Homologous DNA exchanges in humans can be explained by the yeast double-strand break repair model: a study of 17p11.2 rearrangements associated with CMT1A and HNPP

Rearrangements in 17p11.2, responsible for the 1.5 Mb duplications and dele tions associated, respectively, with autosomal dominant Charcot-Marie-Tooth type 1A disease (CMT1A) and hereditary neuropathy with liability to pressu re palsies (HNPP) are a suitable model for studying human recombination, Re arrangements in 17p11.2 are caused by unequal crossing-over between two hom ologous 24 kb sequences, the CMT1A-REPs, that flank the disease locus and o ccur in most cases within a 1.7 kb hotspot, We sequenced this hotspot in 28 de novo patients (25 CMT1A and three HNPP), in order to localize precisely , at the DNA sequence level, the crossing-overs. We show that some chimeric CMT1A-REPs in de novo patients (10/28) present conversion of DNA segments associated with the crossing-over, These rearrangements can be explained by the double-strand break (DSB) repair model described in yeast, Fine mappin g of the de novo rearrangements provided evidence that the successive steps of this model, heteroduplex DNA formation, mismatch correction and gene co nversion, occurred in patients, Furthermore, the model explains 17p11.2 rec ombinations between chromosome homologues as well as between sister chromat ids, In addition, defective mismatch repair of the heteroduplex DNA, observ ed in two patients, resulted in two heterozygous chimeric CMT1A-REPs which can be explained, as in yeast, by post-meiotic segregation. This work suppo rts the hypothesis that the DSB repair model of DNA exchange may apply univ ersally from yeasts to humans.