Human Molecular Genetics, Vol 5, 745-753, Copyright © 1996 by Oxford University Press
H Kiyosawa and PF 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
SacI 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.
ARTICLES
Primate origin of the CMT1A-REP repeat and analysis of a putative transposon-associated recombinational hotspot
Division of Neurology, Children's Hospital of Philadelphia, Pennsylvania 19104, USA.
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