CMT History Part 2

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I am reposting this abstract (which can be found in our files)

Scroll down to the last few lines where it says CMT 1A Rep goes back 6-7 million

years. Certainly puts things into a vast 'historical'

perspective. ~ Gretchen

Primates CMT1A Research

Hum Mol Genet. 1996 Jun;5(6):745-53

Primate origin of the CMT1A-REP repeat and analysis of a putative

transposon-associated recombinational hotspot.

Kiyosawa H, Chance PF.

Division of Neurology, Children's Hospital of Philadelphia,

Pennsylvania 19104, USA.

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.