As we learn more about the associations between genes and disease, a growing number of diagnostic tests have been developed to detect mutations that increase the risks of various diseases. However, anyone who wants to develop a diagnostic test or a treatment based on human genes faces a potential roadblock: gene patents. A 2005 study [1
] reported that 4,382 human genes (~20% of the total number in our genome) are covered by patents or other intellectual property claims. These patents cover a wide range of methods for assaying the DNA sequence of an individual for the presence of disease-associated mutations. For example, one of the most consequential gene patents covers mutations in the BRCA1
] and BRCA2
] genes, which are associated with a significantly increased risk of breast and ovarian cancer [4
]. The BRCA gene patents, which are held by Myriad Genetics, cover all known cancer-causing mutations in addition to those that might be discovered in the future. No one can develop a commercial diagnostic test or a treatment based on the BRCA gene sequences without a license from Myriad. Although a US federal court recently overturned seven of Myriad's BRCA patents, Myriad is appealing the ruling, and it holds 16 other BRCA-related patents that it claims are unaffected by the court's ruling [7
As the cost of DNA sequencing falls, the idea of testing for mutations one gene at a time is rapidly becoming obsolete. We are also rapidly approaching the day when it will be cheaper to fully sequence a genome before testing the sequence for all known genetic mutations associated with a given disease than to conduct multiple separate tests for each gene. Currently Myriad charges more than $3000 for its tests on the BRCA genes, while sequencing one's entire genome now costs less than $20,000. Furthermore, once an individual's genome has been sequenced, it becomes a resource that can be re-tested as new disease-causing mutations are discovered.
In contrast to whole-genome sequencing, standard methods for identifying mutations in BRCA1
use PCR to amplify the genome regions containing each mutation [8
]. As more mutations are discovered, these tests need to be augmented with additional PCR assays, adding to their cost. The commercial assay available from Myriad Genetics interrogates a limited number of sites by PCR and sequencing, which can miss clinically relevant mutations; for example, a recent study [9
] reported that 12% of women from high-risk families with deleterious mutations in BRCA1
had false negative results from this assay. Even if the test were perfect, a gene-centered approach will be far more expensive over time than a computational assay based on an individual's genome, because the genome only needs to be sequenced once, after which it can be used to test all 22,000+ human genes.
Regardless of how easy it might be to test for mutations, the restrictive nature of the BRCA gene patents means that anyone wishing to examine any mutation in BRCA1 or BRCA2 will have to obtain permission from the patent holder Myriad Genetics. This restriction applies even if testing your own genome. If you wanted to look at other genes, you would have to pay license fees for any of them that were protected by patents. In practice, although it may seem absurd, this means that before scanning your own genome sequence, you might be required by law to pay thousands of license fees to multiple patent holders.
We believe that any individual should be allowed to interrogate his or her genome for all mutations of interest, regardless of whether a private company claims to 'own' the rights to particular gene mutations. To challenge the restrictive gene patenting system, we have developed a computational assay that, as a proof-of-concept, tests for 68 known variants of the BRCA1
genes. In other words, we empower any individual using our software (whether this is a private individual, a clinician or a clinical or basic researcher) to test for these mutations and circumvent the gene patents. Here we demonstrate the method on the publicly available DNA sequence from three human genomes: a Caucasian female, an African male and an Asian male [10
We have made the software freely available (at http://cbcb.umd.edu/software/BRCA-diagnostic
) under an open source license, allowing others to use, modify and redistribute it. The software is flexible and can easily be adapted to search for mutations in other genes. The method uses the raw sequence reads that are produced by a high-throughput sequencer; it does not require genome assembly nor any other processing of the raw data. This software provides a relatively simple, do-it-yourself home testing method for interrogating a genome for the presence of mutations in the BRCA genes. All one needs, besides the software, is the sequence data from an individual human.