New chapter for HapMap

Image by Broad Institute Communications Group

Genetically, humans differ from one another by less than one percent, but understanding that small fraction promises to unlock the genetic factors that contribute to disease risk. In a landmark 2005 paper, researchers unveiled an initial genome-wide survey of human genetic variation, creating a so-called haplotype map, or HapMap. Nearly two years to the day after the first map was revealed, the second phase of this effort is now complete, yielding an even denser map that contains three times more markers than the initial version. That gives researchers a better tool to detect genetic variants that contribute to common diseases, explore the structure of human genetic variation, and learn how environmental factors have shaped the human genome.

The new analyses, published in the October 18 issue of Nature, were led by the International HapMap Consortium, a public-private partnership of researchers and funding agencies from Canada, China, Japan, Nigeria, the United Kingdom, and the United States. Scientists from the Broad Institute of MIT and Harvard are among the HapMap’s many contributors and leaders. These include researchers in the Broad’s Genetic Analysis Platform, led by platform director Stacey Gabriel, and the Program in Medical and Population Genetics, led by program director David Altshuler, who is also an associate professor at Harvard Medical School and Massachusetts General Hospital (MGH). Mark Daly, an assistant professor in the Center for Human Genetic Research at MGH and a Broad associate member, is one of the paper’s two corresponding authors.

The human genome contains roughly 10 million common genetic variations that involve a single letter change, known as a single nucleotide polymorphism, or SNP. These differences travel in chunks, so that nearby SNPs on the same chromosome are inherited together in blocks known as haplotypes. The HapMap, which demarcates which SNPs occur in which haplotypes, enables more efficient studies of genetic variation by reducing the number of bases that must be analyzed. The second phase HapMap springs from analyses of DNA samples from the same 270 volunteers who contributed to the project’s first phase. These individuals represent four worldwide populations: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Han Chinese in Beijing; and Utah residents with northern and western European ancestry.

While the first edition HapMap identified one SNP per 5,000 bases of DNA, the second phase HapMap pinpoints three times that many, totaling over 3 million polymorphisms. Containing an estimated 25 to 35 percent of common SNP variation in the populations surveyed, the higher resolution map enhances the statistical power of genome-wide association studies, which attempt to link SNPs to common diseases such as type 2 diabetes, cardiovascular disease, and prostate cancer.

Because the results from the first and second phases of HapMap analyses were made immediately available, researchers around the globe were able to rapidly put them to use and have associated more than 60 common DNA variants with risk of disease. At the Broad Institute, scientists are using the HapMap to help identify genetic variants associated with a growing list of conditions that already includes type 2 diabetes, inflammatory bowel disease, and multiple sclerosis.

“The original HapMap provided the backbone for genome-wide association studies that have uncovered previously unsuspected genetic components of many diseases, leading to new areas of research,” says Mark Daly, co-senior author of the report, Broad senior associate member, and assistant professor at Massachusetts General Hospital. “The second phase has tripled the amount of genetic variation assessed and describes up to 95 percent of common single-letter variations in the human genetic code.”

In addition to facilitating whole genome studies, the new analysis uncovers some interesting findings about human evolution. The consortium reported a surprising extent of recent common ancestry found in all four population groups studied. Roughly 10 to 30 percent of the DNA segments analyzed in each population showed shared regions, indicating descent from a common ancestor within 10 to 100 generations.

The researchers also found that rates of genetic shuffling, or recombination, varied more than six-fold among different gene classes. Rates of recombination were highest among immune system genes and lowest among genes for chaperone proteins, which function to help other proteins fold properly. As suggested by the researchers, one explanation for the variation may be that recombination in genes affecting responses to infection or environmental pressures provide a survival advantage.

In a companion paper in Nature, a research team led by Broad Institute scientists describes how the second phase HapMap can help pinpoint key changes in the human genome that arose in recent history. These changes, now common among various populations worldwide, became prevalent through positive natural selection – meaning that they were somehow beneficial to human survival.

Data from the dense second phase HapMap revealed hundreds of genomic regions that carry signs of recent positive natural selection. These regions are large, often extending for millions of nucleotides and including multiple genes. To focus their search, the researchers developed computational guidelines to locate the single letter changes that influenced evolutionary change.

Several intriguing genetic variations were uncovered that may reveal insights into the influence of biology on natural selection in humans. These include changes in EDAR and EDA2R genes which are common in Asian populations and which help form hair follicles and sweat glands, as well as other structures. Among African populations, variations in LARGE and DMD genes may play a role in viral entry into cells and could be linked to resistance to Lassa fever, a viral infection common in Western Africa.

The findings underscore one of the study’s key themes – that multiple genes, acting together in the same biological process, often show signs of positive selection, both in humans and other organisms. These findings may bolster efforts to understand the biological consequences of human genetic variation.

“Human history and the genome have been dramatically shaped by environmental factors, diet, and infectious disease,” said co-first author Pardis Sabeti, who is a postdoctoral fellow at the Broad and will join Harvard University as an assistant professor of systems biology and organismal and evolutionary biology in January 2008. “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.”