BETA-CATENIN - ONE PLAYER, 2 GAMES

Genome fluidity is limited by several factors, two of which are sequen ce 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 muscul ar dystrophy (EMD) encompassing the emerin gene, suggests models that twist chromosomes (and the imagination) into alternative configuration s'. Intra- and inter-chromosomal misalignment of long repeats - motifs of nearly-identical sequence that occur in cis and sandwich interveni ng sequence - have been implicated as the cause of several disorders. Intrachromatid recombination via the parallel alignment of two inverte d 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 sy ndrome(4), although here, interchromosomal misalignment is proposed, w hereby 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 direc tion. 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 c ontents 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 approx imately 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 hap pen? Is the inversion intrachromosomally mediated, with a single recom bination event, or interchromosomally mediated, with recombination occ uring in both repeats? Assigning maternal or paternal inheritance to t hese inversions may help to answer this question - a study of the exch ange 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 assesse d, the current study provides a neat resolution of the discrepancy bet ween physical mapping and the low recombination frequency noted in thi s region, and an instructive lesson for those faced with such discrepa ncies in other areas of the genome.