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Snapshot: What is a Genome-Wide Association Study (GWAS)?

A genome is a person’s complete set of DNA which provides the instructions to make and maintain their body’s functions. Throughout the entire genome, there are genetic differences between individuals known as single nucleotide polymorphisms or SNPs (pronounced “snips”). These variations may be unique or may occur in many people. Normally, these SNPs do not directly cause diseases. But SNPs can sometimes be associated with diseases, and can provide interesting and potentially important information. A genome-wide association study (GWAS) looks at the genomes of many individuals to identify these variations, with the goal of linking more of these variations to particular diseases.

a mural of A, C, T, G repeated over and over again fading off into the distance. It is the genetic code of DNA. — An art piece of repeating A, T, C, and G DNA base pairs, which encode our entire genome. Photo by Stefano on Flickr.

What can these types of studies tell us?

Scientists have gathered plenty of information from GWAS. Once these genetic variations are identified, researchers can use this information to learn more about how diseases occur and affect certain people. For example, GWAS have successfully identified genetic variations that can contribute to diabetes, obesity, and heart disease.

These kinds of studies can also help with creating personalized medicine – where different strategies can be used by doctors to treat patients based on their genetic makeup. This can allow doctors to give patients the most effective treatments, while limiting bad side effects.

How are these kinds of studies conducted?

Researchers typically look at two groups of people: individuals with the disease that is being studied, and people without the disease. DNA is obtained from people in each group to be studied, typically through a blood sample, or skin cells. In order for these studies to work, researchers try to look at as many people as possible. It is a big task, and requires not just hundreds, but thousands of participants! This allows researchers to be confident in the conclusions that they make.

In the early 2000’s, researchers mapped out the complete human genome. Since then, more genetic information from more people have been catalogued. Databases have been created that make it easier for researchers to compare new genomes to ones that have already been sequenced. This makes it quicker and easier to identify genetic variations and how they can contribute to disease.

What has GWAS taught us about SCA?

Some forms of Spinocerebellar ataxia (SCAs) are members of a larger group of diseases known as polyglutamine diseases. This group of diseases are caused by an abnormally long stretch of repetitive segments in the DNA. Scientists have identified that more repeats generally correspond with earlier disease onset, however, this is not always the case. Therefore, scientists have established that disease onset may be affected by other things, such as their environment or other parts of their genome or genetic factors. If researchers can identify these genetic factors, it could improve how these diseases are treated.

The cells in your body are equipped with machinery that helps identify and repair damage to DNA that occurs thousands of times a day from normal cellular processes or the environment (such as sun damage). A few years ago, GWAS revealed that genes involved in these pathways could affect SCA disease onset, and this opened up a new and exciting route of discovery for scientists! Many scientists are currently exploring this route, and more will be done in the coming years to see if we can find new therapies.

If you are interested in reading more about this GWAS report, c heck out our summary on the paper.

If you would like to learn more about Genome-Wide Association Studies, take a look at these resources by the National Human Genome Research Institute and MedlinePlus.

Snapshot written by Dr. Claudia Hung, edited by Dr. Ray Truant and Celeste Suart.

Discovery of a new molecular pathway in spinocerebellar ataxia 17

Written by Dr. Sriram Jayabal Edited by Dr. Ray Truant

A potential new pathway for SCA17: gene therapy that in mice restores a critical protein deficit protects brain cells from death in SCA17.

Neurodegenerative ataxias are a group of brain disorders that progressively affect one’s ability to make fine coordinated muscular movements. This makes is difficulty for people with ataxia to walk. Spinocerebellar ataxia type 17 (SCA17) is one such late-onset neurological disease which typically manifests at mid-life. The life expectancy after symptoms first appear is approximately 18-20 years. Besides ataxia, SCA17 can cause a number of other symptoms ranging from dementia (loss of memory), psychiatric disorders, dystonia (uncontrollable contraction of muscles), chorea (unpredictable muscle movements), spasticity (tightened muscles), and epilepsy.

Brain imaging and post-mortem studies have identified that the cerebellum (often referred to as the little brain) is one of the primary brain regions that is affected. That being said, other brain regions such as the cerebrum (cortex or the big brain) and brainstem (distal part of the brain found after the cerebellum) could undergo degeneration. Further, the genetic mutation that leads to SCA17, is a CAG-repeat expansion mutation, similar to several other forms of ataxias. In most other ataxias, where the function of the mutated protein is unknown. However in SCA17, the function of the mutated protein, TATA-box binding protein, is very well understood. Despite this unique advantage, we are yet to completely understand how the mutant gene leads to SCA17. This is why current treatment strategies often focus on treating the symptoms, but not the underlying cause.

person holding laboratory flask — Photo by Chokniti Khongchum on Pexels.com

SCA17 mutation leads to Purkinje cell death

Researchers from China have shed more light on how the mutant gene causes SCA17. TATA-box binding protein is a transcription initiation factor is a protein that turns on the production of RNA from genes. It is widely found across the brain including the cerebellum. TATA-box binding protein controls the amount of protein manufactured from several genes. This raised a very important question: pertinent not only to SCA17 but also more generally to several SCAs – why is that the cerebellar neurons, especially the most sensitive neuron, the Purkinje cells die?

