Consortium publishes phase II map of human genetic variation

The International HapMap Consortium today published analyses of its second-generation map of human genetic variation, which contains three times more markers than the initial version unveiled in 2005. In two papers in the journal Nature, the consortium describes how the higher resolution map offers greater power to detect genetic variants involved in common diseases, explore the structure of human genetic variation and learn how environmental factors, such as infectious agents, have shaped the human genome. The first phase of HapMap is already revolutionising our ability to study the genetic basis of human disease.

Any two humans are more than 99 percent the same at the genetic level. However, it is important to understand the small fraction of genetic material that varies among people because it can help explain individual differences in susceptibility to disease, response to drugs or reaction to environmental factors. Variation in the human genome is organised into local neighbourhoods, called haplotypes, that usually are inherited as intact blocks of information. Consequently, researchers refer to the map of human genetic variation as a haplotype map, or HapMap.

The International HapMap Consortium is a public-private partnership of researchers and funding agencies from the United Kingdom, Canada, China, Japan, Nigeria and the United States. UK researchers played a major role in the HapMap project through genetic typing during the first phase, at the Wellcome Trust Sanger Institute, and much of the analyses of both phases was undertaken at the University of Oxford. The UK has been centrally involved in several other major international research projects into human genetics, including the Human Genome Project, and the Wellcome Trust Case Control Consortium (WTCCC) - one of the largest and most successful studies into the genetic causes of human disease.

The second-generation haplotype map, or Phase II HapMap, contains more than 3.1 million genetic variants, called single nucleotide polymorphisms (SNPs) - three times more than the approximately 1 million SNPs contained in the initial version. The more SNPs that are on the map, the more precisely researchers can focus their hunts for genetic variants involved in disease. The rapid growth of genome-wide association studies over the past year and half has been fuelled by the HapMap consortium's decision to make its SNP datasets immediately available in public databases, even before the first and the second versions of the map were fully completed.

Researchers around the globe have now associated more than 60 common DNA variants with risk of disease or related traits, with most of the findings coming in the past nine months. In the UK, for example, the WTCCC looked at 14,000 cases and 3,000 shared controls, finding more than 20 variants associated with increased risk of a number of diseases, including coronary artery disease, Crohn's disease, rheumatoid arthritis, type 1 diabetes and type 2 diabetes. In June this year the WTCCC published their findings in the journal Nature, which led to a great deal of media interest from around the world.

The University of Oxford was the only British university selected to be involved with the HapMap project. 'We are thrilled that the worldwide scientific community is taking advantage of this powerful new tool and we anticipate even more exciting findings in the future,' says Professor Gil McVean of the University of Oxford's Department of Statistics and Wellcome Trust Centre for Human Genetics, who co-led the analysis of Phase II HapMap and is one of two corresponding authors on the paper. 'The improved SNP coverage offered by the Phase II HapMap, along with better statistical methods, promises to further increase the accuracy and reliability of genome-wide association studies.'

One of the co-chairs of the analysis group, Professor Peter Donnelly, FRS, Director of Oxford University's Wellcome Trust Centre for Human Genetics, said: 'Understanding the differences between people's genomes, and why those differences exist, is at the core of many questions in modern biomedical research. The HapMap project has transformed this area of research, giving new insights into areas as diverse as why some people are more susceptible to disease, and our evolutionary history.'

The Phase II HapMap was produced using the same DNA samples studied in the Phase I HapMap. That DNA came from blood collected from 270 volunteers from four geographically diverse populations: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Han Chinese in Beijing; and Utah residents with ancestry from northern and western Europe. No medical or personal identifying information was obtained from the donors, but the samples were labelled by population group.

To provide information on less common variations and to enable researchers to conduct genome-wide association studies in additional populations, there are plans to extend the HapMap even further. Among the populations donating additional DNA samples are: Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Tuscans in Italy; Gujarati Indian in Houston; Chinese in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States.

In its overview paper in Nature, the consortium estimates that the Phase II HapMap includes 25 to 35 percent of common genetic variation in the populations surveyed. The consortium also confirmed that use of Phase II HapMap data has helped to improve the coverage of various commercial technologies currently being used to identify disease-related variants in genome-wide association studies. Researchers did note, however, that current technologies tend to provide better coverage in non-African populations than in African populations because of the greater degree of genetic variability in African populations.

The overview paper also reports that the Phase II HapMap has provided new insights into the structure of human genetic variation. One new finding was the surprising extent of recent common ancestry found in all the population groups. Taking advantage of the map's increased resolution, the researchers identified stretches of identical DNA between pairs of donor chromosomes and then compared these stretches both within and across individuals. Their analysis showed that 10 to 30 per cent of the DNA segments analysed in each population showed shared regions, indicating descent from a common ancestor within 10 to 100 generations.

In addition, the new map enabled researchers to quantify more precisely the rates of shuffling, or recombination, seen among different gene classes in the human genome. In their overview paper, researchers report that recombination rates vary more than six-fold among different gene classes. The highest rates of recombination were found among genes involved in the body's immune defence, while the lowest rates appear among genes for 'chaperones,' which are proteins that play a crucial role in making sure other proteins are folded properly. In general, genes that code for proteins associated with the surface of cells and external functions, such as signalling, were found to be more prone to recombination than those that code for proteins internal to cells.

While the reasons for the varying recombination rates remain to be determined, the findings pose interesting evolutionary questions. In their paper, researchers suggest that one explanation may be that some recombinations in areas of the genome that affect responses to infectious agents or other environmental pressures may be selected for because they provide a survival advantage.

A related study appearing in the same issue of Nature describes how the enhanced map can help pinpoint pivotal changes in the human genome that arose in recent history. These changes, now common among various populations worldwide, became prevalent through natural selection - meaning they were somehow beneficial to human health. Although these DNA variants may still be important, their biological significance remains largely unknown.

'Human history and the genome have been dramatically shaped by environmental factors, diet and infectious disease,' said co-first author Pardis Sabeti, PhD, who is a postdoctoral fellow at the Broad Institute of MIT and Harvard. 'The gene variants identified in our study open new windows on these evolutionary forces and provide a launching point for future biological studies of human adaptation.'