New analysis method for Major Histocompatibility Complex

Scientists from the Clinical Research Division, led by Dr. Effie Petersdorf, have developed a new method for analyzing the Major Histocompatibility Complex (MHC) of the human genome. The new tool may have the potential to be 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.

Found on chromosome 6, the large, highly diverse MHC region 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 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.

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.

The new lab method, described in the paper, "Long-range Multi-locus Haplotype Phasing of the MHC," appears in the May 2 issue of the Proceedings of the National Academy of Sciences. The paper was co-authored by Drs. Zhen Guo and Mari Malkki of the Clinical Research Division; and Dr. Leroy Hood of Seattle's Institute for Systems Biology.

Determining haplotypes

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."

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.