Investigators from six countries have completed the second phase of the International HapMap Project, an effort to identify and catalog genetic similarities and differences among populations around the world. Information provided in the first phase of the HapMap, completed in 2005, has led to the development of techniques facilitating the search for genes associated with common diseases -- such as schizophrenia and heart disease -- and the identification of more than 50 such disease-associated genes.
In the past year, using data and methods based on the HapMap, MGH researchers have published new genetic contributors to conditions such as type 2 diabetes, Crohn's disease, elevated blood cholesterol, rheumatoid arthritis, multiple sclerosis, and prostate cancer. These studies and many others used a suite of analytical methods developed at MGH and its partner institutions.
"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, PhD, of the Massachusetts General Hospital (MGH) Center for Human Genetic Research, co-senior author of the report in the Oct. 18 issue of Nature. "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."
While the Human Genome Project confirmed that the more than 3 billion "letters" of DNA in each human were 99.9 percent identical, analyzing the small fraction that differ -- including about 10 million distinct, single-letter variations, also called SNPs -- remained a daunting task. In 2001 Daly and colleagues showed that adjacent DNA variations are inherited together in segments called haplotypes, with the boundaries between adjacent segments defined by locations of enhanced recombination -- the shuffling of DNA segments between the chromosomes inherited from each parent. Based in part on those findings, the HapMap project was started to create a map of SNPs and haplotypes across the genomes of 270 individuals from Nigeria, China, Japan and the U.S. While the first phase identified and cataloged about 1.3 million SNPs, the second phase has brought the total to more than 3.1 million SNPs catalogued in the same population.
"The increased density of identified SNPs in the second phase has allowed us to much more specifically understand the nature of these recombination 'hotspots.' " says Daly. "Another interesting finding is that we can identify, among apparently unrelated individuals, chromosome segments that clearly have been inherited without change from common ancestors who lived hundreds to a thousand years ago. The ability to detect these more recently inherited segments of DNA may hold the key to rare disease-associated variations that have been hard to detect with current tools." Daly is an assistant professor of Medicine at Harvard Medical School and a senior associate member of the Broad Institute of Harvard and Massachusetts Institute of Technology.
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 defense, 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 signaling, 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.
The information in the HapMap is freely accessible to researchers around the world. The data assembled in the second phase was added to the public database as it became available and already has been used in a number of research studies. As the project continues, it will use new sequencing techniques to further analyze genetic variations in the same study group and in a larger population.
"While the completion of Phase 2 of the HapMap Project makes possible comprehensive studies of common SNPs in the sampled populations, there remains much work to be done," says David Altshuler, of the MGH Center for Human Genetic Research. "Current efforts aim to catalogue genetic variation in more diverse samples from around the world, to define larger chromosomal alterations that might be missed by SNPs-based approaches and to find rare genetic variations that might have potent effects on individual patients. Only by combining all these approaches can we hope to have a complete understanding of the genetic root causes of common human diseases." Altshuler is also an associate professor of Genetics and Medicine at HMS, director of the Program in Medical and Population Genetics at the Broad Institute, and co-chair for Analysis of the International HapMap Project.
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