New method designed to analyze the genes that regulate the immune system

Apr 20 2006

Seattle scientists 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 early edition of the Proceedings of the National Academy of Sciences, published Monday, April 17. 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 researchers are Dr. Zhen Guo and Dr. Mari Malkki of the Division of Clinical Research at the Fred Hutchinson Cancer Research Institute (FHCRC) in Seattle, Dr. Leroy Hood of Seattle's Institute for Systems Biology, and Dr. Effie Petersdorf of the Division of Clinical Reseearch at FHCRC and the Division of Medical Oncology, Department of Medicine at the University of Washington.

The MHC is one 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 MCH genes and therefore can receive transplants from each other without risk of rejection. The MHC also is likely to be governing many as yet unknown functions in the human body.

Segments of MHC are almost always inherited as an entire block, called a haplotype from a word meaning 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 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.

The Seattle researchers attempted to overcome the limitations of these other tools. Their decision to work on a laboratory tool to study particular sections of the MHC 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.

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