Lee Rowen, Kai Wang, Inyoul Lee, Cecilie Boysen, Ben F. Koop[1] and Leroy Hood.
Department of Molecular Biotechnology, University of Washington, Seattle, Washington 98195.
T cell receptors play a major role in immunity and autoimmune diseases. For this reason, their genomic sequence has been chosen as a model system for the development of strategies and tools related to the human genome project. The complete genomic sequence of a multigene locus enables a delineation of genes and gene boundaries, and an assessment of the proportion of pseudogenes. Additionally, it provides PCR access to microsatellite markers and other possible sites of polymorphic variance and, therefore, will facilitate efforts to discover mutations related to disease susceptibility. Strong sequence homologies found in a cross-species comparison between human and mouse counterparts will assist in identifying regulatory regions, new genes and alternative functions for DNA sequence information The cross-species comparison will also conduce to an understanding of the evolutionary mechanisms that underlie overall gene organization.
Over a megabase of the T cell receptor beta loci from human and mouse have been sequenced using the shotgun strategy, leading to the following discoveries.
Approximately half of the human T cell receptor beta locus is comprised of long homologous repeats in which members of multigene subfamilies are embedded. These repeats suggest a mechanism for the divergence of gene function. Indeed, a portion of the human TCR beta locus has even been translocated to another chromosome. The mouse locus, by way of contrast, contains far less repeated DNA. In this regard, the comparative genomic sequences have provided an explanation for why there are twice as many TCR beta variable gene segments in human as mouse, even though both species have about the same number of subfamilies.
The T cell receptor beta locus is also the site of the human and mouse pancreatic trypsinogen multigene family, suggesting that genes with apparently unrelated functions can occupy the same genomic space. In contrast to the situation with the V betas, the mouse locus has undergone a greater expansion in the number and variety of trypsinogen genes than the human counterpart. For the most part, this expansion has not occurred through the recent duplication of DNA repeat units.
[1] Department of Biology, University of Victoria, Victoria, British Colombia, CA V8W 2Y2.