LONDON - The sequence of the most highly variable region of the human genome - the major histocompatibility complex (MHC) - is now available. One of the first substantial regions of the human genome to be completely sequenced, the gene map of the MHC, is expected to be invaluable for researchers wanting to track down the genes responsible for many common diseases.

According to the MHC Sequencing Consortium, which reports its map of the region in the Oct. 28 issue of Nature, in a letter titled, "Complete sequence and gene map of a human major histocompatibility complex," an estimated 40 percent of the expressed genes present in the MHC are associated with the immune system. In the published map, which is also available on the Nature web site, 224 genes are identified.

The same issue of Nature also features the sequence of the MHC of the chicken, in a letter titled, "The chicken B locus is a minimal essential major histocompatibility complex."

Jim Kaufman, of the Institute for Animal Health in Compton, UK, and colleagues report that the chicken MHC is about 20 times smaller than that of the human. This information is expected to aid the development of better vaccines to protect domestic fowl against infectious diseases.

The human MHC sequence, however, is expected eventually to reveal the loci of many different genes responsible for autoimmune diseases such as diabetes and rheumatoid arthritis. That for the skin disorder psoriasis already has been narrowed down to an area featuring just four genes.

Because of the region's exceptional variability, some genes have more than 200 different alleles (variants) whereas most other genes have only a handfu. More than half of the MHC has been sequenced twice. Work is also already under way to resequence the MHC of several common haplotypes (genetic variants) in an effort to identify further disease genes.

Many of the MHC genes encode proteins that appear on the surface of antigen-presenting cells, such as macrophages. These MHC molecules "present" peptides from pathogens such as bacteria and viruses to T lymphocytes, which then trigger an immune response directed at the pathogen. MHC molecules are also responsible for graft rejection.

The role of the MHC molecules in combating pathogens is thought to explain why the genes encoding these proteins are so variable. There is pressure on the pathogen to mutate, so that its peptides no longer bind to the MHC molecules, and a corresponding pressure on the MHC genes to mutate, so that the peptides continue to bind. Pathogens also have many ways of avoiding the immune system. For example, the influenza virus wreaks its havoc within three or four days of infection, beating the immune response.

Kaufman told BioWorld International, "The chicken MHC is much smaller and simpler than the human MHC and the functional consequences of that are enormous. The textbook example of resistance and susceptibility to infectious pathogens determined by the MHC is the chicken. Individual chickens basically live or die depending on the particular MHC they have and whether it can recognize the pathogen."

Whereas the human MHC has three genes, which can make molecules on the surface of antigen-presenting cells - and thus three chances to make a molecule that recognizes a particular peptide from a particular pathogen - the chicken MHC has only one such gene, Kaufman said. The down side, he added, is that for humans there is triple the risk that MHC molecules will recognize and attack a self-peptide, thus triggering autoimmune disease.

This could explain, Kaufman said, why there are so many associations between MHC genes and autoimmune diseases in humans, while this is not true for chickens. He added, "In my view, the reason why we have so much autoimmune disease associated with the MHC in humans is that the MHC is so good at recognizing foreign pathogens that it sometimes gets it wrong and recognizes us as well. In chickens, you probably will not get autoimmune disease as often, but this means that you miss particular pathogens."

Kaufman and his colleagues say in their letter to Nature that they have identified a kind of gene in the chicken MHC that they did not expect to find. This gene encodes a receptor that normally appears on the surface of natural killer (NK) cells. The receptor is used to identify and destroy cells that do not have MHC molecules on their surface. Many such cells will be infected with viruses, because one of the strategies deployed by viruses is to downregulate the production of MHC molecules, so that these cannot present peptides to antigen-presenting cells.

Kaufman's team is carrying out further studies to find out if, as suspected, the NK receptor genes found alongside certain MHC genes work together in a coupled way. They also believe that it may be possible to improve many avian vaccines, to which many chickens do not currently respond, probably for the same reasons that they do not respond to certain pathogens.

Commenting on the two papers in a News and Views in the same issue of Nature, Peter Parham, of the departments of Structural Biology and Microbiology and Immunology at Stanford University, said they show that working MHCs come in all shapes and sizes.

His article, titled, "Soaring costs in defence," concludes: "The HLA complex [human MHC] is the sort of muddled mix of chaotic junk and organized function that one has come to expect from diverse and changeable selection by pathogens. By contrast the simple elegance of the chicken MHC appears more the work of a single selective pressure which may or may not have anything to do with defence against pathogens. Nevertheless, having crossed that particular road, the chicken is seen to have put a lot of immunological eggs in a rather small basket."