Population differences of chromosome 22q11.2 duplication structure predispose differentially to microdeletion and inversion

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Abstract
Chromosome 22q11.2 microdeletion syndrome (22q11.2DS) is mediated by high-identity polymorphic low-copy repeats (LCRA-to-D) that have been challenging to sequence characterize. We sequence-resolved 135 chromosome 22q11.2 haplotypes from diverse humans and define 63 distinct structural configurations differing in size by 11-fold for LCRA. This diversity is driven by a 105 kbp segmental duplication flanked by 25 kbp inverted repeats that arose in the apes but expanded in humans ~1 million years ago. African LCRA haplotypes are significantly longer ( p = 0.0047) and predicted to be more protective against 22q11.2DS ( p = 1.14×10 -6 ) due to enrichment of inverted 105 kbp repeats. We identify nine distinct (including five recurrent) inversions spanning LCRA-D. Sequencing four families indicates LCRA-D deletions map to 105 kbp repeats, whereas inversions map to the 25 kbp repeats. Here, we show specific haplotype LCR architectures and recurrent large-scale inversions modulate susceptibility to 22q11.2DS and help explain its reduced prevalence among individuals of African ancestry.
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Funding Information
  • National Human Genome Research Institute (HG010169)
  • National Human Genome Research Institute (HG010971)
  • National Human Genome Research Institute (HG007497)
  • Howard Hughes Medical Institute (N/A)
  • Stichting Marguerite-Marie Delacroix RVC/B-534
  • Terry Fox Research Institute (1074)
  • Canada Foundation for Innovation (40044)
  • Canada Foundation for Innovation (43153)
  • Fonds Wetenschappelijk Onderzoek (G0A2622N)
  • KU Leuven (C14/22/125)

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