Snapshot: What are Astrocytes?

The human brain contains about 170 billion cells. Half of these are neurons and the other half are lesser known cells called glia. Glial cells include astrocytes, oligodendrocytes and microglia. Astrocytes tile the entire brain and interact closely with neurons. Astrocytes are very important for neuronal function, in many ways playing a parenting-like role. They provide energy and support to neurons, and they clean after them. Astrocytes make sure that neuronal surroundings are “just right” for optimal function of neurons. They can also actively influence neuronal activity.

An astrocyte cell grown in tissue culture stained with antibodies to GFAP and vimentin. The GFAP is coupled to a red fluorescent dye and the vimentin is coupled to a green fluorescent dye. Both proteins are present in large amounts in the intermediate filaments of this cell, so the cell appears yellow, the result of combining strong red and green signals. The blue signal is DNA revealed with DAPI, and shows the nucleus of the astrocyte and of other cells in this image. — An astrocyte cell imaged using a microscope and colored antibodies. Imaged courtesy of Wikimedia.

Similar to neurons, there are important differences in astrocytes from different brain regions. For instance, in the cerebellum there are about 5 times more neurons than astrocytes. Meanwhile in the cortex there are 10 times more astrocytes than neurons. In addition, astrocytes in the cerebellum and hippocampus (a brain region that plays an important role in memory) express different sets of proteins. These brain region differences can contribute to the role that astrocytes play in neuronal function in health as well as in disease.

Bergman Glia: An Important type of Astrocyte in Ataxia

In the cerebellum, there is a special type of astrocyte called Bergman glia that are very closely connected with Purkinje cells, neurons that are often vulnerable in ataxia. In fact, the relationship between Purkinje cells and Bergmann glia is often referred to as the most intimate neuron-astrocyte relationship in the brain. This is important as in brain injury and neurodegenerative diseases astrocytes undergo process called gliosis that changes their function. Gliosis can make them either more neuroprotective (helpful) or harmful.

For instance, when there is disease Bergmann glia can increase their support to help Purkinje neurons maintain their function and delay onset of disease symptoms. But also, Bergmann glia can become harmful worsening the dysfunction of Purkinje neurons and more severe disease symptoms.

Bergmann glia help support Purkinje cells early on in ataxia, but as the disease progresses they can actual make symptoms worse. — Illustrating intimate relationship between Bergmann glia (BG) and Purkinje cells (PC). Bergmann glia may increase their support to Purkinje cells early in disease. However, they can become harmful with disease progression. Image desgined by Marija Cvetanovic.

It is important to learn more about how astrocytes are altered in ataxia for these reasons. We can use that knowledge about astrocytes to develop novel therapies to delay onset of ataxia symptoms and their severity.

If you would like to learn more about astrocytes, take a look at these resources by Khan Academy and Tempo Bioscience.

Snapshot written by Dr. Marija Cvetanovic and edited by David Bushart.

Levels of Capicua may make SCA1 neurodegeneration worse in parts of the brain

Written by Stephanie Coffin Edited by Dr. Brenda Toscano

Ataxin-1 may not be the only protein important in driving neurodegeneration in SCA1

Why does a protein that cause disease only cause toxicity in specific regions of the brain, despite being in all cells of the body? This is the question authors attempt to answer in this article, with a focus on spinocerebellar ataxia type 1 (SCA1) and the disease causing protein, Ataxin-1. SCA1 is a polyglutamine expansion disorder, meaning patients with the disease have a CAG repeat in the ATXN1 gene that is larger than that of the healthy population. This mutant allele is then translated into a mutant protein, causing SCA1. Ataxin-1 protein is expressed throughout the entire brain, however, toxicity (cell death and problems) is mainly restricted to neurons of the cerebellum and brainstem. This phenomenon is called “selective vulnerability” and refers to disorders in which a restricted group of neurons degenerate, despite widespread expression of the disease protein. Selective vulnerability occurs in many diseases, including Alzheimer’s, Huntington’s, and Parkinson’s disease and is currently under investigation by many scientists in the field of neurodegeneration.

