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The genome of the African murine rodent Nannomys setulosus was found to harbor several thousand major histocompatibility complex (MHC) class I genes instead of the 30-40 genes found in conventional laboratory mice, which are mostly of Mus musculus domesticus origin. Other genes of N. setulosus, either functionally or physically linked to class I genes, are not amplified. Amplified genes derive from as few as three ancestors and amplification has likely occurred after the divergence of the two Nannomys species, N. setulosus and N. minutoides, which took place about three million years ago. Amplified genes are mostly pseudogenes. Statistical analysis of dinucleotide frequencies leads us to propose that inactivation of the genes has occurred through the repeat induced mutation process, a possible "newcomer" in the evolution of the MHC.

We have determined the nucleotide sequence of Q8/9d gene of the BALB/c strain of mice, isolated from Steinmetz's cosmid library. As for all other class I genes of the Qa region, the Q8/9d gene spans approximately 4.7 kilobases (kb) and consists of seven exons and six introns. A seven bases deletion in exon 3 results in the occurrence of an early termination codon. Thus the Q8/9d gene cannot encode a normal class I protein. Comparison of the nucleotide sequence of the Q8/9d gene with that of other class I MHC genes revealed a stronger homology to Q7 and Q8 than to K, D, L, TL, and other Q genes. However, the gene cannot originate from a mere fusion between Q8 and Q9 genes except if the ancestor to putative Q8d was markedly different from the present Q8b gene. Using polymerase chain reaction (PCR) technology, we have confirmed the presence of a Q8/9 gene, identical to that present in cosmid 46.1, in the genome of BALB/cJ (Qa-2low). Finally, it has been reported that cDNA clone 94-A, which codes for a Qa-2 antigen, could derive from a transcript of gene Q8/9d. The nucleotide sequences of gene Q8/9d and of cDNA clone 94-A are distinctly different in their 5' regions, in spite of an almost perfect matching in their 3' regions. Thus, clone 94-A cannot derive from an mRNA transcribed from the Q8/9d gene.

The MRL/lpr (H-2k) inbred strain, a model for the autoimmune disease systemic lupus erythematosus, differs from the healthy inbred strain MRL +/+ (H-2k) by only 0.1% of its genome. Southern blot analysis using class I and class II probes confirmed the H-2k genotype of both strains. Among the Iak-positive peritoneal cells, cells with an unexpected expression of Iad specificities were detected in a radioimmunoassay using several monoclonal antibodies and one conventional antiserum. This was only found in aged (6- to 9-month-old) mice both in the MRL/lpr strain (32% Iad-positive mice) and in the MRL +/+ strain (42% Iad-positive mice). Furthermore, 24% of aged MRL/lpr mice exhibited strong spontaneous cytotoxic T lymphocyte (CTL) activities against P815 (H-2d) target cells, and 57% had a weaker but still detectable level of cytotoxicity. In contrast, such a CTL activity has never been found in the MRL +/+ strain. These results suggest that the anti-H-2d CTL plays a role in the onset of the autoimmune process in MRL/lpr mice.

Two recombinant mice have been recovered from the progeny of Ttf/tw32 + animals. They have lost the tw32 lethality factor(s) and gained tufted, presumably from the T chromosome. Southern blot analysis of class I genes of these two new partial tPA027 and tPA286 haplotypes indicates that they have retained at least part of the major histocompatibility complex of the tw32 chromosome (H-2 haplotype H-2w28). We have prepared a phage library of Eco RI-digested DNA from homozygous tPA027 animals. Upon screening the library with a cDNA probe specific for H-2K genes, we isolated a class I gene displaying all of the distinctive features of a genuine H-2K gene, and which could thus be defined as an H-2Kw28 gene. The H-2Kw28 gene is 92-95% homologous to H-2Kb and H-2Kd genes and differs significantly from the other class I genes sequenced so far. Homology with the H-2Kb sequence reaches nearly 100% in the 3' part of the H-2Kw28 gene. Moreover, the homology with an H-2Kq cDNA sequence reaches 99.8%. Several hypotheses can account for the near identity of H-2Kb, H-2Kq, and H-2Kw28 gene sequences: either recombination between H-2w28 and H-2b and H-2q sequences occurred before or at the time the strain was established, or the class I genes of the tw32 chromosome and the H-2b and H-2q genes found in inbred strains of mice have separated from each other rather recently.