Human Molecular Genetics, 2000, Vol. 9, No. 12 1881-1889
© 2000 Oxford University Press
Unequal exchange at the Charcot–Marie–Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate
1Molecular Biology Program, Center for Computational and Experimental Genomics, University of Southern California, 835 West 37th Street, Los Angeles, CA 90089-1340, USA, 2Department of Pediatrics, Box 356320, University of Washington, Seattle, WA 98195, USA and 3Department of Mathematical and Computer Sciences, Colorado School of Mines, Golden, CO 80401-1887, USA
An increasing number of human diseases and syndromes are being found to result from microduplications or microdeletions arising from meiotic recombination between homologous repeats on the same chromosome. The first microduplication syndrome delineated, Charcot–Marie–Tooth disease type 1A (CMT1A), results 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 analysis of human unequal recombination. Previous studies of CMT1A patients showed 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 region using sperm from four normal individuals. Surprisingly, unequal recombination between the REPs occurs at a rate no greater than the average rate for the male genome (~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. Finally, the CMT1A hot-spot stands in sharp contrast to the human MS32 minisatellite-associated hot-spot that exhibits highly enhanced recombination initiation in addition to positional specificity. One possibility is that the CMT1A hot-spot may consist of a region with genome average recombination potential embedded within a recombination cold-spot.
+ Present address: University of Basel, Department of Research, ZLF 406, Hebelstrasse 20, 4031 Basel, Switzerland §To whom correspondence should be addressed. Tel: +1 213 740 7675; Fax: +1 213 740 8631; Email: arnheim@usc.edu
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