The chromosomal world turned upside down

John Armour, University of Nottingham

It is tempting to make the simplifying assumption that variation, where it exists, will come in forms that make analysis straightforward. There may be different flavours of variation, such as in the distinction between substitutional and tandem repeat variation, but these will all be superimposed on a fixed background. Different copies of the book of life will have textual variants of spelling, perhaps, and the occasional omitted or repeated word, but it will not have entire chapters missing, or the story told in a different order. Wrong! A recent paper in Nature Genetics shows that there can be variation in the order of loci along a chromosome. The authors investigated the region of human chromosome 7 responsible for Williams-Beuren Syndrome (WBS), an uncommon (1 in 20,000) cause of mental retardation and developmental abnormalities. Most cases of WBS are due to the heterozygous deletion of about 1.5Mb of DNA on 7q11.3, a region which includes at least 17 genes. This deleted region is flanked by a pair of “duplicons”, stretches totalling about 400kb in which the two copies either side of the deleted region have nearly identical sequences arranged in both tandem and inverted orientation.

It is assumed that deletions causing WBS result from illegitimate crossover between duplicon tandem copies; similar events involving inverted copies would be expected to invert the 1.5Mb region separating them. The investigators therefore examined the order of loci in this region of chromosome 7, and were able to find an inverted order in unaffected members of four families with WBS deletions. The inversion was not found in 26 unaffected controls, and the presence of the inversion in the parents of de novo deletion carriers suggests that the inversion may predispose to subsequent deletion. The frequency of the inversion was not investigated in larger numbers of unaffected controls, so it is difficult to know whether the word “polymorphism” in the title is being used correctly. This may be a rare variant, in which case the association with WBS is all the more dramatic. This work is mainly important in providing one of the first examples of large-scale structural variation in the human genome. This kind of variation is hard to look for and is for that reason mostly ignored, but my guess is that the more we look, the more we’ll find!

Osborne L.R. et al. (2001). A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nature Genetics 29, 321-325.