beta-catenin - One player, two games

Genome fluidity is limited by several factors, two of which are sequence constraints and the viability of the prescribed phenotype. On page 96, Kersten Small and colleagues present data that reflect both; their dissection of a deletion on the X chromosome in Emery-Dreifuss muscular dystrophy (EMD) encompassing the emerin gene, suggests models that twist chromosomes (and the imagination) into alternative configurations'. Intra- and inter-chromosomal misalignment of long repeats - motifs of nearly-identical sequence that occur in cis and sandwich intervening sequence - have been implicated as the cause of several disorders. Intrachromatid recombination via the parallel alignment of two inverted repeats is known to disrupt factor VIII, giving rise to haemophilia A(2), and has been recently indicted as a cause of Hunter syndrome(3). Large repeats also bear the burden of blame in Charcot-Marie-Tooth syndrome(4), although here, interchromosomal misalignment is proposed, whereby a repeat proximal to the critical PMP-22 gene misaligns with a distal repeat and recombination between the two clinches a duplication. In this case, however, the repeats are necessarily in the same direction. The X-chromosomal rearrangement revealed by Small er al. implies a combination of these features: the long, highly homologous repeats that flank the critical region in EMD are inverted, but the shuffled contents of the intervening region in a patient with EMD suggest a mon exotic mechanism involving interchromosomal alignment (see Fig. 1). On recognising the potential of these impressive repeats (each is approximately 11.3 kb and has 99% sequence identity with the other), Warren and colleagues examined normal X chromosomes and, surprisingly, found that 33% of females carry an inversion between them. How does this happen? Is the inversion intrachromosomally mediated, with a single recombination event, or interchromosomally mediated, with recombination occuring in both repeats? Assigning maternal or paternal inheritance to these inversions may help to answer this question - a study of the exchange leading to haemophilia A suggests that intrachromatid exchange is roughly 300 times more common in male than in female gametogenesis(5), While the sex effect on the 'emerin' inversion has yet to be assessed, the current study provides a neat resolution of the discrepancy between physical mapping and the low recombination frequency noted in this region, and an instructive lesson for those faced with such discrepancies in other areas of the genome.