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MBE Advance Access published online on May 18, 2005
Molecular Biology and Evolution, doi:10.1093/molbev/msi166
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© The Author 2005. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Accepted May 12, 2005

Research Article

Interchromosomal Segmental Duplications Explain the Unusual Structure of PRSS3, the Gene for an Inhibitor-Resistant Trypsinogen

Lee Rowen 1* {sect}, Eleanor Williams 2 {sect}, Gustavo Glusman 1, Elena Linardopoulou 2, Cynthia Friedman 2, Mary Ellen Ahearn 3, Jason Seto 4, Cecilie Boysen 5, Shizhen Qin 1, Kai Wang 6, Amardeep Kaur 1, Scott Bloom 1, Leroy Hood 1, and Barbara J. Trask 2

1 Institute for Systems Biology, Seattle WA 98103
2 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA 98109
3 Dept. of Pediatrics/Genetics, Univ. of Miami School of Medicine, Miami, FL 33136
4 Bioinformatics and Computational Biology Program, George Mason University, Manassas VA 20110
5 ViaLogy, Altadena, CA 91001
6 PhenoGenomics Corp., Bellevue, WA 98005

* To whom correspondence should be addressed.
Lee Rowen, E-mail: lrowen{at}systemsbiology.org


  Abstract

Homo sapiens possesses several trypsinogen or trypsinogen-like genes of which three (PRSS1, PRSS2 and PRSS3) produce functional trypsins in the digestive tract. PRSS1 and PRSS2 are located on chromosome 7q35, while PRSS3 is found on chromosome 9p13. Here, we report a variation of the theme of new gene creation by duplication: the PRSS3 gene was formed by segmental duplications originating from chromosomes 7q35 and 11q24. As a result, PRSS3 transcripts display two variants of exon 1. The PRSS3 transcript whose gene organization most resembles PRSS1 and PRSS2 encodes a functional protein originally named mesotrypsinogen. The other variant is a fusion transcript, called trypsinogen IV. We show that the first exon of trypsinogen IV is derived from the non-coding first exon of LOC120224, a chromosome-11 gene. LOC120224 codes for a widely conserved transmembrane protein of unknown function. Comparative analyses suggest that these inter-chromosomal duplications occurred after the divergence of Old World monkeys and hominids. PRSS3 transcripts consist of a mixed population of mRNAs, some expressed in the pancreas and encoding an apparently functional trypsinogen, and others of unknown function expressed in brain and a variety of other tissues. Analysis of the selection pressures acting on the trypsinogen gene family shows that, while the apparently functional genes are under mild to strong purifying selection overall, a few residues appear under positive selection. These residues could be involved in interactions with inhibitors.

Keywords: segmental duplication; fusion gene; selection; trypsinogen.

{sect}these authors contributed equally to the work


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