Interchromosomal Duplications of the Adrenoleukodystrophy Locus: A Phenomenon of Pericentromeric Plasticity

• Published in: Human molecular genetics Vol. 6; no. 7; pp. 991 - 1002
• Main Authors: Eichler, Evan E., Budarf, Marcia L., Rocchi, Mariano, Deaven, Larry L., Doggett, Norman A., Baldini, Antonio, Nelson, David L., Mohrenweiser, Harvey W.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.1997
• Subjects: Adrenoleukodystrophy - genetics; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Biological Evolution; Centromere - genetics; Chromosome Breakage; Chromosome Mapping; Chromosomes, Human; Errors of metabolism; Humans; Lipids (lysosomal enzyme disorders, storage diseases); Male; Medical sciences; Metabolic diseases; Molecular Sequence Data; Phylogeny; Repetitive Sequences, Nucleic Acid; Sequence Analysis - methods; Sequence Homology, Amino Acid; X Chromosome; Endocrinopathy; Human; Sex linked character; Pseudogene; Nervous system diseases; Nucleotide sequence; Enzyme; Metabolic diseases; Lipids; Cerebral disorder; Genetic disease; Molecular evolution; Adrenoleukodystrophy; Gene; Adrenal gland diseases; Gene rearrangement; Genetics; Gene duplication
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/6.7.991

A 9.7 kb segment encompassing exons 7–10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric 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 during the course of higher primate evolution (5–10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric-directed transposition. The breakpoint sequence 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 the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non-homologous interchromosomal exchange.