These days, most genetic tests are based on looking at the DNA code, but there was a time when this was not the case. Until a few decades ago, the concept of investigating someone’s genes to determine whether they were predisposed to a particular disease was still unheard of. This blog post describes the development of the very first DNA-based genetic test for a hereditary disease, the Huntington’s Disease test.
Genetic testing before DNA-based testing
In the mid-1960s, the genetic code was decyphered, linking each combination of three bases (letters in DNA) to an amino acid. It is this knowledge of the genetic code that forms the basis of many of our current DNA tests. Before this, testing for some hereditary diseases did exist, but those tests didn’t use DNA. Instead, they detected certain proteins or other markers in the blood that would only show up for certain conditions.
To move from these early tests to DNA-based genetic testing, we needed more information about the genetics underlying disease. Our modern genetic tests are possible because we know a) which gene is linked to a disease, b) where to find that gene in the genome and c) which genetic variants of the gene occur in people with the disease.Since the Human Genome Project in the early 2000s, we now know where all human genes are located. In the 1970s, we did not. Trying to map a gene – to find its location on the genome – was impossible at the time. But new techniques were on the horizon, and in 1983, the gene for Huntington’s Disease was the first disease gene to be mapped.
Huntington’s Disease is a neurodegenerative disease, affecting movement, personality, and cognitive function. Patients usually start showing symptoms as adults, and the disease progresses over time. It’s named after George Huntington, who first described the disease symptoms in 1872. He recognised that the disease was inherited as an autosomal dominant condition. That means that one copy of the disease-linked gene variant is enough to cause Huntington’s Disease, and children of affected individuals have a 50% chance of inheriting the disease-causing variant. Because of the late onset of the disease, many patients already had children by the time they were a diagnosed.
Nancy Wexler’s mother was diagnosed with Huntington’s Disease in 1968. It ran in her family. Her grandfather and uncles were also affected. Inspired to find a solution, Wexler’s father founded the Hereditary Disease Foundation (HDF) to support research into the disease. At the time her mother was diagnosed, Wexler was studying for a PhD in clinical psychology, but after becoming involved with her father’s foundation, she developed an interest in genetics research. Wexler was determined to find the genetic cause of her mother’s condition.
Mapping the Huntington’s Disease gene
In 1979, at one of the HDF’s very collaborative meetings, Nancy Wexler proposed using restriction fragment length polymorphism (RFLP) to try to locate the Huntington’s Disease gene. This technique was new at the time, and provided some information on the difference in DNA between two people. To use this method to map the Huntington’s Disease gene would require a very large number of patient samples. Luckily, Wexler had just that. She had visited a community in Venezuela where Huntington’s Disease affected a large number of people.
Over the next years, researchers collected thousands of blood samples from the affected Venezuelan families. In 1983 James Gusella finally found the location of the Huntington’s Disease gene on chromosome 4. They now also had a genetic marker for the disease. This could be used to distinguish family members who would develop the disease from relatives who would not.
A genetic test for Huntington’s Disease
Huntington’s Disease was the very first human disease gene to be mapped, and genetic tests were available soon after. Since the mid-eighties, relatives of Huntington’s Disease patients have been able to get tested to find out if they carry the marker for the disease-linked variant. But the sequence of the gene was still not known at this point! It took until 1993 for the full sequence of the Huntingtin (HTT) gene to be identified, including the “CAG repeats” associated with the disease. The same year, Nancy Wexler won a Lasker Award for her work.
Rapid progress in genetic testing
It took three years to find the location of the Huntington’s Disease gene, and another ten years to learn the full genetic sequence. Another ten years after that, the full sequence of the human genome was finalised. Now we know where all the genes are, and discovering genes linked to disease and developing genetic tests for them is much quicker.
However, knowing the location and sequence of a gene is only one of the steps required. To determine whether someone’s DNA predisposes them to a certain disease also requires knowing which genes are linked to which diseases, and which genetic variants in those gene cause those diseases. We are making rapid progress in these areas, but there is still work to be done. And we are still only at the beginning of using the knowledge to development treatments and cures for genetic diseases. This is likely to be where the most exciting advances happen over the next decades.
Image: CAG repeats in the Huntington’s Disease gene (by NIGMS/NIH, via Wikimedia Commons.)