TY - JOUR
T1 - LINE- and Alu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV
AU - Szafranski, Przemyslaw
AU - Kośmider, Ewelina
AU - Liu, Qian
AU - Karolak, Justyna A.
AU - Currie, Lauren
AU - Parkash, Sandhya
AU - Kahler, Stephen G.
AU - Roeder, Elizabeth
AU - Littlejohn, Rebecca O.
AU - DeNapoli, Thomas S.
AU - Shardonofsky, Felix R.
AU - Henderson, Cody
AU - Powers, George
AU - Poisson, Virginie
AU - Bérubé, Denis
AU - Oligny, Luc
AU - Michaud, Jacques L.
AU - Janssens, Sandra
AU - De Coen, Kris
AU - Van Dorpe, Jo
AU - Dheedene, Annelies
AU - Harting, Matthew T.
AU - Weaver, Matthew D.
AU - Khan, Amir M.
AU - Tatevian, Nina
AU - Wambach, Jennifer
AU - Gibbs, Kathleen A.
AU - Popek, Edwina
AU - Gambin, Anna
AU - Stankiewicz, Paweł
N1 - Publisher Copyright:
© 2018 Wiley Periodicals, Inc.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/12
Y1 - 2018/12
N2 - Transposable elements modify human genome by inserting into new loci or by mediating homology-, microhomology-, or homeology-driven DNA recombination or repair, resulting in genomic structural variation. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal neonatal developmental lung disorder caused by point mutations or copy-number variant (CNV) deletions of FOXF1 or its distant tissue-specific enhancer. Eighty-five percent of 45 ACDMPV-causative CNV deletions, of which junctions have been sequenced, had at least one of their two breakpoints located in a retrotransposon, with more than half of them being Alu elements. We describe a novel ∼35 kb-large genomic instability hotspot at 16q24.1, involving two evolutionarily young LINE-1 (L1) elements, L1PA2 and L1PA3, flanking AluY, two AluSx, AluSx1, and AluJr elements. The occurrence of L1s at this location coincided with the branching out of the Homo-Pan-Gorilla clade, and was preceded by the insertion of AluSx, AluSx1, and AluJr. Our data show that, in addition to mediating recurrent CNVs, L1 and Alu retrotransposons can predispose the human genome to formation of variably sized CNVs, both of clinical and evolutionary relevance. Nonetheless, epigenetic or other genomic features of this locus might also contribute to its increased instability.
AB - Transposable elements modify human genome by inserting into new loci or by mediating homology-, microhomology-, or homeology-driven DNA recombination or repair, resulting in genomic structural variation. Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal neonatal developmental lung disorder caused by point mutations or copy-number variant (CNV) deletions of FOXF1 or its distant tissue-specific enhancer. Eighty-five percent of 45 ACDMPV-causative CNV deletions, of which junctions have been sequenced, had at least one of their two breakpoints located in a retrotransposon, with more than half of them being Alu elements. We describe a novel ∼35 kb-large genomic instability hotspot at 16q24.1, involving two evolutionarily young LINE-1 (L1) elements, L1PA2 and L1PA3, flanking AluY, two AluSx, AluSx1, and AluJr elements. The occurrence of L1s at this location coincided with the branching out of the Homo-Pan-Gorilla clade, and was preceded by the insertion of AluSx, AluSx1, and AluJr. Our data show that, in addition to mediating recurrent CNVs, L1 and Alu retrotransposons can predispose the human genome to formation of variably sized CNVs, both of clinical and evolutionary relevance. Nonetheless, epigenetic or other genomic features of this locus might also contribute to its increased instability.
KW - DNA repair
KW - genome instability
KW - nonrecurrent structural variants
UR - http://www.scopus.com/inward/record.url?scp=85052471208&partnerID=8YFLogxK
U2 - 10.1002/humu.23608
DO - 10.1002/humu.23608
M3 - Article
C2 - 30084155
AN - SCOPUS:85052471208
VL - 39
SP - 1916
EP - 1925
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 12
ER -