THE GENE CODING FOR THE BETA-CHAIN OF C4B-BINDING PROTEIN (C4BPB) HASBECOME A PSEUDOGENE IN THE MOUSE

C4BP beta is one of the two polypeptides that in humans compose the pl asma glycoprotein C4b-binding protein (C4BP). C4BP beta binds the anti coagulant vitamin K-dependent protein S. Two, nonmutually exclusive, r oles have been proposed for the C4BP-protein S interaction. It has bee n suggested to play a role in the control of the protein C anticoagula tory pathway. In addition, it may serve an important role in localizin g C4BP to the surface of injured or activated cells. While the physiol ogical significance of C4BP-protein S interaction is unclear, it has c linical relevance because elevated plasma levels of C4BP are associate d with increased risk for thromboembolic disorders in humans, due to a n inactivation of the protein C anticoagulatory pathway. Using a human C4BP beta cDNA probe, we have isolated and characterized a genomic DN A fragment that includes the murine C4BPB gene. Murine C4BPB is a sing le-copy gene that maps close to the C4BPA gene in chromosome 1. It con tains two exons homologous to the exons coding for the SCR-1 and SCR-2 repeats of the human C4BP beta polypeptide chain. Sequence analysis o f the C4BPB exons in the Mus musculus inbred strains CBA, Balb/c, and C57BL/6, in pen-bred Swiss mice, and in Mus spretus demonstrated the p resence of two in-phase stop codons that are incompatible with the exp ression of a functional C4BP beta polypeptide. Thus, the characterizat ion of the murine C4BPB gene documents the peculiar situation of a sin gle-copy gene that is functional in humans but has become a pseudogene in the mouse. Interestingly, the loss of a functional C4BPB gene is a relatively recent event in the evolution of the mouse. In addition, o ur data indicate that this genetic change has been fixed in the mouse population, suggesting that those individual lacking the C4BP beta pol ypeptide were conferred with some kind of selective advantage. (C) 199 4 Academic Press, Inc.