title: The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes.
abstract: Duplication and deletion of the 1.4-Mb region in 17p12 that is delimited by two 24-kb low copy number repeats (CMT1A-REPs) represent frequent genomic rearrangements resulting in two common inherited peripheral neuropathies, Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP). CMT1A and HNPP exemplify a paradigm for genomic disorders wherein unique genome architectural features result in susceptibility to DNA rearrangements that cause disease. A gene within the 1.4-Mb region, PMP22, is responsible for these disorders through a gene-dosage effect in the heterozygous duplication or deletion. However, the genomic structure of the 1.4-Mb region, including other genes contained within the rearranged genomic segment, remains essentially uncharacterized. To delineate genomic structural features, investigate higher-order genomic architecture, and identify genes in this region, we constructed PAC and BAC contigs and determined the complete nucleotide sequence. This CMT1A/HNPP genomic segment contains 1,421,129 bp of DNA. A low copy number repeat (LCR) was identified, with one copy inside and two copies outside of the 1.4-Mb region. Comparison between physical and genetic maps revealed a striking difference in recombination rates between the sexes with a lower recombination frequency in males (0.67 cM/Mb) versus females (5.5 cM/Mb). Hypothetically, this low recombination frequency in males may enable a chromosomal misalignment at proximal and distal CMT1A-REPs and promote unequal crossing over, which occurs 10 times more frequently in male meiosis. In addition to three previously described genes, five new genes (TEKT3, HS3ST3B1, NPD008/CGI-148, CDRT1, and CDRT15) and 13 predicted genes were identified. Most of these predicted genes are expressed only in embryonic stages. Analyses of the genomic region adjacent to proximal CMT1A-REP indicated an evolutionary mechanism for the formation of proximal CMT1A-REP and the creation of novel genes by DNA rearrangement during primate speciation.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Dewar
authors.forename: N
authors.initials: N
authors.lastname: Katsanis
authors.forename: L T
authors.initials: LT
authors.lastname: Reiter
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
authors.forename: K L
authors.initials: KL
authors.lastname: Devon
authors.forename: D W
authors.initials: DW
authors.lastname: Wyman
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
authors.forename: B
authors.initials: B
authors.lastname: Birren
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D016678:Genome; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D020071:Interspersed Repetitive Sequences / Q000235:genetics; D008297:Male; D051379:Mice; D009185:Myelin Proteins / Q000235:genetics; D020161:Physical Chromosome Mapping; D011544:Pseudogenes; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods; D015238:Sulfotransferases / Q000235:genetics
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human; C489545:Pmp22 protein, mouse; D015238:Sulfotransferases; C102180:heparan sulfate D-glucosaminyl 3-O-sulfotransferase