LINE- and Alu-containing genomic instability hotspot at 16q24.1 associated with recurrent and nonrecurrent CNV deletions causative for ACDMPV

Hum Mutat. 2018 Dec;39(12):1916-1925. doi: 10.1002/humu.23608. Epub 2018 Aug 22.


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.

Keywords: DNA repair; genome instability; nonrecurrent structural variants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements
  • Chromosomes, Human, Pair 16 / genetics*
  • DNA Copy Number Variations*
  • Evolution, Molecular
  • Forkhead Transcription Factors / genetics
  • Genetic Predisposition to Disease
  • Genomic Instability*
  • Humans
  • Long Interspersed Nucleotide Elements
  • Pedigree
  • Persistent Fetal Circulation Syndrome / genetics*
  • Point Mutation


  • FOXF1 protein, human
  • Forkhead Transcription Factors