caa a22 4500 397574185 CHVBK 20180308164850.0 cr unu---uuuuu 161202e199606 xx s 000 0 eng 10.1093/hmg/5.6.745 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.6.745 Primate Origin of the CMT1A-REP Repeat and Analysis of a Putative Transposon-Associated Recombinational Hotspot [Elektronische Daten] [Hidenori Kiyosawa, Phillip F. Chance] The CMT1A-REP repeat on chromosome 17p11.2-12 is proposed to mediate misalignment and meiotic unequal crossover leading to a 1.5 Mb pair duplication associated with Charcot-Marie-Tooth neuropathy type 1A (CMT1A) and a reciprocal deletion associated with hereditary neuropathy with liability to pressure palsies (HNPP). Restriction enzyme endonuclease mapping indicated that the size of the CMT1A-REP repeat is approximately 24 kb and DNA sequence analysis determined that the repeat is flanked by inverted Alu sequences. Full length Alu sequences are present at the centromeric ends of the proximal and distal CMT1A-REP repeats and at the telomeric end of the distal repeat. A truncated Alu sequence is present at the telomeric end of the proximal repeat suggesting that the distal CMT1A-REP repeat is the progenitor copy. The crossover breakpoints for a series of unrelated CMT1A and HNPP patients were mapped using a variant Sad site found only in the proximal CMT1A-REP repeat. Seventy-six percent (66/85) of patients had breakpoints which mapped to a 3.2 kb interval, providing further evidence for a recombinational hotspot within the CMT1A-REP repeat. A mariner-like element was mapped within the CMT1A-REP repeat approximately 700 bp centromeric to the 3.2 kb interval containing the hotspot. Analysis of this sequence suggested that it does not encode a functional transposon. By Northern blot analysis a cloned fragment from the CMT1A-REP repeat containing the mariner-like sequence detected a 2.2 kb transcript only in testis. Two cDNA clones which contain the mariner-like element were isolated from a human testis cDNA library. These clones which are interrupted by Alu and other repeats appear to be non-functional versions of the transposon. The functional relationship of the mariner-like element to the recombinational hotspot remains unknown. The origin of the CMT1A-REP repeat was investigated through an analysis of homologous sequences in non-human primates. Southern blot analysis indicated that the chimpanzee has two copies of a CMT1A-REP-like sequence, whereas gorilla, orangutan, and gibbon have a single copy. A high degree of conservation amongst non-human primates for restriction fragments specific to the human distal CMT1A-REP repeat provides further evidence that the distal repeat is the progenitor copy. The mariner-like sequence was detected in association with the CMT1A-REP sequence in all primates studied suggesting that the mariner-like element was introduced into the progenitor CMT1A-REP sequence prior to emergence of the proximal and distal CMT1A-REP repeats. These observations suggest that CMT1A-REP sequence appeared as a repeat before the divergence of chimpanzee and human, but after gorilla and human around 6 to 7 million years ago. © 1996 Oxford University Press Kiyosawa Hidenori Division of Neurology, The Children's Hospital of Philadelphia and Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA aut Chance Phillip F. Division of Neurology, The Children's Hospital of Philadelphia and Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA aut Human Molecular Genetics Oxford University Press 5/6(1996-06), 745-753 0964-6906 5:6<745 1996 5 hmg https://doi.org/10.1093/hmg/5.6.745 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.6.745 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kiyosawa Hidenori Division of Neurology, The Children's Hospital of Philadelphia and Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA aut NATIONALLICENCE 700 1- Chance Phillip F. Division of Neurology, The Children's Hospital of Philadelphia and Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/6(1996-06), 745-753 0964-6906 5:6<745 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford