Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD)locus of the X chromosome has duplicated to specific locations near thepericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11.Comparative sequence analysis reveals 92-96% nucleotide identity,indicating that the autosomal ALD paralogs arose relatively recently duringthe course of higher primate evolution (5-10 million years ago). Analysisof sequences flanking the duplication region identifies the presence of anunusual GCTTTTTGC repeat which may be a sequence-specific integration sitefor the process of pericentromeric- directed transposition. The breakpointsequence and phylogenetic analysis predict a two-step transposition model,in which a duplication from Xq28 to pericentromeric 2p11 occurred once,followed by a rapid distribution of a larger duplicon cassette among thepericentromeric regions. In addition to facilitating more effectivemutation detection among ALD patients, these findings provide furtherinsight into the molecular basis underlying a pericentromeric-directedmechanism for non- homologous interchromosomal exchange.