On a sunny Saturday in June, geneticists, genetic counselors, professors, researchers and students gathered at the University of Connecticut to learn about a new scientific technology that has the world talking.
This technology has become the new star in genetic editing technologies (and will quite literally be in the plot of a new and upcoming “self-titled” television show with Jennifer Lopez); it’s called CRISPR.
The term CRISPR was coined in 2002, but scientists have only been using this technology since 2012. What has CRISPR been able to do? What has it contributed to research? With the technology affecting so many areas of science, UCONN’s event focused on it’s impact on imprinting disorders, discussed below…

 Photo Credit  sciencemag.com

Photo Credit sciencemag.com


CRISPR stands for Clustered Regularly-Interspaced Short Palindromic Repeats, but don’t get lost in the name.  In short, CRISPR  can “delete” and “replace” genes, which is referred to as ‘editing the genome’. But did you know that CRISPR can also modify the epigenome? The epigenome is the collection of DNA modification that does not change the DNA sequence, but rather affects the activity of genes, meaning which genes will be expressed and the rate of expression.
 Photo Credit:  Pinterest

Photo Credit: Pinterest


Think of the genome (DNA) as a piano with the piano keys representing genes. Editing the genome would be like taking a key out or replacing one. Whereas modifying the epigenome would be like changing which notes are actually being played and how often they are being played. CRISPR technology can now accomplish both methods of editing. For a more complete explanation of how this technology works, check out our blog post, CRISPR Technology Explained.
 Photo Credit:  UCONN

Photo Credit: UCONN


Chris Stoddard, who operates the Human Genome Editing Core at UCONN Health, elaborates on how these two different CRISPR editing methods work,
“[In genome editing] CRISPR [Cas-9 proteins] are directing a double stranded break in the DNA, this stimulates a repair pathway. If we include DNA into this system it will use it as a template to repair this double stranded break. [To modify the epigenome] you mutate two domains in the CRISPR-Cas9 protein, it becomes ‘dead’ Cas9 and won’t cut the DNA anymore. The guide RNA is like the GPS and tells the Cas9 protein where to go. In the truck of the Cas9 protein will be the cargo, the effector proteins, which will do the work on the epigenome. You can recruit proteins to activate or silence genes.”
The UCONN Health CRISPR expert also shared the origin of CRISPR, “CRISPRs [are derived from] the bacterial adaptive immune system. They are a way for bacteria to recognize invading DNA and destroy it. Once a bacteriophage/virus infects a bacteria, and the bacteria survives, it has a memory of that DNA. A later transduction by that bacteriophage/virus will get destroyed and the bacteria will survive again. Every time a bacteria gets attacked and survives, that bacteria incorporates a part of the genome from the bacteriophage/virus. The CRISPR locus just keeps growing. When that bacteria divides all of its descendents contain [this information].”
 Photo Credit  UCONN

Photo Credit UCONN


Dr. Michael O’Neill, the Assistant Director of the Institute for Systems Genomics and Associate Professor at UCONN, is utilizing CRISPR to study autism spectrum disorder by exploring how genes on the X chromosome may play a role.
Although estimates show that roughly 1,000 genes play a role in autism, the mutations that have been associated with the condition are fairly common. Dr. O’Neill explains that it’s only when dozens of these mutations are brought together that a threshold is reached for a person to be considered on the autism spectrum.
Since this disorder affects males more than females (4 to 1), the thought is that some of the genes involved could be X-linked (an inheritance pattern affecting primarily males). To conduct his research, Dr. O’Neill is using mice cells with Turner’s syndrome, a sex chromosome disorder where females only have one instead of two X chromosomes. The parental origin of the single X chromosome in these mice are also identified as maternally or paternally derived. Armed with CRISPR, Dr. O’Neill compares the gene expression rates between maternal and paternal X chromosomes in the Turner syndrome mice cells.

Dr. Stormy Chamberlain and Dr. Marc Lalande are pioneers in researching the imprinting disorders, Angelman Syndrome and Prader-Willi Syndrome. These two disorders don’t appear similar. Angelman Syndrome patients suffer from lack of speech, seizures, development delays,  and walking and balance issues; Prader-Willi Syndrome patient’s symptoms include obesity, intellectual disability, and shortness in height.
Here’s the catch, these disorders are caused by the same genetic mutation, usually a small deletion on chromosome 15. How does the same deletion cause two different disorders? It depends on the parental origin of the chromosome with the deletion. If the deletion is on the chromosome that was inherited from the mother, that patient has Angelman Syndrome. If the same deletion is on the chromosome that was inherited from the father, that patient has Prader-Willi Syndrome. This is due to the phenomenon called genomic imprinting.
Genomic imprinting is an epigenetic occurrence in which specific genes are silenced based on parental origin of a chromosome (condensed units of DNA). Instead of genes being expressed from both chromosomes, certain genes will be silenced or inactivated on one chromosome. For example, if a gene from the father is imprinted (turned “off”) the same gene on the maternally inherited chromosome will be expressed (assembled into proteins). It’s important to note that not all genes are imprinted, only some have this effect.
 Photo Credit  havenhillbaptistchurch.com

Photo Credit havenhillbaptistchurch.com


Dr. Stormy Chamberlain, Assistant Professor of Genetics and Genome Sciences and Associate Director of Graduate Program in Genetics and Developmental Biology at UCONN Health, is researching Angelman Syndrome through neuron cells. These neuron cells have a point mutation in the UBE3A gene, and therefore have Angelman Syndrome. Dr. Chamberlain designed a CRISPR that specifically targets this mutation. An interesting find is that this gene (UBE3A) is imprinted in neurons, but not in most cell types.
 Photo Credit:  hartfordbusiness.com

Photo Credit: hartfordbusiness.com


Dr. Marc Lalande, who holds the Physicians Health Services Chair in Genetics and Developmental Biology at UCONN, is researching if he can “turn on” imprinted copies of genes in Prader-Willi Syndrome. The genes involved in these disorders are located on chromosome 15 and are imprinted or “turned off” in the maternal chromosome. Dr. Lalande is attempting to turn those genes “on” to prevent/treat Prader-Willi Syndrome. This process starts by identifying the vital genes to be which need to be “turned on”. Similar to Dr. Chamberlain, Dr. Lalande is using CRISPR on neuron cells to conduct his research. So far his experiments have worked!
If you are interested in learning more about UCONN’s genetics, check out their Diagnostic Genetic Sciences program! UCONN is also currently developing a genetic counseling graduate program and targeting a Fall 2019 opening, more details to come.