Fingers and toes

The mammalian Hox gene clusters display remarkable 'quantitative colinearity', meaning not only does the temporal and spatial expression during development reflect the order of genes on the chromosome, but genes at the 5' end of the cluster are expressed at the highest levels. In the November 14 Nature, Kmita et al. describe analysis of a series of deletion mutations within the mouse Hoxd locus designed to investigate the mechanisms underlying quantitative colinearity in limbs (Nature 2002, 420:145-150). Deletion and duplications of the Hoxd13, Hoxd12 and Hox11 genes were generated using targeted meiotic recombination (TAMERE) technology. Disruption or deletion of the Hoxd13 gene results in very different digit phenotypes, and deletion affects the expression of neighbouring genes. The location within the gene cluster is critical, and Hoxd genes are functionally upregulated when they are shifted to replace their upstream neighbours. Duplications of Hoxd genes and their promoter regions result in down-regulation of downstream genes. These observations led Kmita et al. to develop a promoter-competition model to explain the targeted effects of a distant enhancer element. They propose that enhancer preference for the 5' extremity of the cluster explains the observed 'quantitative colinearity'.