The evolution of a genetic locus encoding small serine proteinase inhibitors

Abstract

We previously identified a locus on human chromosome 20 that encompasses 14 genes of postulated WFDC-type proteinase inhibitors with a potential role in innate immunity. In an extended study, homologous loci are here described on mouse chromosome 2, rat chromosome 3, and dog chromosome 24. As in humans, the murine and canine loci are divided into two sub-loci separated by 0.2Mb. The majority of genes are conserved in all species, but there are also species-specific gains and losses of genes, e.g., several duplications have yielded four SLPI genes in the rat and, most surprisingly, there is no murine elafin gene. Two human pseudogenes were identified due to the discovery of functional rodent genes. The conservation of different WFDC domains varies considerably, and it is hypothesized that this reflects a dual role of WFDC inhibitors in natural immunity, which is directed both against microbes and proinflammatory cells.

Fig. 1

The nucleotide sequences were aligned using the program bl2seq. Exon sequences are written in capital letters and translations are given with the one-letter code. Gaps are indicated by dots and conserved nucleotides are indicated by vertical bars. The conserved Cys residues are indicated by bold letters. (A) Identification of a human pseudogene with homology to mouseWfdc15a andWfdc15b. The frame-shifting deletion and the mutation of the Cys codon are indicated by shaded boxes. (B) Identification of a pseudoexon in humanWFDC6, with homology to exons encoding the kunitz domain of mouse Wfdc6a and Wfdc6b. The frame-shifting insertion and the mutated nucleotide of the conserved Cys codon are shaded. (C) Identification of a human pseudogene with homology to mouseWfdc16. The mutated splice acceptor site and the two in-frame stop codons are shaded.

Fig. 2

Schematic illustration of the WFDC loci in man, mouse, rat, and dog. Equally sized arrows indicate the direction of transcription and approximate location of the genes. Black arrows indicate functional genes and arrows shaded in grey indicate pseudogenes. The horizontal bars illustrating the dog locus symbolize DNA contigs of the genomic sequence, which is not yet fully assembled. (A) Loci homologous with the human centromeric sub-locus. Semen coagulum proteins are illustrated with unfilled arrows. (B) Loci homologous with the human telomeric sub-locus. The broken line of the dog locus symbolizes the DNA contigs, which are not fully assembled.