Human Meiotic Recombination Products Revealed by Sequencing a Hotspot for Homologous Strand Exchange in Multiple HNPP Deletion Patients

• Published in: American journal of human genetics Vol. 62; no. 5; pp. 1023 - 1033
• Main Authors: Reiter, Lawrence T., Hastings, Philip J., Nelis, Eva, De Jonghe, Peter, Van Broeckhoven, Christine, Lupski, James R.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.05.1998; University of Chicago Press
• Subjects: Biological and medical sciences; Charcot-Marie-Tooth Disease - genetics; Chromosomes, Human, Pair 17; CMT1A-REPs; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Gene Deletion; HNPP deletion; Homologous recombination; Hotspot; Humans; mariner-like element; Medical sciences; Meiosis; Minimum efficient processing segments; Nervous system (semeiology, syndromes); Neurology; Peripheral Nervous System Diseases - genetics; Polymerase Chain Reaction; Recombination, Genetic; Repetitive Sequences, Nucleic Acid; CMT1A-REPs; Hotspot; Minimum efficient processing segments; Homologous recombination; mariner-like element; HNPP deletion; Genetic mapping; Human; Neuromuscular diseases; Nervous system diseases; Motor system disorder; Pathogenesis; Repeated sequence; Exploration; Meiosis; Peripheral neuropathy; Genetic determinism; Genetic disease; Gene; Charcot Marie Tooth disease; Chromosome E17; Central nervous system disease; Sensory disorder; Degenerative disease; Peripheral nerve disease; Paralysis; Technique; Spinal cord disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/301827

The HNPP (hereditary neuropathy with liability to pressure palsies) deletion and CMT1A (Charcot-Marie-Tooth disease type 1A) duplication are the reciprocal products of homologous recombination events between misaligned flanking CMT1A-REP repeats on chromosome 17p11.2-p12. A 1.7-kb hotspot for homologous recombination was previously identified wherein the relative risk of an exchange event is 50 times higher than in the surrounding 98.7% identical sequence shared by the CMT1A-REPs. To refine the region of exchange further, we designed a PCR strategy to amplify the recombinant CMT1A-REP from HNPP patients as well as the proximal and distal CMT1A-REPs from control individuals. By comparing the sequences across recombinant CMT1A-REPs to that of the proximal and distal CMT1A-REPs, the exchange was mapped to a 557-bp region within the previously identified 1.7-kb hotspot in 21 of 23 unrelated HNPP deletion patients. Two patients had recombined sequences suggesting an exchange event closer to the mariner-like element previously identified near the hotspot. Five individuals also had interspersed patches of proximal or distal repeat specific DNA sequence indicating potential gene conversion during the exchange of genetic material. Our studies provide a direct observation of human meiotic recombination products. These results are consistent with the hypothesis that minimum efficient processing segments, which have been characterized in Escherichia coli, yeast, and cultured mammalian cells, may be required for efficient homologous meiotic recombination in humans.