Unequal exchange at the Charcot-Marie-Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate

An increasing number of human diseases and syndromes are being found to res ult from microduplications or microdeletions arising from meiotic recombina tion between homologous repeats on the same chromosome. The first microdupl ication syndrome delineated, Charcot-Marie-Tooth disease type 1A (CMT1A), r esults from unequal crossing over between two >98% identical 24 kb repeats (CMT1A-REPs) on chromosome 17. In addition to its medical significance, the CMT1A region has features that make it a unique resource for detailed anal ysis of human unequal recombination, Previous studies of CMT1A patients sho wed that the majority of unequal crossovers occurred within a small region (<1 kb) of the REPs suggesting the presence of a recombination hot-spot. We directly measured the frequency of unequal recombination in the hot-spot r egion using sperm from four normal individuals, Surprisingly, unequal recom bination between the REPs occurs at a rate no greater than the average rate for the male genome (similar to 1 cM/Mb) and is the same as that expected for equally aligned REPs. This conclusion extends to humans the findings in yeast that recombination between repeated sequences far apart on the same chromosome may occur at similar frequencies to allelic recombination. Final ly, the CMT1A hot-spot stands in sharp contrast to the human MS32 minisatel lite-associated hot-spot that exhibits highly enhanced recombination initia tion in addition to positional specificity. One possibility is that the CMT 1A hot-spot may consist of a region with genome average recombination poten tial embedded within a recombination cold-spot.