Population differences of chromosome 22q11.2 duplication structure predispose differentially to microdeletion and inversion
Abstract
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.
Article Details
Authors (224)
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 Čechová
Mark J. P. Chaisson
Pi-Chuan Chang
Xian Chang
Jitender Cheema
Haoyu Cheng
Claudio Ciofi
Hiram Clawson
Sarah Cody
Vincenza Colonna
Holland C. Conwell
Department of Biomolecular Engineering, University of California
Robert Cook-Deegan
Mark Diekhans
Maria Angela Diroma
Daniel Doerr
Zheng Dong
Danilo Dubocanin
Richard Durbin
Jana Ebler
Jordan M. Eizenga
Parsa Eskandar
Eddie Ferro
Anna-Sophie Fiston-Lavier
Sarah M. Ford
San Diego Zoo Wildlife Alliance
Willard W. Ford
Giulio Formenti
Adam Frankish
Mallory A. Freeberg
Qichen Fu
Stephanie M. Fullerton
University of Washington, Seattle, WA, USA.
Robert S. Fulton
Yan Gao
Gage H. Garcia
Obed A. Garcia
Joshua M. V. Gardner
Shilpa Garg
Erik Garrison
Nanibaa’ A. Garrison
John E. Garza
Margarita Geleta
Mohammadmersad Ghorbani
Tina A. Graves-Lindsay
Richard E. Green
Cristian Groza
Bida Gu
Andrea Guarracino
Melissa Gymrek
Maximilian Haeussler
Leanne Haggerty
Ira M. Hall
Nancy F. Hansen
Yue Hao
Mohammad Amiruddin Hashmi
David Haussler
Prajna Hebbar
Peter Heringer
Glenn Hickey
Todd L. Hillaker
S. Nakib Hossain
Neng Huang
Sarah E. Hunt
Toby Hunt
Alexander G. Ioannidis
Nafiseh Jafarzadeh
Nivesh Jain
Erich D. Jarvis
Maryam Jehangir
Juan Jiang
Eimear E. Kenny
Juhyun Kim
Bonhwang Koo
Sergey Koren
Milinn Kremitzki
Charles H. Langley
Ben Langmead
Heather A. Lawson
Daofeng Li
Heng Li
Wen-Wei Liao
Jiadong Lin
Tianjie Liu
Glennis A. Logsdon
Ryan Lorig-Roach
Jonathan LoTempio
Hailey Loucks
Jane E. Loveland
Jianguo Lu
Shuangjia Lu
Julian K. Lucas
Walfred Ma
Juan F. Macias-Velasco
Kateryna D. Makova
Maximillian G. Marin
Christopher Markovic
Tobias Marschall
Franco L. Marsico
Fergal J. Martin
Mira Mastoras
Capucine Mayoud
Brandy McNulty
Jack A. Medico
Julian M. Menendez
Karen H. Miga
Anna Minkina
Matthew W. Mitchell
Saswat K. Mohanty
Younes Mokrab
Jean Monlong
Shabir Moosa
Avelina Moreno-Ochando
Shinichi Morishita
Jonathan M. Mudge
Njagi Mwaniki
Nasna Nassir
Chiara Natali
Shloka Negi
Lingbin Ni
Adam M. Novak
Pilar N. Ossorio
Chie Owa
Sadye Paez
Benedict Paten
Clelia Peano
Adam M. Phillippy
Brandon D. Pickett
Laura Pignata
Nadia Pisanti
Pjotr Prins
Anandi Radhakrishnan
T. Rhyker Ranallo-Benavidez
Brian J. Raney
Mikko Rautiainen
Alessandro Raveane
Luyao Ren
Arang Rhie
Fedor Ryabov
Samuel Sacco
Farnaz Salehi
Michael C. Schatz
Laura B. Scheinfeldt
Aarushi Sehgal
William E. Seligmann
Department of Biomolecular Engineering, University of California
Mahsa Shabani
Kishwar Shafin
Shadi Shahatit
Ruhollah Shemirani
Vikram S. Shivakumar
Swati Sinha
Jouni Sirén
Linnéa Smeds
Steven J. Solar
Marco Sollitto
Nicole Soranzo
Andrew B. Stergachis
Marie-Marthe Suner
Yoshihiko Suzuki
Arda Söylev
Ahmad Abou Tayoun
Jack A. S. Tierney
Chad Tomlinson
Francesca Floriana Tricomi
Mohammed Uddin
Matteo Tommaso Ungaro
Rahul Varki
Flavia Villani
Ivo Violich
Mitchell R. Vollger
Brian P. Walenz
Charles Wang
Lisa E. Wang
Ting Wang
Department of Radiation Oncology The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou China
Aaron M. Wenger
Conor V. Whelan
Zilan Xin
Zheng Xu
Kai Ye
Wenjin Zhang
Ying Zhou
Xiaoyu Zhuo
Giulia Zunino
Peter M. Lansdorp
Joris R. Vermeesch
Evan E. Eichler