Analyzing Our Genetic Blueprints

Found in nearly all our cells, our deoxyribonucleic acid (DNA) contains our genetic blueprints — the foundation which helps guide the creation and maintenance of everything we’re biologically made of.

The human genome is made up of 3 billion pairs of DNA letters or “bases.” This multitude of adenine (A), cytosine (C), guanine (G), and thymine (T) bases comprises an estimated 20,000 genes that spell out instructions for making proteins, along with regulatory and other non-coding DNA regions whose functions are not fully known. Scientists study genetics in many ways, such as following diseases or other traits through family pedigrees or identifying the exact order of DNA bases (the DNA “sequence”) that code for a given trait. More recent genetic tools enable scientists to manipulate genes and other genetic features to better understand how the brain works and how to treat it in cases of dysfunction or disease.

Scientists often don’t know which gene or other DNA feature controls a trait. At the outset, a particular trait could be encoded on any of the 23 pairs of chromosomes in a typical human cell. But with genetic linkage studies, researchers have begun to map gene locations. First, researchers must identify another trait with a known chromosomal location that tends to be inherited with or “linked” to the trait of interest. This technique, which narrows down the likely location of the gene of interest, is the first step toward identifying the genetic basis of many neurological disorders.

When you think about muta­tions, you probably think of harmful changes in one or several DNA bases within a gene. But some disorders re­sult from an overabundance of copies or repeats of a stretch of DNA. This is the case with Huntington’s disease. The normal HTT gene has about a dozen repeats of a small stretch of DNA within the gene, but Hunting­ton’s patients can have more than 100 of these repeats. Researchers now use DNA chips or microarrays to identify such variations in copy num­ber. The “array” of a microarray refers to the thousands of spots arrayed in rows and columns on the surface of the chip; each spot contains a known DNA sequence or gene, which can grab onto corresponding bits of the genome being analyzed. Using this tool, scientists are able to compare DNA samples of two people, perhaps one healthy and one with a disorder, to see if certain pieces of DNA are repeated more in one person than in the other. Another type of microar­ray helps researchers determine if a patient has a chromosomal translo­cation — a chunk of a chromosome that has been misplaced onto another chromosome.

Recent years have seen great ad­vances in DNA sequencing methods, allowing researchers to more efficiently and affordably explore the exact DNA sequence that might underlie brain disorders. In the early 2000s, the Hu­man Genome Project made public much of the human genome sequence; in the years that followed, the science of genomics has enhanced scientists’ understanding of brain function at the level of genes, cells, and circuits. Genomics can help identify genetic variations that cause conditions ranging from depression to schizophre­nia to movement disorders.

Genetics research now goes far beyond reading the sequence of bases in the genome. In the last few years, scientists have harnessed a molecular tool that can edit the genome more precisely and efficiently than was previously possible. This tool, called CRISPR (which stands for Clustered Regularly Interspaced Short Palin­dromic Repeats), evolved as a bacte­rial immune system that targets viral invaders. Scientists have harnessed CRISPR’s components to home in on specific DNA sequences in lab animals and human cell cultures. By tethering DNA-cutting enzymes to this targeting system, scientists can recreate mutations found in patients with neurological disorders, or even insert new bits of DNA to test their effect. With CRISPR, scientists have been able to mimic Alzheimer’s in rodents in order to study the disease and its potential treatments. CRISPR is also used to study mutated human neurons in Petri dishes. Research­ers can observe how mutations that cause autism, Parkinson’s disease, or other conditions affect neuronal growth and function.

Optogenetics is another intersection of genetic tools with brain science. This technique allows researchers to control brain activity with flashes of light. Scientists genetically modify a lab animal, like a mouse, so that its neurons produce a light-responsive protein. Then, optical fibers are inserted into the brain to allow light to shine on those neurons — either activating or silencing them. Optogenetics has helped scientists better understand how neurons work together in circuits. This technique has also been used to control animal behaviors ranging from sleep to drug addiction.

Oddly enough, genetics is not always about genes. As mentioned above, much of the human genome contains DNA sequences that are not genes, whose job is to regulate gene activity. These regulatory sequences, and the enzymes that make changes to them, help determine under what conditions (in what cells, at what age, etc.) a gene is expressed or repressed. These epigenetic changes occur in cells when chemical tags are placed on the regulatory regions of certain genes; the tags influence whether those genes will be turned on or off. In the past decade, epigenetics research has begun to clarify the role of gene regulation in brain development and learning. Epigenetics has also revealed how mutations in the regulatory regions of DNA can cause disease, just as muta­tions can in genes.

Genetics in Neurological Diseases

The impact of mutations varies from person to person, and from dis­ease to disease. A particular mutation might explain some cases of a disorder but not others, or it could be only one of several genetic changes affect­ing a patient. Lissencephaly is a brain malformation in which the surface of the brain is smooth, unlike normal brains whose surfaces have ridges and grooves. It affects development. Babies with lissencephaly start having spasms in the first months of life and develop drug-resistant epilepsy and severe intel­lectual and motor disabilities. Although about 70% of these patients have mutations in the LIS1 gene, at least two other mutations have been associated with the condition. Another complex genetic condition, Kabuki syndrome, is marked by intellectual disabilities, a distinctive facial appearance, slow growth in infancy, and other physical problems. Kabuki syndrome is hard to diagnose because some symptoms, such as intellectual disability, range from mild to severe. DNA sequencing has found that most patients, but not all, have mutations in the KMT2D gene — and some patients carry the muta­tions in only some of their cells. In ad­dition, people with Kabuki syndrome may have mutations in other genes that function like KMT2D.

It is also possible for a person to carry a mutation but exhibit no outward signs. Fragile X syndrome, the most common form of congenital intel­lectual disability in males, is caused by an excessive number of DNA sequence (CGG) repeats within the FMR1 gene. The protein product of the FMR1 gene, which is important for synapse function, is disrupted by these repeats. While some people with elevated numbers of the sequence repeats may not be affected, they are carriers with a risk of passing it on to their children.

Adapted from the 8th edition of Brain Facts by Susan Rojahn.