Over the past decade, pioneering mutation hunter Prof Richard Cotton has seen international mutation databases expand rapidly, become more diverse, and increasingly frustrating to use.
The founder and director of the Genomic Disorders Research Centre (GDRC) in Melbourne says that geneticists and clinicians around the world have collected a host of single nucleotide polymorphisms (SNPs) along with many overt mutations that, in many cases, have been detected with the innovative base-pair mismatch detection techniques he invented.
“But we don’t have much in the way of biology—a way of connecting the SNPs to [phenotypic] variation,” Cotton says. “One of the great things about SNP-ing is understanding the effects of each variant, through association studies, but many are never published.
“At the moment we have a whole lot of well-meaning but disparate expert studies, but they’re uncoordinated. We need coordinated research and consistent collection and recording of the data.
“There is a large literature from which we can collect data, but much of it is either wrong or incomplete, or large amounts of data remain unpublished.
“We have to give researchers incentives to collect them—they need to get a publication out of it, and a PubMed ID. We need to encourage diagnostic labs around the world to put mutations into databases, where it becomes useful to others.
“Perhaps we could make publication a condition of licensing. We need sticks as well as carrots, and the people I’ve discussed it with don’t find these ideas too outrageous.”
In an effort to bring order to the field, Cotton has organized The Human Variome Project Meeting in Melbourne, from June 20-23, at Melbourne’s Park Hyatt Hotel. The major sponsors are the GDRC, the World Health Organization and the American Association of Clinical Geneticists.
The Human Genome Project delivered a template against which all human genetic variation can be compared. The Melbourne meeting will formally initiate the Human Variome Project (HVP), an attempt to identify and record all human genetic variation relevant to common and rare genetic disorders, and drug side effects.
Cotton says that, currently, an Australian clinician who encounters a novel SNP or mutation associated with a familial disorder may be unaware that other cases have been identified and treatments developed elsewhere in the world—the information may not have been recorded, or finding it may involve frustrating hours of research on the web because it is scattered across multiple sites, and is not in a consistent format.
To address the problem, he has invited 55 of the world’s leading bioinformaticians, clinical geneticists, researchers, database curators, diagnostic laboratory heads, common disease-variation experts, and representatives of each the World Health Organization’s administrative regions.
“We’ve tried to get all the top people in the field, and the stakeholders,” Cotton says. “We hope that the meeting will affirm the name ‘Human Variome Project’, and the need for such a global body.” Another outcome might be an international committee, representing all stakeholders, to coordinate the project.
Cotton hopes the HVP will create a single, international database that will provide researchers and clinical geneticists with complete, accurate information on SNPs and mutations, linked to phenotype data from association studies. He envisages that governments and research funding agencies will also use the database.
“We already have an initiative for a pharmacogenetics network—a representative of the network will be at the Melbourne meeting,” Cotton says.
“We’ve got the two top people working on SNP databases, very senior clinical geneticists. It would be very interesting, if you sequenced every human on the planet, to see what percentage of the three billion bases in the human genome varied. I don’t think it has ever been attempted.
“The data are out there, and growing, but I don’t believe anyone has tried to collect all human variation in a systematic way, and make it available online—it’s an enormous task. We’re looking for coordination, consistency and a set of rules for recording it.
“Some of the information is interesting to other fields of research—before people began studying mitochondrial and Y-chromosome DNA, rare inherited diseases were used to trace the movement of different ethnic groups around the world.”
Below the Radar
Cotton says only a minority of estimated 24,000 human genes—around 2000—have so far been implicated in genetic disease. Yet more than 1000 mutations have been identified in just one gene—the cystic fibrosis gene.
“The current estimate is that 60 per cent of individuals will be affected by a mutation during their lifetimes, excluding mutations involved in cancer,” he says.
“That means several billion people worldwide have been, or will be affected. Why hasn’t this been noted? Because many of the diseases are so rare that they’re hardly noticeable.
“One of the most difficult things with breast cancer or colon cancer genes is to work out whether a mutation is pathogenic or not.
“Ten per cent of any disease is genetic, but there are also a host of sporadic and familial genetic disorders that involve interactions between normal alleles of genes and the environment.”
For more on the Human Variome Project, see www.humanvariomeproject.org