Multiple independent pseudogene derivations indicate increased instability of the Mdm2 locus in Mus caroli

Abstract

Under conditions of genomic stress, the Mdm locus in human and in mouse is prone to instability manifested as amplification and oncogenesis. The Mdm2 gene is a known oncogene that is amplified in approximately one-third of sarcomas and whose protein product interacts with the tumor suppressor p53. Concimitant with such gene amplification events is the activation and mobilization of endogenous retroelements, typically through the relaxation of epigenetic controlling mechanisms. Processed pseudogenes, which can be formed through endogenous LINE retroelement activity, may indicate increased genomic instability. We have isolated processed pseudogenes for Mdm2 in Mus caroli DNA, likely formed from independent events in different individuals. This is the first identification and characterization of an Mdm2 pseudogene in any organism. Multiple retrotransposition events are suggested by the variable sequence and genomic structure of the identified pseudogenes across all exons and the 3'UTR. The high degree of similarity between the gene and each pseudogene, as well as the lack of evidence for an Mdm2 pseudogene in several other species of Mus, indicate evolutionarily recent retrotransposition events leading to the formation of the Mdm2 pseudogenes in M. caroli. Previous studies on the Mdm2 locus in Mus caroli showed amplification and overexpression of this gene on double minute chromosomes in a Mus musculus x Mus caroli interspecific hybrid. The identification of an Mdm2 retropseudogene within this species further highlights the predisposition to instability for this region of the genome.