International Mammalian Genome Society

F9 Gene Discovery: Novel Mouse and Human ß-Defensins

David Adler, James Holloway, Scott Presnell, Paul Sheppard, Nand Banduir, Mark Rixon, Zeren Gao, Betty Haldeman, Dao Mai, Kathleen M. Walker and Stephanie Beigel. ZymoGenetics Inc., Seattle, Washington

Mammalian defensins are small amphipathic peptides that have antimicrobial activity against a variety of pathogenic microorganisms. In addition, defensin peptides exhibit pro-inflammatory and immuno-stimulatory activities. The known defensin genes cluster at a single chromosomal locus in a number of mammalian genomes, including mouse and human. The defensin cluster includes genes encoding two subfamilies of defensins which differ in their cysteine spacing and disulfide bridge pattern. Mining of EST databases yielded candidates for additional, novel ß-defensin genes in human and mouse. These EST's provided a starting point for identifying mRNA's and genomic fragments which lead to the determination of full-length coding sequences and predicted peptides for two new human and two new mouse defensins. These new genes were localized by radiation hybrid mapping to the corresponding known defensin clusters on human chromosome 8 and mouse chromosome 8. The predicted mature peptide for one of the human b-defensins was chemically synthesized and the biological activities of this protein were investigated. Sequence analyses and comparisons of the new defensins with previously reported genes was carried out in an attempt to identify orthologous pairs between mouse and human and to explore the evolution of the defensin clusters.