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News / 09.25.06

Researchers map genetic variability in key immune region

By Nicole Davis, Communications
A crown from the Middle Ages.
A crown from the Middle Ages
Photo courtesy of Bart Parren, iStockphoto

An international research team has shed new light on a key piece of the human genome — one that is essential for the body’s defense against infection — by cataloguing its variability among different individuals. The results, which appear in the September 24 advance online edition of Nature Genetics, provide the information needed for scientists to begin systematically searching for the common genetic differences in humans that contribute to immune-related diseases.

Thanks to a stretch of DNA called the "major histocompatibility complex" (MHC, for short), the human body has the ability to destroy different pathogens and to shield its own tissues from friendly fire (a process known as "autoimmunity"). While arguably one of the crown jewels of the genome, the MHC is also associated with more diseases than any other piece of human DNA. Topping the list are several common diseases, such as atherosclerosis, arthritis, diabetes, HIV, lupus, multiple sclerosis and Crohn’s disease.

Nailing down the genetic factors that underlie these diseases, though, has been no easy task. Normally, the MHC varies substantially from one person to another — a feature that hardwires the body with the tools to detect a range of different microbes. This quality, together with the tendency for humans to inherit DNA in large chunks called "haplotypes," have made it difficult for scientists to determine which genetic changes in the MHC contribute to disease and which do not.

To understand the genetic variability in the MHC, a group of scientists led by John Rioux, an associate professor at the Montreal Heart Institute and the Université de Montréal and a visiting Broad scientist, analyzed the region in more than 350 individuals from diverse geographic regions, including Africa, Europe, China and Japan. Nearly three quarters of the DNA samples analyzed were similarly studied as part of the International HapMap Project.

The scientists, including first authors Paul de Bakker, a researcher at the Broad and the Center for Human Genetic Research, Massachusetts General Hospital; Gil McVean, a researcher at the University of Oxford; Marcos Miretti, a researcher at the Wellcome Trust Sanger Institute; and Broad researcher Pardis Sabeti, "read" ~7,500 single-letter changes in the genetic code called single nucleotide polymorphisms (SNPs). They also sequenced short segments of DNA from a particular set of highly variable genes within the MHC, called "HLA genes." These genes, which together form a distinctive fingerprint used by an individual’s immune system to distinguish foreign tissues from "self" tissues, are frequently analyzed ("HLA typed") in patients who receive organ transplants or suffer from autoimmune disease. Other Broad scientists who contributed to this study include Mark Daly, Todd Green, Angela Richardson and Emily Walsh.

Importantly, this work, together with HapMap data, provides the tools to begin looking for the common genetic variants that underlie immune-related disease. Such endeavors, involving researchers at the Montreal Heart Institute, the University of California, San Francisco and the Broad Institute, are now underway for several immune system diseases.

In addition, the results offer insights into the evolutionary history of the MHC region — its early origins and the evolutionary forces that have helped to shape it over time. The findings also suggest that analyzing specific SNPs within the HLA region could offer a more economical alternative than to current HLA typing methods for characterizing genetic variation in HLA genes.

Paper cited:

de Bakker P.I.W. et al. (2006) A high resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nature Genetics doi:10.1038/ng1885