graph shows that the 10 largest genes account for half of the “protein-coding” DNA in the first 1 Mb. To put it another way, you are twice as likely to disrupt SHANK3 than it neighbor MAPK8IP2, simply because SHANK3 is twice as large. SHANK3 is 16 times larger than SYCE3. So, when studying gene disruption, SHANK3 can show up more often simply because it is big. Scientists are aware of this size effect. They have developed gene disruption scores that take into account the size of a gene (i.e., probability of loss-of-function intolerance, pLI).
As I noted above, no one has carefully studied the impact of a complete deletion of SHANK3 without disrupting other genes involved in brain development and function. It may seem surprising, but a damaged gene can actually have a more severe impact compared to deleting the gene altogether (see When missing a gene is a good thing). A pathogenic variant of SHANK3 (an atypical and harmful version of the gene often resulting from damage) can contribute to 22q13 deletion syndrome, especially when SHANK3 is the only gene affected. But SHANK3‘s contribution to 22q13 deletion syndrome when many genes are missing is remains poorly understood. There are other 22q13 genes that have severe neurodevelopmental consequences after deletion whether or not SHANK3 is involved. Future blogs will discuss some of these genes in detail.
The take-home message is that certain genes are more likely to come under the microscope (literally and figuratively) simply because they are larger genes. Being large makes a gene easier to study (usually), but it does not necessarily confer importance. Measures like pLI have been developed to separate size from importance. This measure was used in a study of Phelan-McDermid syndrome that is discussed in the blog Which PMS genes are most important?.
When a gene gets popularized in the scientific literature, lots of papers are published on that one gene, at least for a while. Scientists will focus on genes that get them grants and publications. That is how science typically works, even if it is not necessarily the best approach to finding effective treatments that families really need. The direction of science can be influenced by patient groups, but choosing the right direction requires a deep understanding of the science (the current state of research), science (the discipline) and scientists (who do science).
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction