Human Molecular Genetics, Vol 8, 2285-2292, Copyright © 1999 by Oxford University Press
J Lopes, S Tardieu, K Silander, I Blair, A Vandenberghe, F Palau, M Ruberg, A Brice and E LeGuern
Rearrangements in 17p11.2, responsible for the 1.5 Mb duplications and
deletions associated, respectively, with autosomal dominant Charcot-
Marie-Tooth type 1A disease (CMT1A) and hereditary neuropathy with
liability to pressure palsies (HNPP) are a suitable model for studying
human recombination. Rearrangements in 17p11.2 are caused by unequal
crossing-over between two homologous 24 kb sequences, the CMT1A-REPs, that
flank the disease locus and occur 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 mapping of the de novo rearrangements
provided evidence that the successive steps of this model, heteroduplex DNA
formation, mismatch correction and gene conversion, occurred in patients.
Furthermore, the model explains 17p11.2 recombinations between chromosome
homologues as well as between sister chromatids. In addition, defective
mismatch repair of the heteroduplex DNA, observed in two patients, resulted
in two heterozygous chimeric CMT1A-REPs which can be explained, as in
yeast, by post-meiotic segregation. This work supports the hypothesis that
the DSB repair model of DNA exchange may apply universally from yeasts to
humans.
ARTICLES
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
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