EPISODIC EVOLUTION AND RAPID DIVERGENCE OF MEMBERS OF THE RAT MULTIGENE FAMILY ENCODING THE SALIVARY PROHORMONE-LIKE PROTEIN SMR1

In rodents, the variable coding sequence (VCS) multigene family displa ys extensive evolutionary divergence in the protein-coding region. Whi le certain VCS genes coding for proline-rich proteins (hPR-PB, mMSG1, rPR-VB1) are conserved in primates and rodents, others seem to be spec ific to certain genera. This appears to be the case for the Rattus gen es forming the A-subclass. This subclass is composed of three genes in R. norvegicus and probably five genes in R. rattus. The first describ ed VCSA gene (Rn VCSA1) was found to encode a prohormone-like protein named SMR1 (-VA1), expressed mainly in the submandibular glands (SMG) of male rats. To further understand the evolution of this variable mul tigene family, we have cloned the two additional genes (Rn. VCSA2 and Rn. VCSA3) forming the R. norvegicus A-subclass and three VCSA genes ( Rr. VCSA1a, b and Rr, VCSA2) of R. rattus. The putative SMR1 proteins encoded by all these genes display the same prohormone-like structure as Rn.SMR1-VA1. However, we observe a polymorphism in some internal cl eavage sites which suggests that multiple processing of the SMR1 prote ins could result in the liberation of peptides differing in structure and length, The phylogenetic analysis of the sequences reveals that th e duplication events giving rise to the VCSA1, -A2, and -A3 progenitor s were anterior to the R. norvegicus and R. rattus split, and that a V CSA1 duplication event likely occurred specifically in R. rattus. A st riking observation is that the coding sequences of the VCSA genes have rapidly diverged from their ancestors. Along all branches of the phyl ogeny, the nonsynonymous divergence rate is identical or superior to t he synonymous divergence rate. We suggest that frequent changes in fun ctional requirements are mainly responsible for the episodic evolution and the rapid divergence of the VCSA genes.