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New method to analyse the Major Histocompatibility Complex (MHC) of the human genome

Scientists at Fred Hutchinson Cancer Research Center have developed a new method for analyzing the Major Histocompatibility Complex (MHC) of the human genome. This large region, found on chromosome 6, encodes more than 400 known genes. The best known of these genes are the HLA genes that govern tissue type and participate in the immune system by protecting people from infection or by governing susceptibility to autoimmune diseases or cancer.

The researchers’ new lab method is described in the paper "Long-range Multi-locus Haplotype Phasing of the MHC" which was published today (April 21) in the early edition of the Proceedings of the National Academy of Sciences. The paper will appear in the May 2 print edition. The method may have the potential of being an efficient way to map genes in the MHC that are responsible for many human diseases, and might also be useful in studying other gene complexes that have a lot of variability.

The senior and corresponding author is Effie Petersdorf, M.D., member of the Clinical Research Division. Fellow researchers are Zhen Guo, Ph.D., and Mari Malkki, Ph.D., of the Clinical Research Division; and Dr. Leroy Hood of Seattle’s Institute for Systems Biology.

The MHC is one of the most diverse regions of the human genome, and its diversity is thought to have been shaped by widely varying evolutionary forces. Many of its genes are ancient and may have remained unchanged throughout human evolution.

The MHC also governs the degree of people’s acceptance or rejection of transplanted organs or bone marrow transplants. Identical twins, for example, have identical MHC genes and therefore can receive transplants from each other without risk of rejection. The MHC also is likely to govern many as yet unknown functions in the human body.

Segments of MHC are almost always inherited as an entire block, called a haplotype, a word that means "single unit," rather than as separate genes. Haplotypes may be one of the genetic reasons behind complex diseases that are not associated with just one gene or one genetic mutation, but with sets of genes.

About a year ago, an international collaboration of scientists produced a haplotype map of the human genome named the HapMap. The project was an effort to catalog genetic variation throughout the human genome, including the MHC region.

Family studies and statistical analysis are among the tools used to determine haplotypes. In addition, several laboratory methods have been developed to define haplotypes. However, these methods have limitations in studying the MHC because of its extensive diversity, the uneven distribution of its coding variation and the physical distances between genes within the MHC region.

"Population genetic epidemiology studies of unrelated individuals may lack family studies to definitely ascertain the physical linkage of genes or markers on haplotypes," Petersdorf said. "To address this need, we developed a method to link HLA genes across long distances of chromosome 6. This method provides haplotype information without a family study, and may be useful for mapping genes of the MHC that cause common diseases in large unrelated populations."

The researchers decided to work on a laboratory tool to study particular sections of the MHC, a choice that was motivated by the importance of these genes in disease studies, in anthropological research, and in the selection of potential donors for organ transplants or blood and marrow transplants. They wrote that it might be possible to expand their method to span the entire MHC, but this would require reconstructing the huge complex into several overlapping segments.

The new lab method, the researchers noted, could possibly fulfill an unmet need for tools to use in conducting genetic studies in populations of unrelated individuals. The researchers have applied for a U.S. non-provisional patent for their haplotyping method.

Dean Forbes | EurekAlert!
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