International consortium completes most important genetic map since the Human Genome Project

27 October 2005

The International HapMap Consortiumwww.hapmap.org published a comprehensive catalogue of human genetic variation today, a landmark achievement that is already accelerating the search for genes involved in common diseases, such as asthma, diabetes, cancer and heart disease. Oxford is the only British university to be involved in the project, and is one of just two UK institutions involved (the other being the Wellcome Trust Sanger Institute).

In the 27 October edition of Nature www.nature.com,more than 200 researchers from Canada, China, Japan, Nigeria, the United Kingdom and the United States describe the initial results from their public-private effort to chart the patterns of genetic variation that are common in the world’s population. Their findings show that the search for clinically relevant genes can be simplified – and hence dramatically hastened – by using the map of variation developed by the HapMap Project.

At the project’s outset in October 2002, the consortium, which includes Oxford University Professors Peter Donnelly (Department of Statistics) and Lon Cardon (Wellcome Trust Centre for Human Genetics), set an ambitious goal of creating a human haplotype map, or HapMap, within three years. The Nature paper marks the attainment of that goal with its detailed description of the Phase I HapMap, consisting of more than one million markers of genetic variation, called single nucleotide polymorphisms (SNPs, pronounced ‘snips’). The consortium is also nearing completion of the Phase II HapMap that will contain nearly three times as many markers as the initial version and will enable researchers to focus their gene searches even more precisely on specific regions of the genome.

Any two unrelated people are 99.9 per cent identical at the genetic level. However, it is important to understand the 0.1 percent difference because it can help explain why one person is more susceptible to a disease or responds differently to a drug or an environmental factor than another person.

The HapMap shows the boundaries of neighbourhoods of correlated genetic variation, or haplotypes, across the entire human genome. With these haplotypes defined, HapMap provides an efficient method for choosing ‘tag SNPs’ that capture the genetic variation in each neighbourhood with a minimum amount of work. By using HapMap data to compare the SNP patterns of people affected by a disease with those of unaffected people, researchers can survey genetic variation across the whole genome and identify genetic contributions to common diseases far more efficiently than is possible with traditional approaches.

Gene hunters around the world have been quick to recognize the potential of the HapMap, tapping into its publicly-available data even before the first draft of the map was completed. For example, in studies published in March in Sciencewww.sciencemag.org, scientists used HapMap data to uncover a genetic variation that substantially increases the risk of age-related macular degeneration, the leading cause of severe vision loss in the elderly.

In addition to assisting in the identification of genetic factors involved in disease, the HapMap can help to pinpoint genetic variations that may affect people’s response to medications, toxic substances and environmental factors. Such information can be used to help doctors prescribe the right drug in the right dose for each patient, as well as recommend prevention strategies that take into account individuals’ varying responses to environmental factors such as diet.

On top of its intended function as a resource for studies of human health and disease, the Phase I HapMap has yielded fascinating information about the process of genetic inheritance. Genetic diversity in humans is increased by recombination, which is the swapping of DNA from the maternal and paternal lines. Oxford-led research has found that in humans, most such swapping occurs primarily at a limited number of ‘hotspots’ in the genome. By analyzing the HapMap data, the Oxford researchers have produced a genome-wide inventory of where recombination takes place www.admin.ox.ac.uk/po/news/2005-06/oct/26.shtml, published in Science www.sciencemag.org .This will enable more detailed studies of this fundamental property of inheritance, as well as serve to improve the design of genetic studies of disease.

Professor Peter Donnelly from Oxford’s Department of Statistics, one of two corresponding authors on the HapMap report, said: ‘This report describes a remarkable step in our journey to understand human biology and disease. The human genome sequence provided us with the list of many of the parts to make a human. The HapMap provides us with indicators – like Post-It notes – which flag areas to focus on in looking for genes involved in common disease.

‘The HapMap also provides unparalleled information about the targets of natural selection in the genome, and about the process of recombination, by which DNA from both our parents is combined and shuffled when we pass it on to our children.’

As was the case with all of the data generated by the Human Genome Project, HapMap data are being made swiftly and freely available in public databases.

Details on the project’s scientific design and rationale, and frequently asked questions on the science behind HapMap www.genome.gov/11511175

More information on the ethical, legal and social implications of the International HapMap Project www.genome.gov/17015413

Complete list of participating research organizations and funders www.genome.gov/17915414