title: Breakage-fusion-bridge cycles leading to inv dup del occur in human cleavage stage embryos.
abstract: Recently, a high incidence of chromosome instability (CIN) was reported in human cleavage stage embryos. Based on the copy number changes that were observed in the blastomeres it was hypothesized that chromosome breakages and fusions occur frequently in cleavage stage human embryos and instigate subsequent breakage-fusion-bridge cycles. In addition, it was hypothesized that the DNA breaks present in spermatozoa could trigger this CIN. To test these hypotheses, we genotyped both parents as well as 93 blastomeres from 24 IVF embryos and developed a novel single nucleotide polymorphism (SNP) array-based algorithm to determine the parental origin of (aberrant) loci in single cells. Paternal as well as maternal alleles were commonly rearranged in the blastomeres indicating that sperm-specific DNA breaks do not explain the majority of these structural variants. The parent-of-origin analyses together with microarray-guided FISH analyses demonstrate the presence of inv dup del chromosomes as well as more complex rearrangements. These data provide unequivocal evidence for breakage-fusion-bridge cycles in those embryos and suggest that the human cleavage stage embryo is a major source of chromosomal disorders.
authors.affiliation: Center for Human Genetics, KULeuven-UZ Gasthuisberg, Herestraat 49, Leuven, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Voet
authors.forename: Evelyne
authors.initials: E
authors.lastname: Vanneste
authors.forename: Niels
authors.initials: N
authors.lastname: Van der Aa
authors.forename: Cindy
authors.initials: C
authors.lastname: Melotte
authors.forename: Sigrun
authors.initials: S
authors.lastname: Jackmaert
authors.forename: Tamara
authors.initials: T
authors.lastname: Vandendael
authors.forename: Matthias
authors.initials: M
authors.lastname: Declercq
authors.forename: Sophie
authors.initials: S
authors.lastname: Debrock
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Yves
authors.initials: Y
authors.lastname: Moreau
authors.forename: Thomas
authors.initials: T
authors.lastname: D'Hooghe
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D000465:Algorithms; D001757:Blastomeres / Q000648:ultrastructure*; D002872:Chromosome Deletion; D058674:Chromosome Duplication / Q000235:genetics*; D007446:Chromosome Inversion / Q000235:genetics*; D002970:Cleavage Stage, Ovum / Q000648:ultrastructure*; D053960:DNA Breaks; D056915:DNA Copy Number Variations / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012303:Ring Chromosomes; D059010:Single-Cell Analysis; D013094:Spermatozoa / Q000648:ultrastructure