Observations regarding the dosage of CMT1A-REP-specific restriction fragments suggested that the CMT1A duplication and HNPP deletion arose from recombination events within a limited region of CMT1A-REP (33). The CMT1A-REP copies are approx 99% identical. The sequence differences between the two paralogous copies, which resulted in different restriction endonuclease recognition sites, were exploited for the mapping of the strand exchanges (i.e., crossovers) within CMT1A-REP. Such paralogous sequence variations, or differences between the two copies located on the same chromosome homolog, are referred to as c/s-morphisms to distinguish them from polymorphisms-variations of allelic copies on homologous chromosomes (34). The majority of crossovers occurred within a limited region of CMT1A-REP defining a recombination hotspot. This was the first NAHR hotspot defined-initially in a US cohort (35,36) and confirmed in a European cohort (37). The CMT1A-REP recombination hotspot was also found in the French (38), Japanese (39), and Chinese (40) populations. Such NAHR recombination hotspots have been identified in all genomic disorders in which the strand exchanges have been studied at the nucleotide sequence level (41).
Examination of the products of recombination in the recombinant CMT1A-REP from both patients with the HNPP deletion (42) and the CMT1A duplication (43) revealed evidence for gene conversion. The products of recombination are best explained by the double-strand break model for homologous recombination. Although cis acting recombinogenic sequences that might stimulate double strand breaks have been postulated (41-43) none have been either verified experimentally or shown to be common among different hotspots.
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