title: A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full-length LINE-1 element.
abstract: The long interspersed element-1 (LINE-1 or L1) retrotransposition has altered the human genome in many ways. In particular, recent in vitro studies have demonstrated that the retrotranspositional insertion of L1 elements has resulted in significant genomic deletions. Here we provide evidence for its operation in the human genome by identifying a approximately 46-kb pathological genomic deletion in the PDHX gene directly linked to the insertion of a full-length L1 element, in a patient with pyruvate dehydrogenase complex (PDHc) deficiency. Both the deduced bottom and top strand cleavage sites in the PDHX gene coincide with the consensus L1 endonuclease (EN) target sequence 5'-TTTT/A-3', while the full-length L1 element is followed by a 67-bp poly(A) tail. Interestingly, two hairpin structures, potentially formed by the inverted repeats present immediately 5' to the top strand nick site and 3' to the bottom strand nick site, may have facilitated the accessibility of L1 EN to the target sequences and also brought the two otherwise distantly located sequences into close proximity. Since the L1 element inserted in the PDHX gene is full-length, we favor the model of the template jumping as opposed to that of the microhomology-mediated end-joining for linking the 5' end of the nascent L1 copy to its genomic target. Our finding not only serves as an important complement to the in vitro approaches to studying L1 retrotransposition, but also reveals a novel mechanism causing human genetic disease.
authors.affiliation: Centre de Recherches Thérapeutiques en Ophtalmologie, Faculté de Médecine Necker, Paris, France.
authors.forename: Manuèle
authors.initials: M
authors.lastname: Miné
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Michèle
authors.initials: M
authors.lastname: Brivet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Dominique
authors.initials: D
authors.lastname: Marchant
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Aral
authors.initials: A
authors.lastname: Bernard
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Marc
authors.initials: M
authors.lastname: Abitbol
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricquier
authors.forename: Cécile
authors.initials: C
authors.lastname: Marsac
mesh_terms: D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009690:Nucleic Acid Conformation; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry / Q000235:genetics*; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000235:genetics
chemical_list: C045867:PDHX protein, human; D011768:Pyruvate Dehydrogenase Complex