Gene conversion-like missense mutations in the human cationic trypsinogen gene and insights into the molecular evolution of the human trypsinogen family

Over the past decade, gene conversion has been shown increasingly to be a cause of human disease. Through this process, a functional gene is converted into a mutant by a homologous, nonfunctional one. In this article, we demonstrate that gene conversion is a likely cause of the mutations of the human cationic trypsinogen (PRSS1) gene that are associated with hereditary or sporadic pancreatitis, including the R122H (CGC>CAT: c.365-366 GC>AT), N29I (AAC>ATC: c.86A>T), and A16V (GCC>GTC:c.47C>T) missense mutations. This hypothesis is strongly supported by four lines of observation. First, human group I trypsinogen genes are tandemly repeated and share a high sequence homology between them. Secondly, a possible donor sequence for each variant is present in the PRSS1 gene's paralog(s). Thirdly, there exist uninterrupted sequence tracts ranging from 30 to 114 bp in the putatively converted regions. Finally, Chi-like and palindromic sequences are found in the vicinity of these missense mutations. This theory, if correct, will make the pancreatitis-associated PRSS1 mutations a unique example, as it shows that a functional gene may be converted by several paralogs, and that such an event may even occur between two functional genes (i.e., the N29I mutation), resulting in disease. This adds further to the diversity of genetic mechanisms underlying human disease. In addition, this genetic finding provides, for the first time, concrete evidence of the contribution made by gene conversion to the molecular evolution of the human trypsinogen family. (C) 2000 Academic Press.