The Major Histocompatibility Complex (MHC) consists of hundreds of genes on human chromosome 6 that are important in most autoimmune conditions, when our biological defences turn on our own systems. The MHC has the major role in type 1 diabetes and rheumatoid arthritis. The MHC is also pivotal in response to infection, including malaria and AIDS.
Genes in the MHC can differ dramatically between people, and the differences among us affect medical events as diverse as tissue transplant rejection, arthritis, asthma and disease resistance. A detailed study of this region in different people will shed light on which genes are most important.
"We analysed the entire MHC region in detail from three individuals that carried different susceptibility to disease," explained Dr Stephan Beck, leader of the team at the Wellcome Trust Sanger Institute. Key differences were then further analysed in a much larger population of 140 DNA samples.
"Within the sea of over 20,000 sequence variations across the 4 million MHC bases, we found one island of stability," continued Dr Beck. "A region of 160,000 bases that is up to 200-fold less variant between chromosomes sharing part of the same HLA type, suggesting these individuals most likely shared a common ancestor as recently as 50,000 years ago."
Swapping of ancestral sequence blocks is a potential mechanism (identity-by-descent) whereby certain gene combinations, which presumably have favoured immunological advantage (e.g. resistance to infectious disea se), can spread across haplotypes and populations.
Professor John Trowsdale, at the Department of Pathology, University of Cambridge, said, "The region, called DR-DQ, where we find this island of stability is one of the most variable in our genome, yet in some people it has been 'fixed'. We suggest that ancestral DR-DQ blocks have been shuffled into different MHC backgrounds and subsequently expanded in frequency across European populations.
"These 'fixed' haplotypes might then have expanded because they protected against infection and disease. We hope to show, in further studies, whether this stable region was a key to disease resistance in our recent past."
The study further described over 300 amino acid changing variants in gene sequences. These variants are strong candidates for functional studies to understand the role of variation in MHC-associated disease.
Autoimmune disease affects about 3 million people in the UK. The three haplotypes studied here display different susceptibilities to diseases such as type 1 diabetes, myasthenia gravis and multiple sclerosis.
For some common autoimmune diseases the MHC provides by far the largest genetic contribution by a single chromosome region. For example, the MHC accounts for at least 30% of the familial aggregation in type 1 diabetes and rheumatoid arthritis.
"Data generated by projects such as the MHC Haplotype Project will feed into the recently announced Wellcome Trust Case-Control Consortium," explained Professor John Todd, Professor of Medical Genetics at the Cambridge Institute for Medical Research, "and the WTCCC search for the genetic signposts for eight common diseases will be accelerated by the new markers reported here. At an ever increasing rate, we are developing the necessary tools and sample collections to make a real difference to the study, diagnosis and, we hope, treatment of diseases such as TB, coronary heart disease, diabetes and rheumatoid arthrit is."
The MHC Haplotype Project is creating a public resource to assist the discovery of genetic factors influencing these medical traits and to shed light on the evolution of the MHC. Access to complete sequences across several MHC haplotypes that exhibit differences in disease susceptibility will help researchers to home in on specific variants (susceptibility alleles) and to rule out regions contributing to a given disease.
Haplotypes and the MHC
Haplotypes are combinations of gene and sequence variants that tend to occur together in an individual genome. This may be purely fortuitous, or it may reflect selection of given combinations (they have been successful in the past), or it may reflect a population bottleneck, where only a few, perhaps similar, genomes have contributed to the further population growth.
The MHC is among the most gene-dense regions of the human genome and the most variable, as might be expected from a region involved in fighting infection (as well as other functions). Over evolutionary time, the MHC has been driven to become the most variable region of our genome.
The MHC Haplotype Project is studying in fine detail the sequence of eight of the most common human haplotypes, selected for conferring protection against or susceptibility to common disease. The detailed analysis of the third of these eight is reported here and compared with the two previously described.
The COX haplotype has been associated with susceptibility to a wide range of diseases, including type 1 diabetes, systemic lupus erythematosus and myasthenia gravis. The PGF haplotype provides protection against type 1 diabetes and predisposes to other diseases such as multiple sclerosis and systemic lupus erythematosus. The QBL haplotype is positively associated with Graves' disease and type 1 diabetes.