AN 85-KB TANDEM TRIPLICATION IN THE SLOW WALLERIAN DEGENERATION (WLD(S)) MOUSE

Wallerian degeneration is the degeneration of the distal stump of an i njured axon. It normally occurs over a time course of around 24 hr but it is delayed in the slow Wallerian degeneration mutant mouse (C57BL/ Wld(s)) for up to 3 weeks. The gene, which protects from rapid Walleri an degeneration, Wld, previously has been mapped to distal chromosome 4. This paper reports the fine genetic mapping of the Wld locus, the g eneration of a 1.4-Mb bacterial artificial chromosome and P1 artificia l chromosome contig, and the identification of an 85-kb tandem triplic ation mapping within the candidate region. The mutation is unique to C 57BL/Wld(s) among 36 strains tested and therefore is a strong candidat e for the mutation that leads to delayed Wallerian degeneration. There are very few reports of tandem triplications in a vertebrate and no e vidence for a mutation mechanism so this unusual mutation was characte rized in more detail. Sequence analysis of the boundaries of the repea t unit revealed a minisatellite array at the distal boundary and a mat ching 8-bp sequence at the proximal boundary. This finding suggests th at recombination between short homologous sequences (''illegitimate'' or ''nonhomologous'' recombination) was involved in the rearrangement. In addition, a duplication allele was identified in two Wld(s) mice, indicating some instability in the repeat copy number and suggesting t hat the triplication arose from a duplication by unequal crossing over .