Population differences of chromosome 22q11.2 duplication structure predispose differentially to microdeletion and inversion
- David Porubsky
- DongAhn Yoo
- Nidhi Koundinya
- Erika Souche
- Philip C. Dishuck
- Nicolas Dierckxsens
- William T. Harvey
- Katherine M. Munson
- Kendra Hoekzema
- Daniel D. Chan
- Tiffany Y. Leung
- Marta S. Santos
- Senne Meynants
- Ann Swillen
- Jeroen Breckpot
- Vasiliki Tsapalou
- Patrick Hasenfeld
- Jan O. Korbel
- Derek Albracht
- Ivan A. Alexandrov
- Jamie Allen
- Alawi A. Alsheikh-Ali
- Nicolas Altemose
- Casey Andrews
- Dmitry Antipov
- Lucinda Antonacci-Fulton
- Mobin Asri
- Marcelo Ayllon
- Jennifer R. Balacco
- Floris P. Barthel
- Edward A. Belter
- Halle D. Bender
- Andrew P. Blair
- Davide Bolognini
- Katherine E. Bonini
- Christina Boucher
- Guillaume Bourque
- Silvia Buonaiuto
- Shuo Cao
- Andrew Carroll
- Ann M. Mc Cartney
- Monika Cechova
- Mark J. P. Chaisson
- Pi-Chuan Chang
- Xian Chang
- Jitender Cheema
- Haoyu Cheng
- Claudio Ciofi
- Hiram Clawson
- Sarah Cody
2026-04-18
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.