AbstractThe superfamily of serine proteinase inhibitors (serpins) is involved in wide arrays of fundamental biological processes such as blood coagulation, complement activation, fibrinolysis, angiogenesis, inflammation and tumor suppression. The average protein size of a serpin family member is 350-400 amino acids, but gene structure varies in terms of number and position of exons and introns. All known serpins can be grouped into 16 clades and 10 orphan sequences. Vertebrate serpins can be conveniently classified into six sub-groups, based on three independent biological features - genomic organization, diagnostic amino acid sites and rare indels.The objective of this study was to elucidate the phylogenetic kinships of serpins involved in surveying the secretory pathway routes against uncontrolled proteolytic activity. Though phylogenetic classification of vertebrate serpins into six groups based on gene organisation is well established, the evolutionary roots beyond the fish/tetrapod split are unresolved. This study illustrates that the analysis of microsynteny and other rare characters can provide insight into the intricate family history of metazoan serpins. Rare genomic characters/changes (RGC) are used to decipher that orthologs of neuroserpin, a prominent representative of vertebrate group 3 serpin genes, exist in early diverging deuterostomes and probably also in cnidarians, indicating that the origin of a mammalian serpin can be traced back far in the history of eumetazoans.