Cmt1arep An Lcrmediating Nahr

Physical analysis revealed proximal 17p region-specific LCR (CMT1A-REP) that flank the genomic region duplicated in the CMT1A duplication (20). The CMT1A-REP LCR was not found in early mammals (mouse and hamster) (20), but instead shown to have evolved during primate speciation. CMT1A-REP segmental duplication occurred after the divergence of gorilla and chimpanzee because there were two copies noted in the chimpanzee genome, whereas only

Fig. 1. Multiple methods reveal evidence for duplication. Shown are four separate methods (A-D) that originally enabled visualization of the duplication (74). Simple sequence repeat or short tandem repeat analysis showed three alleles in informative affected individuals. Restriction fragment length polymorphism (RFLP) analysis showed a dosage difference in heterozygous affected individuals, whereas some patients with the CMT1A duplication were fully informative with three different RFLP alleles observed. Pulsed-field gel electrophoresis identified a patient-specific junction fragment of approx 500 kb in size. Fluorescence in situ hybridization (FISH) showed the duplicated segment (two adjacent red dots) only in interphase (this is not resolved in metaphase nuclei) where the control probe (green dots) was not replicated enabling one to distinguish duplication from replication. Note the duplicated chromosome has two red signals and one green signal compared to the normal (one red and one green) control chromosome 17 homolog. (E) Fiber FISH (bottom) reveals the predicted three copies of CMT1A-REP (green) and two copies of PMP22 (red) in the CMT1A duplication bearing chromosome (75).

Fig. 1. Multiple methods reveal evidence for duplication. Shown are four separate methods (A-D) that originally enabled visualization of the duplication (74). Simple sequence repeat or short tandem repeat analysis showed three alleles in informative affected individuals. Restriction fragment length polymorphism (RFLP) analysis showed a dosage difference in heterozygous affected individuals, whereas some patients with the CMT1A duplication were fully informative with three different RFLP alleles observed. Pulsed-field gel electrophoresis identified a patient-specific junction fragment of approx 500 kb in size. Fluorescence in situ hybridization (FISH) showed the duplicated segment (two adjacent red dots) only in interphase (this is not resolved in metaphase nuclei) where the control probe (green dots) was not replicated enabling one to distinguish duplication from replication. Note the duplicated chromosome has two red signals and one green signal compared to the normal (one red and one green) control chromosome 17 homolog. (E) Fiber FISH (bottom) reveals the predicted three copies of CMT1A-REP (green) and two copies of PMP22 (red) in the CMT1A duplication bearing chromosome (75).

one copy was present in the gorilla genome (21-23). Segmental duplications occurring during primate genome evolution are a recurrent theme in genome architectural features associated with rearrangements causing genomic disorders (24) .The proximal CMT1A-REP and distal CMT1A-REP share about 24,000 bp of approx 99% DNA sequence identity (23). The proximal (centromeric) copy of CMT1A-REP derived from the distal (telomeric) copy. The COX10 gene, encoding the hemeA:farnesyltransferase that farnesylates the hemeA group that is incorporated into cytochrome oxidase, spans the distal CMT1-REP. Proximal CMT1A-REP represents a segmental

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