- Venezuelan adventures: the isolation of the Huntington's gene
- Ethnicity, religion, and the gene-hunting companies
- The biggest pedigree of all: deCODE genetics and the Icelandic population
- How many disease genes are there?
Ethnicity, religion, and the gene-hunting companies
As Nancy Wexler's Venezuelan pedigree for Huntington's chorea shows, certain populations are particularly suitable candidates in the search for disease genes. For example, Mormons are a favorable population for the discovery of new disease genes. Mark Skolnick, a University of Utah scientist, realized this many years ago when he became interested in the genetics of breast cancer. In 1991, he was one of the founders of Myriad Genetics of Salt Lake City, Utah, and is currently the chief scientific officer of the company.17
Utah's Mormon population was established in the 1840s. Its founders were often polygamous, had large families, and seldom moved. Mormons also marry young so the time span between generations is relatively short. Furthermore, they keep meticulous genealogical records and Myriad Genetics has the rights to these records. As a result, the company has been involved in the identification of the two genes involved in 80% of hereditary breast cancer cases (BRCA1, BRCA2) as well as genes important in prostate cancer, colon cancer, melanoma, and also genes disposing individuals to risks other than cancer. The company has developed predictive tests for these genes. Their gene-searching technology is especially useful for such cancer genes because, in addition to having available a computerized genealogy of Mormon pioneers and their descendants, the company can access the Utah Tumor Registry. The registry has required that a record be kept of every cancer occurring in the state since 1973. Using these tools in combination has proved a powerful way of finding tumor genes.
The molecular diagnostic products marketed by Myriad Genetics are "designed to analyze genes and their mutations to assess an individual's risk for developing disease later in life or a patient's likelihood of responding to a particular drug, assess a patient's risk of disease progression and disease recurrence, and measure a patient's exposure to drug therapy to ensure optimal dosing and reduced drug toxicity."18 Myriad's molecular diagnostic revenues in 2009 were $326.5 million, a 47% increase over the previous year. One reason for this profitability is that Myriad is currently the exclusive provider of tests for the BRCA1 and 2 genes, which are protected by patents. These patents, which are under legal challenge (Chapter 5, "Genes and cancer"), prevent gene-testing companies like 23andme or deCODE genetics from offering tests for these genes, although they do offer tests for other potential genetic risk factors for breast cancer. This is a potential source of confusion for the uninitiated because these companies assess some, but not all, of the potential breast cancer genetic risk. This is why it is of critical importance for people sending off a saliva or cheek swab sample to a gene-testing company to consult with professionals who can inform them as to exactly what the tests will and will not tell them.
One advantage the Mormon population lacks for gene hunters is that, unlike the Amish, it is not inbred.19 Although Brigham Young founded Salt Lake City in July 1847 with around 2,000 followers, colonization proceeded rapidly so that by 1890, when most immigration into Utah had ended, there was a total population of 205,889, of whom about 70% were Mormons. They included a great many Mormon converts who frequently came from Great Britain and Scandinavia.
Certain populations benefit the gene hunter by originating from small founding populations. Just by chance, this sometimes means that a deleterious gene may be amplified in the founding population as compared with the population from which it was derived. For example, Tay-Sachs is a common genetic disease among Ashkenazi Jews. Suppose you have a settlement containing 100 couples (excluding children for the purpose of the example) giving a population of 200. Suppose that 10 individuals are carriers of the gene. This yields a carrier frequency of 5%. If 10 couples from the original population decide to form a new settlement and, by chance, they include the 10 carriers, the frequency of carriers rises to 50%. This is the founder effect and accounts for the high frequency of some genetic diseases among certain populations (see Chapter 3, "Ethnicity and genetic disease").
When such a population can be identified and has remained relatively homogenous, it becomes an attractive target for a gene-hunting company. At the Genome 2001 Tri-conference held in San Francisco in March 2001, Phillipe Douville, Vice President and Chief Business Officer of Galileo Genomics Inc. of Montreal, remarked that the "main recognized founder populations in the world are those of Quebec, Finland, Sardinia, Iceland, Costa Rica, the northern Netherlands, Newfoundland, and several discrete ethnic groups including the Ashkenazi Jews."20
In fact, it was the population of Quebec that Galileo, now called Genizon BioSciences, planned to focus on. About 15,000 French settlers arrived in eastern Canada in the course of the seventeenth century.21 Around 2,600 of these hardy souls made their way to Quebec. This population has expanded 800 times over the ten generations since, with intermarriage within the group predominating. Thus, the Quebec founder population is relatively homogenous. Genizon BioSciences claims to have over 47,000 subjects in its biobank, 95% of whom have authorized the company to contact them again.22 Genizon has research teams investigating eight complex conditions, including Alzheimer's disease, obesity, and schizophrenia by means of genome wide association studies. The company hopes to identify specific patterns of genetic variation that correlate with these conditions and, ultimately, to tie each condition to specific genetic markers (see Chapters 3 and 4 for a fuller discussion).
Gene hunting can be an expensive and unprofitable business. It is usually supported for a while by grants, contracts, venture capital, and deep-pocketed drug companies, but, eventually, it must be profitable. The fate of IDgene Pharmaceuticals Ltd., a Jerusalem genomics start-up founded in 1999, shows what can happen when the path to profitability is not achieved soon enough.
The founder effect, coupled with homogeneity and inbreeding, means that the Ashkenazi Jews are favorable material for the discovery of new disease and susceptibility genes. Hence, IDgene Pharmaceuticals' goal was to search for disease genes among the Ashkenazim.23 Suitable patients with major chronic ailments that had four Ashkenazi grandparents were asked to donate a single blood sample for genetic testing. Written consent was required and the results were kept anonymous. Israeli Ashkenazi Jews suffering from asthma, type 2 diabetes, schizophrenia, Parkinson's disease, Alzheimer's disease, breast cancer, and colon cancer were studied. Using this method, the company's president, Dr. Ariel Darvasi, and colleagues reported strong genetic evidence supporting the hypothesis that a gene called COMT encoding an enzyme involved in the breakdown of certain neurotransmitters is involved in schizophrenia (see Chapter 6, "Genes and behavior").24 But, subsequently, IDgene failed to raise sufficient capital to continue in operation and closed down in 2004.25