Biomedicine

Gene Hunting in Canada

Genizon is using the genetic homogeneity of French Canadians to find new drug targets – and redefine human disease.

In the 17th century, 15,000 French immigrants bravely made their way to eastern Canada. Some headed further west, many returned to France, but a hardy few stayed in Quebec. Starting with a total of just 2,600 people between 1608 and 1760, this group would grow 800-fold over the next 10 or so generations, with little marriage outside the group. The result is the Quebec “founder” population – a genetically homogenous group of individuals that is ideally suited to the genetic study of disease.

Geneticists have long taken advantage of founder populations – so named because only a few ancestors founded the entire population – such as the Ashkenazi Jews and Icelandic people. Members of these groups share long stretches of DNA, which simplifies genetic studies of disease by reducing the background noise of other genetic variations.

Today’s best-known gene-hunting company, deCODE genetics, an Icelandic gene and drug discovery company, has identified genes for diabetes, heart disease, and asthma within the small Icelandic population. Now a biotech company, Genizon BioSciences, is finding similar success with the French Canadians of Quebec. Based in Quebec, the company is taking advantage of new advances in genomics to find disease genes that have been hard to detect with other methods.

[To see some of the genetic studies work by Genizon, click here.]

Gene-hunting studies have traditionally focused on families in which some members are afflicted with a disease, a technique known as linkage analysis. Because families share so much DNA, scientists can survey the genome in relatively few spots to find a region that looks different in those with the disease. This technique is efficient at identifying genes that play a large role in rare diseases because it is easy to identify those individuals with the disease.

Identifying genes for common diseases, however, such as diabetes, in which many genes are likely to play a small role, has been more difficult. Because different genes may contribute to the disease in different family members, such an analysis requires larger numbers of people than are available in family-based studies. DeCODE has had success identifying genes involved in common diseases because Iceland has extensive genealogy records and a much larger population than a typical family study.

To study large groups of unrelated people, scientists must survey many more spots on the genome, a technique known as whole genome association. The size of these studies provides greater statistical power, meaning that researchers can identify genes that play a smaller role in common diseases. Such studies are becoming more common as genotyping technologies become faster and cheaper and resources – such as the HapMap, a recently published database of human genetic variation – enable scientists to survey only the most crucial chunks of DNA.

Genizon has spent the last five years refining this whole genome approach. The company is now studying 20 different diseases – including Crohn’s disease, asthma, schizophrenia, and diabetes – and it hopes to develop new drugs that target the genes they uncover.

Researchers at Genizon started out by building a genetic map, much like the HapMap, but unique to the Quebec founder population. Their map uses strategically placed genetic markers so that scientists can look for genetic changes in areas they know have lots of genetic change, while ignoring the areas that tend to remain the same. Because the Quebec founder population is more genetically homogenous than the general population, scientists can do genome-wide association studies with fewer markers, and thus greater speed.

The initial Genizon map, completed in 2004, was created from 1,500 members of the Quebec founder population and had about 81,000 markers. Genizon has now improved its gene hunting capabilities even further, by using a gene chip produced by Illumina, a genetic toolkit company in California, which incorporates markers from both the HapMap and original Quebec map, for a total of more than 350,000 markers per individual. Studies that initially took scientists three months now take just a week, says John Hooper, president and chief executive officer Genizon.

To uncover genetic variants that increase risk for a disease, scientists start with DNA from patients and use the gene chips to sift through the markers, searching for particular variants that appear more frequently in people with the disease. Once scientists have identified genes of interest, they create a map of the interacting genes.

“That gives us a picture of the biochemical pathways involved in the disease,” says Tim Keith, chief scientific officer at Genizon. “We can compile all the mechanisms that lead to development of the disease, which allows you to look at the best point of intervention for new therapeutics.”

Genizon has already made such maps for psoriasis, a chronic skin disease, and Crohn’s disease (an inflammatory bowel disease). Their analysis confirmed some biochemical pathways know to be involved in Crohn’s disease, such as inflammation. But it also identified some unexpected biochemical players that might give new insight into the roots of the disease.

“We identified new pathways that could potentially lead to a paradigm shift in drug development,” says Hooper. Because Genizon is seeking patents on these targets, Hooper declined to elaborate on the new targets.

The company is quickly moving down its list of diseases. Scientists have already completed preliminary analysis on the gene hunt for baldness, schizophrenia, and longevity, and are gearing up to do studies on Attention Deficit Hyperactivity Disorder, Type II diabetes, osteoporosis, and macular degeneration.

Stay tuned for a Q&A with Kari Stefansson, CEO of deCODE, later this week.

Home page image courtesy of Genizon BioSciences.

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