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

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

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

Volume / Issue Vol. 17, Issue 1
Published April 18, 2026
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (224)

D

David Porubsky

D

DongAhn Yoo

N

Nidhi Koundinya

E

Erika Souche

P

Philip C. Dishuck

N

Nicolas Dierckxsens

W

William T. Harvey

K

Katherine M. Munson

K

Kendra Hoekzema

D

Daniel D. Chan

T

Tiffany Y. Leung

M

Marta S. Santos

S

Senne Meynants

A

Ann Swillen

J

Jeroen Breckpot

V

Vasiliki Tsapalou

P

Patrick Hasenfeld

J

Jan O. Korbel

D

Derek Albracht

I

Ivan A. Alexandrov

J

Jamie Allen

A

Alawi A. Alsheikh-Ali

N

Nicolas Altemose

C

Casey Andrews

D

Dmitry Antipov

L

Lucinda Antonacci-Fulton

M

Mobin Asri

M

Marcelo Ayllon

J

Jennifer R. Balacco

F

Floris P. Barthel

E

Edward A. Belter

H

Halle D. Bender

A

Andrew P. Blair

D

Davide Bolognini

K

Katherine E. Bonini

C

Christina Boucher

G

Guillaume Bourque

S

Silvia Buonaiuto

S

Shuo Cao

A

Andrew Carroll

A

Ann M. Mc Cartney

M

Monika Čechová

M

Mark J. P. Chaisson

P

Pi-Chuan Chang

X

Xian Chang

J

Jitender Cheema

H

Haoyu Cheng

C

Claudio Ciofi

H

Hiram Clawson

S

Sarah Cody

V

Vincenza Colonna

H

Holland C. Conwell

Department of Biomolecular Engineering, University of California

R

Robert Cook-Deegan

M

Mark Diekhans

M

Maria Angela Diroma

D

Daniel Doerr

Z

Zheng Dong

D

Danilo Dubocanin

R

Richard Durbin

J

Jana Ebler

J

Jordan M. Eizenga

P

Parsa Eskandar

E

Eddie Ferro

A

Anna-Sophie Fiston-Lavier

S

Sarah M. Ford

San Diego Zoo Wildlife Alliance

W

Willard W. Ford

G

Giulio Formenti

A

Adam Frankish

M

Mallory A. Freeberg

Q

Qichen Fu

S

Stephanie M. Fullerton

University of Washington, Seattle, WA, USA.

R

Robert S. Fulton

Y

Yan Gao

G

Gage H. Garcia

O

Obed A. Garcia

J

Joshua M. V. Gardner

S

Shilpa Garg

E

Erik Garrison

N

Nanibaa’ A. Garrison

J

John E. Garza

M

Margarita Geleta

M

Mohammadmersad Ghorbani

T

Tina A. Graves-Lindsay

R

Richard E. Green

C

Cristian Groza

B

Bida Gu

A

Andrea Guarracino

M

Melissa Gymrek

M

Maximilian Haeussler

L

Leanne Haggerty

I

Ira M. Hall

N

Nancy F. Hansen

Y

Yue Hao

M

Mohammad Amiruddin Hashmi

D

David Haussler

P

Prajna Hebbar

P

Peter Heringer

G

Glenn Hickey

T

Todd L. Hillaker

S

S. Nakib Hossain

N

Neng Huang

S

Sarah E. Hunt

T

Toby Hunt

A

Alexander G. Ioannidis

N

Nafiseh Jafarzadeh

N

Nivesh Jain

E

Erich D. Jarvis

M

Maryam Jehangir

J

Juan Jiang

E

Eimear E. Kenny

J

Juhyun Kim

B

Bonhwang Koo

S

Sergey Koren

M

Milinn Kremitzki

C

Charles H. Langley

B

Ben Langmead

H

Heather A. Lawson

D

Daofeng Li

H

Heng Li

W

Wen-Wei Liao

J

Jiadong Lin

T

Tianjie Liu

G

Glennis A. Logsdon

R

Ryan Lorig-Roach

J

Jonathan LoTempio

H

Hailey Loucks

J

Jane E. Loveland

J

Jianguo Lu

S

Shuangjia Lu

J

Julian K. Lucas

W

Walfred Ma

J

Juan F. Macias-Velasco

K

Kateryna D. Makova

M

Maximillian G. Marin

C

Christopher Markovic

T

Tobias Marschall

F

Franco L. Marsico

F

Fergal J. Martin

M

Mira Mastoras

C

Capucine Mayoud

B

Brandy McNulty

J

Jack A. Medico

J

Julian M. Menendez

K

Karen H. Miga

A

Anna Minkina

M

Matthew W. Mitchell

S

Saswat K. Mohanty

Y

Younes Mokrab

J

Jean Monlong

S

Shabir Moosa

A

Avelina Moreno-Ochando

S

Shinichi Morishita

J

Jonathan M. Mudge

N

Njagi Mwaniki

N

Nasna Nassir

C

Chiara Natali

S

Shloka Negi

L

Lingbin Ni

A

Adam M. Novak

P

Pilar N. Ossorio

C

Chie Owa

S

Sadye Paez

B

Benedict Paten

C

Clelia Peano

A

Adam M. Phillippy

B

Brandon D. Pickett

L

Laura Pignata

N

Nadia Pisanti

P

Pjotr Prins

A

Anandi Radhakrishnan

T

T. Rhyker Ranallo-Benavidez

B

Brian J. Raney

M

Mikko Rautiainen

A

Alessandro Raveane

L

Luyao Ren

A

Arang Rhie

F

Fedor Ryabov

S

Samuel Sacco

F

Farnaz Salehi

M

Michael C. Schatz

L

Laura B. Scheinfeldt

A

Aarushi Sehgal

W

William E. Seligmann

Department of Biomolecular Engineering, University of California

M

Mahsa Shabani

K

Kishwar Shafin

S

Shadi Shahatit

R

Ruhollah Shemirani

V

Vikram S. Shivakumar

S

Swati Sinha

J

Jouni Sirén

L

Linnéa Smeds

S

Steven J. Solar

M

Marco Sollitto

N

Nicole Soranzo

A

Andrew B. Stergachis

M

Marie-Marthe Suner

Y

Yoshihiko Suzuki

A

Arda Söylev

A

Ahmad Abou Tayoun

J

Jack A. S. Tierney

C

Chad Tomlinson

F

Francesca Floriana Tricomi

M

Mohammed Uddin

M

Matteo Tommaso Ungaro

R

Rahul Varki

F

Flavia Villani

I

Ivo Violich

M

Mitchell R. Vollger

B

Brian P. Walenz

C

Charles Wang

L

Lisa E. Wang

T

Ting Wang

Department of Radiation Oncology The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou China

A

Aaron M. Wenger

C

Conor V. Whelan

Z

Zilan Xin

Z

Zheng Xu

K

Kai Ye

W

Wenjin Zhang

Y

Ying Zhou

X

Xiaoyu Zhuo

G

Giulia Zunino

P

Peter M. Lansdorp

J

Joris R. Vermeesch

E

Evan E. Eichler