Copy Number Variants: A Window into Psychiatric Illness

The human genome consists of nearly 25,000 protein-coding genes – and a mutation in just one of these can have dramatic effects on our brains.  Remarkably, one tiny change in our genes (which can be as small as 0.000000025 cm!) can lead to visible changes in our behavior.  Schizophrenia, el autismo, bipolar disorder, and ADHD have all been linked to variations in our DNA.  But how do changes in our genetic code result in these complex psychiatric disorders?

The first thing to understand is that genetic variants come in many different flavors: some are small sized, relatively common changes in our DNA, and others are much bigger structural changes that tend to occur less frequently.  Many researchers take the approach of studying common genetic variants (usually occurring in at least 5% of the population).  These common variants tend to slightly increase the risk of developing psychiatric illness.  Because of their modest size effects, studying these variants requires an extremely high number of subjects to detect an association with psychiatric illness.  An alternative approach is to study rare genetic variants (defined by occurring in less than <1% of the population) that produce an ultra-high risk for developing psychiatric illness.  There are fewer people with these rare variants, but the chance that they will develop a psychiatric diagnosis can be quite high.  Why is this so beneficial for researchers interested in psychiatric genetics?  Well, when recruiting individuals with these rare variants, they can be confident that a good portion of them will have a psychiatric illness that they can study.

Image by Nima Chenari

These large genetic variants often present themselves as copy number variants (CNVs), which are big stretches of DNA that are either deleted or duplicated in our genome.  Unlike common variants, which are often one DNA base pair, CNVs can be upward of 3 million base pairs (of which there are around 3 billion total in our genome!).  These changes in our genetic code can have major effects on psychiatric outcomes.

Not all deletions or duplications of DNA are necessarily pathological.  In 2015, researchers from Toronto created a comprehensive map of CNVs within the human genome, occurring in generally healthy individuals.  They found that 9.5% of the human genome consists of either deletions or duplications of DNA!  Moreover, they found that around 100 genes could be deleted from our genome without producing obvious phenotypic effects.

So how do people get CNVs in the first place?  Interestingly, they aren’t necessarily passed on by our parents: they can also happen “de novo” (i.e., occurring for the first time in a parent’s sperm or egg).  Do you remember learning about meiosis in high school biology class?  Well, it’s during that process, when deletions or duplications can occur.

During the process of DNA replication, two strands of DNA have to break apart and come back together.  The individual DNA strands know how to reconnect because the sequence of base pairs on one side has an exact complementary match on the other side (think: Velcro).

DNA often features many similar sequences of base pairs in very close proximity to each other (termed, “low copy repeats” (LCRs)).  Because there are certain parts of our chromosomes that have many LCRs close to each other, sometimes mistakes are made when zipping back up the DNA.  These mistakes can snip out an important section of DNA (deletion), or it can add in an entirely new one (duplication).  This process is called non-allelic homologous recombination (or NAHR, for short).  Sometimes, this can affect just a few base pairs, and other times, it can impact up to several million base pairs.  More importantly, NAHR can have drastic effects on gen products, resulting protein levels, and ultimately, our physiology.

One notable disorder caused by a CNV is 22q11.2 Deletion Syndrome (22q11Del).  In this syndrome, 30-60 genes are deleted from the long arm of chromosome 22 by NAHR.  While non-affected individuals have the usual two copies of each gen, patients with this disorder only have one copy of these 30-60 genes.  Patients with 22q11Del have a greatly elevated risk of developing psychiatric illness – specifically, schizophrenia, el autismo, ADHD, and anxiety disorder.  In fact, having a diagnosis of 22q11Del is the second greatest predictor for developing schizophrenia (having an identical twin with the illness is the first).  The rate of schizophrenia is around 1% in the general population, but about a third of patients with 22q11Del develop schizophrenia.  We know that many of the compromised genes in this syndrome are highly involved in brain development and neurochemistry, leaving 22q11Del as an ideal model for studying the links between genes and psychiatric illness.

Another fascinating example of a disorder caused by a CNV is 22q11.2 Duplication Syndrome (22q11Dup).  As the name implies, instead of having the usual two copies of each gen, they actually have three copies of 30-60 genes.  This mutation is in the same exact spot in the genome as 22q11Del, except instead of losing a copy of each of these genes, they gain one.  The psychiatric phenotype of 22q11Dup is distinct from 22q11Del, and is quite variable.  Though little research has been done on this population so far, some scientists think that there is evidence that patients with 22q11Dup are actually protected against schizophrenia, given their ultra-low rates (0.014%, as compared to 1% in the general population).  Studying 22q11Del and 22q11Dup provides a unique opportunity to investigate gen dosage effects on the development of psychiatric illness.  Although 22q11Del and 22q11Dup seem to manifest distinctively, there are other cases of CNV-related disorders whereby a deletion or a duplication of a set of genes can actually present similar psychiatric phenotypes.  For example, patients with 15q11.2 Deletion Syndrome and 15q11.2-q13 Duplication Syndrome both have high rates of el autismo.

So why are certain CNVs so fundamentally important to our physical and psychiatric well-being, while others seem to have no detectable effect?  Researchers in psychiatric genetics are tirelessly working to answer this question every day.

Copy Number Variants Cover Image
Image by Nima Chenari


Escrito por Rachel Jonas.

Images by Nima Chenari. 



Frazer, Kelly A., et al. “Human genetic variation and its contribution to complex traits.” Nature Reviews Genetics 10.4 (2009): 241-251.

Geschwind, Daniel H., and Jonathan Flint. “Genetics and genomics of psychiatric disease.” Science 349.6255 (2015): 1489-1494.

Nevado, Julián, et al. “New microdeletion and microduplication syndromes: a comprehensive review.” Genetics and molecular biology 37.1 (2014): 210-219.

Rees, Elliott, et al. “Evidence that duplications of 22q11. 2 protect against schizophrenia.” Molecular Psychiatry 19.1 (2014): 37-40.

Zarrei, Mehdi, et al. “A copy number variation map of the human genome.”Nature Reviews Genetics 16.3 (2015): 172-183.

Images adapted from Gershon, Elliot S., and Kay S. Grennan. “Genetic and genomic analyses as a basis for new diagnostic nosologies.” Dialogues in clinical neuroscience 17.1 (2015): 69.

Rachel Jonas

Rachel recibió su licenciatura en Neurociencia del Comportamiento de la Universidad de Lehigh, con una subespecialización en psicología.  Trabajó como una asistente de investigación por dos años en la Universidad de Rutgers, estudiando los trastornos del control de impulso en pacientes con la enfermedad de Parkinson. Obtuvo su doctorado en Neurociencia de UCLA, donde estudia las relaciones entre el comportamiento y el cerebro en individuos con alto riesgo de padecer trastornos psiquiátricos.  Ella usa técnicas comportamentales, neuroimagenológicas y genéticas para investigar como los endofenotipos subyacentes pueden señalar el desarrollo de enfermedades psiquiátricas.