Human Variome project gets underway

Amid the international media fanfare that greeted the first draft of the Human Genome in 2001, an inconvenient problem was largely ignored. Geneticists had already collected a huge volume of information on errors in the human genetic code and their role in hereditary single-gene disorders.

Hundreds of alleles of genes - both common and rare - had been associated with susceptibility to a litany of common health problems: cancers, heart disease, diabetes, hypertension, neurodegenerative disorders and psychiatric illnesses like bipolar disorder and schizophrenia.

But much of this information was not readily accessible to clinicians or researchers investigating diseases of genetic origin. It was strewn cross an immense and burgeoning research literature, or recorded idiosyncratically in databases whose developers had not thought of the big picture. There was no universal gateway, little interoperability and no standardised template for researchers and clinicians to record or annotate their discoveries. Babel ruled.

Professor Dick Cotton, founder and director of the Genomic Disorders Research Centre (GDRC) in Melbourne, founder of the leading international journal Human Mutation and pioneer in the field of chemical detection of mutations, watched it all happening, with growing dismay and frustration.

He had been thinking about the problem since he took sabbatical leave at Oxford University in 1985-86. By the time Cotton founded Human Mutation in 1992, most of his peers agreed with the need to establish an international database to record all human genetic variation - both mutations and gene polymorphisms.

Agreement was one thing; organising it was another. It would take another frustrating decade of effort before international support for the project began to coalesce.

Standing ovation

In Melbourne last month, 55 eminent researchers gave Cotton a standing ovation at the end of the reporting session of the first international planning meeting for what will be known as the Human Variome Project (HVP), a logical and essential sequel the Human Genome Project.

"It was a little embarrassing, but I felt good about it," Cotton said. "It's been a huge battle. "It was a wonderful meeting that produced amazing consensus. Everyone agreed on the need for a Human Variome Project, and that it was timely.

"All the central database developers were excited about being included. We've had great enthusiasm from organisations interested in funding the database, like the March of Dimes in the US, and the European Commission."

Professor Richard Gibbs of the Baylor College of Medicine in the US, said: "I don't know why this projected wasn't considered as a component of the Human Genome Project - it was a natural successor to it."

Cotton said he was particularly pleased that delegates to the meeting endorsed his proposed name for the project - nobody demurred after his GRDC colleague and meeting coordinator Heather Howard suggested it would be strategically wise to call it 'The Human Variome Project' meeting. "People at the meeting realised it's a natural name," he said.

He predicted it would be another five years before all the required components of the HVP are organised and operating efficiently and gathering information about all known human variation.

"After that, it will be fairly automated and template-driven," he said. "At the moment medicine is chugging along looking at genetic variation involved in disease. The HVP will record all normal human genetic variation as well.

"We envisage that this project will run virtually forever, or at least until all variation has been described in all 23,000 human genes, and in intergenic DNA.

He said that, like the Human Genome Project, the HVP will initially provide a core of information that will allow a clinician in Australia or Canada, for example, to look up a mutation originally identified in Finland, and determine what effect it has on their patient.

"There's so much international migration today that, if a Maori patient visits a clinician in New York with a health problem with a particular set of symptoms, he'll know what mutations to look for."

Personalised medicine

Although it was not its primary objective, the Human Variome Project will be a powerful resource for the coming revolution in personalised medicine.

Cotton said it could eventually be a powerful resource for investigating human evolution and migration in prehistoric and recent times. Already, some nations or ethnic groups were considering their own projects - the Arab states, for example, are organising an Arab Variome Project.

The original Human Genome Diversity Project, conceived by former Stanford geneticist Professor Luca Cavalli-Sforza, probably failed because it was not sufficiently inclusive.

Cotton said it was fitting that the Human Variome Project would be coordinated from the GRDC in Melbourne.

An example of the way the HVP database will assist research is current work by GRDC researchers Matthew Law and Gregor Berger to identify SNPs that may be associated with susceptibility to schizophrenia.

Law and Berger are testing the lipid hypothesis of schizophrenia, which proposes that schizophrenia in same cases is due to rare variants of genes involved in arachidonic acid metabolism. Arachidonic acid is one of the lipid components of neuronal membranes in the brain.

They are screening tissue samples from schizophrenic brains with variants in today's web-based mutation databases, and have preliminary evidence for arachidonic acid involvement.

Cotton said they now require more examples from clinical studies of rare SNPs within the dozens of genes involved in transport and breakdown of arachidonic acid.