The latest map of human genetic variation – dubbed HapMap3 – includes 11 populations from across the globe, identifying not only the single nucleotide polymorphisms (SNPs) or single letter changes in the 3 billion letter alphabet of the human genome but also variations that represent differences in the numbers of copies of genes or gene segments.

Important tool

"This map provides an important tool for future genome-wide association studies of diseases that allows scientists to look for both common and rare variations that may be associated with disease or response to drugs," said Dr. Fuli Yu, assistant professor in the Baylor College of Medicine Human Genome Sequencing Center. The Center played a major role in the sequencing studies that are cornerstones of the report that appears in the current issue of the journal Nature.

HapMap3 researchers determined the genetic sequence of 1.6 million common single nucleotide polymorphisms from 1,184 people from 11 populations around the world, which enabled the researchers to identify copy number variations and other polymorphisms. The "map" also contains the complete sequences of 10 100-kilobase regions in 692 of the individuals, which allowed the first real examination of low frequency variation in diverse populations. This important class of variation is now known to be extremely important in human inherited disease.

BCM role

The BCM Human Genome Sequencing Center played a major role in sequencing the actual DNA from the people who were involved in the project. The Center, under the leadership of Dr. Richard Gibbs, led the project along with the Broad Institute of Harvard and MIT and the Wellcome Trust Sanger Institute.

"The two previous HapMap versions included fewer people," said Gibbs. "This newest version allows us to look at both common and low frequency genetic variation in diverse populations."

The BCM Human Genome Sequencing Center sequenced DNA from 700 people drawn from 10 of the population studies. The expansion of people and populations contributing samples helps researchers better understand the extent of human variation around the globe and advances the goal of a "high-resolution map of the landscape of human genetic variation."

HapMap 3 important to study of disease

Current debate centers around the role played by common and rare genetic variation in human disease. Much of that remains unexplained, said the report's authors.

"The information in this study will prove valuable no matter which theory is true," said Yu. "This study sets the foundation."

Statistically, it gives enough data to allow researchers to use a technique called imputation when they need to predict the effect a genetic variation might have on disease.

"For example, if we can only genotype 70 of 100 SNPs, can this information give us the statistical power to accurately impute the 30 missing genotypes?" he said. "HapMap 3 improves our power to impute the rare genetic variants accurately."

Until it becomes feasible – economically and scientifically – to sequence the whole genomes of individuals, this technique combined with gene chips might offer an approach to understanding the importance of variation among individuals.

Participating groups

Among the populations that took part in the study were northern and western Europeans; Han Chinese in Beijing; Japanese in Tokyo; Yoruba in Ibadan, Nigeria (the groups in the first two HapMap projects); people of African ancestry in the United States southwest; Chinese in metropolitan Denver, Colo.; Gujarati Indians in Houston, Texas; Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; people of Mexican ancestry in Los Angeles, Calif. and individuals in the Tuscany region of Italy.

"This will enable us to characterize the frequency spectrum of polymorphisms across diverse populations," said Yu.

One interesting feature was the discovery that 7 percent of mutations occurred independently in two or more populations. They know this because the groups do not share the same lineage or history.

The International HapMap 3 Consortium authored the report. The majority of the work was supported by the National Institutes of Health, the National Human Genome Research Institute, the National Institute on Deafness and Other Communication Disorders and the Wellcome Trust. Other funding came from the Louis-Jeantet Foundation and the National Centre of Competence in Research Frontiers in Genetics, part of the Swiss National Science Foundation.

Gibbs is the Wofford Cain Professor of Molecular & Human Genetics at BCM.