Phylogenetic and Structural Analyses of MMTV LTR ORF Sequences of Exogenous and Endogenous Origins

Abstract

The long terminal repeat (LTR) of mouse mammary tumor virus (MMTV) harbors an open reading frame (ORF) that encodes a glycoprotein and is present in all exogenous and endogenous MMTV proviruses. The ORF protein has been reported to interact with the immune system of mice to cause deletion of specific Vβ-bearing subsets of T cells, Twenty-two MMTV LTR ORF sequences were analyzed. Although highly conserved, the MMTV ORF sequences are not identical, with ≈35% of the total variation clustered at the carboxy terminus. Statistical analysis revealed the presence of two conserved regions in the protein, one of which contained a transmembrane-like domain (residues 45-63). Two potential nuclear localization signals were recognized. Many ORF sequences shared polymorphisms. To analyze relationships, phylogenetic trees were constructed on the basis of alignments of LTR ORF sequences. A tree generated from the carboxy-terminal 35 residues clustered the sequences into three divergent families. The topology of the tree based on the amino-terminal 288 residues differed significantly, with some MMTV sequences rearranged relative to their carboxy-terminal families. A continuum of exogenous-like to endogenous-like character was suggested by the amino-terminal tree. The discordance between the topologies of the two trees suggests that some type of genetic exchange has occurred in the MMTV LTR gene. Mechanisms and implications of such genetic exchange are discussed.