The evolution of the glandular kallikrein locus: identification of orthologs and pseudogenes in the cotton-top tamarin

• Published in: Gene Vol. 343; no. 2; pp. 347 - 355
• Main Authors: Olsson, A. Yvonne, Valtonen-André, Camilla, Lilja, Hans, Lundwall, Åke
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 22.12.2004
• Subjects: 5' Untranslated Regions - genetics; Amino Acid Sequence; Animals; ARE; Base Sequence; Basic Medicine; Conserved Sequence; Enhancer; Evolution; Evolution, Molecular; Humans; Kallikreins - genetics; Luciferases - metabolism; Läkemedelskemi; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinal Chemistry; Medicinska och farmaceutiska grundvetenskaper; Mice; Molecular Sequence Data; Phylogeny; Prostate-specific antigen; Pseudogenes; Rats; Saguinus - genetics; Saguinus oedipus; Tissue Kallikreins - genetics; Transcription, Genetic; AR; KLK1; KLK2A2; ARE; Enhancer; KLK2A1; Prostate-specific antigen; Evolution; hK2; hK1; PSA
• DOI: 10.1016/j.gene.2004.09.020
• ISSN: 0378-1119; 1879-0038

Comparisons of the glandular kallikreins loci in human, mouse and rat revealed remarkable differences. For example, the mouse and the rat lack the genes encoding prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2). In contrast, the intergenic region between KLK1 and KLK15 is devoid of genes and spans only 1.5 kb in humans, but encompasses 23 KLK1-like genes spanning 290 kb in the mouse. To further elucidate the evolution of glandular kallikrein genes, we investigated the structure and organization of these genes in the cotton-top tamarin ( Saguinus oedipus), a New World monkey. We conclude that this species has no PSA gene. Moreover, the ortholog of the hK2 gene is a pseudogene, as it contains several mutations that preclude formation of a functional serine protease. The expression of this gene was probably silenced by a 15-bp deletion observed in an androgen response element in the upstream promoter region. Replacing the deleted base pairs in vitro with nucleotides from the human counterpart dramatically restored the transcriptional activity to a level that even surpassed that of the human ortholog. We also determined the nucleotide sequence of KLK15 and the intergenic region between this gene and KLK1 in the cotton-top tamarin. The region between KLK1 and KLK15 is conserved between the cotton-top tamarin and humans, and there are no signs of the extension seen in the mouse. KLK15 appeared to be functional, thus, we predict that it generates a protease with specificity similar to that of the human ortholog.