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.