Conservation and diversity in the murine major histocompatibility complex: Studies on the T3 subset of the thymus leukemia antigen genes

Abstract

The thymus leukemia (TL) antigens, encoded by genes in the Tla region of the major histocompatibility complex (MHC), are cell-surface glycoproteins sharing some biochemical characteristics with the transplantation antigens H-2K, D and L. However, the TL antigens can not elicit graft rejection, and their expression is limited to thymocytes of certain strains of mice and to certain T cell leukemias.;To study the fine structure and interrelationships of genes in the Tla subregion, a Tla-specific nucleic acid probe was created by subcloning a fragment of a TL-encoding gene, designated Tl3{dollar}\sp{lcub}c{rcub}{dollar}, isolated from BALB/c mice. This probe was specific for sequences mapping to the Tla region by hybridization analysis of Southern blots containing DNA from various recombinant and inbred strains of mice. The specificity of this probe for mRNA was consistent with the known serological detection of TL on various tissues. T3 is also marked by aberrantly spliced transcripts and alternatively initiated transcripts, particularly in TL-expressing leukemia cells.;A Tla{dollar}\sp{lcub}b{rcub}{dollar} gene (T3{dollar}\sp{lcub}b{rcub}{dollar}) was isolated from a genomic library of C57BL/6 strain mice, and a Tla{dollar}\sp{lcub}c{rcub}{dollar} gene ({dollar}T3\sp{lcub}c{rcub}{dollar}) from that of BALB/c strain mice. Complete DNA sequences of both {dollar}T3\sp{lcub}b{rcub}{dollar} and T3{dollar}\sp{lcub}c{rcub}{dollar} genes suggest they are intact genes (without premature translational stop codons), with sequences homologous to the RNA polymerase binding sites and first six exons of H-2K. Comparison of these two genes reveals T3 alleles as highly conserved, unlike alleles of the H-2 region genes. However, T3 genes are the most diverged compared with other groups of class I genes. The T3 genes are conserved throughout the entire genus Mus. Yet these genes are metastable and duplicated as many as six times within a genome. These duplications often appear to occur together with adjacent genes. Evidence is also presented for gene conversion of large stretches of DNA within T3. Thus, gene conversion and gene duplications may be mechanisms in evolution of conservation and diversity within the MHC.