Genomic context of paralogous recombination hotspots mediating recurrent NF1 region microdeletion

Abstract

Recombination between paralogs that flank the NF1 gene at 17q11.2 typically results in a 1.5-Mb microdeletion that includes NF1 and at least 13 other genes. We show that the principal sequences responsible are two 51-kb blocks with 97.5% sequence identity (NF1REP-P1-51 and NF1REP-M-51). These blocks belong to a complex group of paralogs with three components on 17q11.2 and another on 19p13.13. Breakpoint sequencing of deleted chromosomes from multiple patients revealed two paralogous recombination hot spots within the 51-kb blocks. Lack of sequence similarity between these sites failed to suggest or corroborate any putative cis-acting recombinogenic motifs. However, the NF1REPs showed relatively high alignment mismatch between recombining paralogs, and we note that the NF1REP hot spots were regions of good alignment bordered by relatively large alignment gaps. Statistical tests for gene conversion detected a single significant tract of perfect match between the NF1REPs that was 700 bp long and coincided with PRS2, the predominant recombination hot spot. Tracts of perfect match occurring by chance may contribute to breakpoint localization, but our result suggests that perfect tracts at recombination hot spots may be a result of gene conversion at sites at which preferential pairing occurs for other, as-yet-unknown reasons. © 2004 Wiley-Liss, Inc.