In SCA1, this selective vulnerability can be narrowed further in the cerebellum. The cerebellum is broken down into lobules (I-X), with lobules II-V described as the anterior region and lobules IX-X as the nodular zone. Studies have previously shown cerebellar Purkinje cells to be particularly sensitive to mutant ataxin-1, and within the cerebellum, neurons in the anterior region degenerate faster than those in the nodular zone. This paper wanted to understand the mechanism of this interesting biology, hypothesizing that there are genes whose are expressed mainly in these zones could correlate with the pattern of Purkinje cell degeneration. To this end, the authors used the mouse model ataxin-1 [82Q], which overexpresses human ataxin-1 with 82 CAG repeats specifically in cerebellar Purkinje cells.

Doctor howing up a scan of the human brain — Why do some parts of the brain degenerate in SCA1, when the disease causing protein is expressed in all pWhy do some regions of the brain degenerate in SCA1, when the disease-causing protein is expressed in all parts of the body? Why don’t other regions show the same signs of disease? This is what researchers sought to find out in this study. Photo by Anna Shvets on Pexels.com

First, the authors confirmed the finding that neurons from the anterior region of the cerebellum degenerate earlier than those in the nodular zone. They did this by assessing the health and number of Purkinje cells, which indeed appeared to be better in the cells located in the nodular zone. Next, techniques assessing expression of RNA in SCA1 and control cerebellum, showed that there are a number of genes which are uniquely dysregulated in the anterior cerebellum of SCA1 mice. Neurons function and communicate with each other via ion channels, and interestingly, the genes found to be dysregulated in the anterior cerebellum of SCA1 mice were related to ion channel signaling.

Snapshot: What is a Gene?

A gene is the basic physical unitof heredity. Every living cell contains genetic information that determines an organism’s development, form, and function. This genetic information is encoded by two macromolecules: DNA and RNA.

DNA consists of two strands of phosphate and sugar molecules connected by pairs of nitrogenous bases to form a double helix structure. The four nitrogenous bases in DNA are adenine, thymine, cytosine, and guanine (abbreviated A, T, C, and G). Genes are sequences of nucleotides (composed of a sugar, a phosphate group, and a base) that provide the instructions that cells need to make molecules that give rise to an organism’s characteristics. Within the nucleus of each cell, DNA is tightly coiled around specialized proteins called histones, forming compact structures called chromosomes. Each gene occupies a particular position, or locus, on a chromosome.

In your cells, you find your DNA in tightly packed X shapped molecules called chromosomes. If you unwind this DNA, you can see it is made of of nucleotide bases. — Genes are sequences of nucleotides that give rise to an organism’s traits. DNA is tightly coiled around structural proteins and compressed to form chromosomes. Chromosomes are housed in the cell’s nucleus and replicated prior to cell division. Figure created by Chloe Soutar using Biorender.com.

Most genes contain instructions for creating proteins, amino acid-based macromolecules with a wide range of structures and functions. Among their numerous essential functions, proteins contribute to cell structure and repair, signal transmission between cells, and biochemical reactions within cells. Genes are used to create proteins through a two-step process. Double-stranded DNA is first transcribed into single-stranded messenger RNA (mRNA) that serves as a template for protein synthesis. mRNA exits the nucleus and interacts with cellular machinery called ribosomes. Ribosomes then read mRNA and translate its nucleotide sequence into long chains of amino acids, which then fold to form proteins.

DNA is the instructions to make mRNA, which makes amino acid chains that come together to make protiens which build our bodies. — Genes encode proteins through a two-step process. During transcription, enzymes within the nucleus build single-stranded mRNA molecules that are complementary to one strand of DNA. At this stage, the base thymine (T) is substituted for uracil (U). During translation, cellular structures called ribosomes “read” the mRNA within the cytoplasm and translate the nucleotide sequence into a sequence of amino acids. Linear chains of amino acids then undergo patterns of folding to yield intricate protein structures. Figure created by Chloe Soutar using Biorender.com.

An organism’s complete set of genetic material is called a genotype. The human genome is estimated to contain between 20,000 and 25,000 protein-coding genes, varying in size from thousands of nucleotides to over 2 million nucleotides. The complete set of observable traits that results from gene expression is called a phenotype. An organism’s phenotype includes all of its outward characteristics, including height and eye colour, as well as less apparent characteristics such as blood group and intelligence. For example, the genes that determine the amount of pigment in my skin are part of my genotype, but my skin colour is part of my phenotype. Whereas one’s genotype is determined solely by biological factors, one’s phenotype is determined by complex interactions between biological and environmental factors. This distinction between genotype and phenotype is evident in the case of identical twins – even though they have the same genotype, they often look and behave differently due to environmental and lifestyle factors.