Haplotype analysis of the delta 2642 and (CAG)n polymorphisms in the Huntington's disease (HD) gene provides an explanation for an apparent 'founder' HD haplotype.

The discovery of the intragenic delta 2642 deletion/insertion polymorphism in the Huntington's disease (HD) gene provides a tool to explore HD evolution, as the deletion is rare in normal chromosomes but overrepresented in HD chromosomes. Thus, delta 2642 deletion alleles were thought to mark normal chromosomes that are particularly prone to becoming HD chromosomes. We have examined this polymorphism in a range of human and non-human primate populations. Our results suggest that the deletion event probably occurred in the human lineage on a chromosome with a CAG allele length at the upper end of the normal size range, as the deletion seemed to be only associated with human chromosomes with 20 or more repeats. These deletion chromosomes are prone to expansion into the HD range because they are at the upper end of the normal range. These data explain the apparent 'founder' HD haplotype defined by the deletion and suggest that chromosomes carrying the deletion are no more mutable than non-deletion chromosomes with similar sized CAG repeats.