title: Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation.
abstract: Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR1 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a single-nucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located ∼53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected hESCs. These results suggest that a T/C SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 jeannine.gerhardt@gmail.com carl.schildkraut@einstein.yu.edu.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Gerhardt
authors.affiliation: Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10021.
authors.forename: Nikica
authors.initials: N
authors.lastname: Zaninovic
authors.affiliation: Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10021.
authors.forename: Qiansheng
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Advaitha
authors.initials: A
authors.lastname: Madireddy
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Nolin
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ersalesi
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10021.
authors.forename: Zev
authors.initials: Z
authors.lastname: Rosenwaks
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 jeannine.gerhardt@gmail.com carl.schildkraut@einstein.yu.edu.
authors.forename: Carl L
authors.initials: CL
authors.lastname: Schildkraut
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D019175:DNA Methylation; D004261:DNA Replication; D053595:Embryonic Stem Cells / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D018741:Replication Origin; D019680:Trinucleotide Repeat Expansion