Using the linear references from the pangenome to discover missing autism variants
Abstract
Abstract To better understand large-effect pathogenic variation associated with autism, we generated long-read sequencing (LRS) data to construct phased and near-complete genome assemblies (average contig N50 = 43 Mbp, QV = 56) for 189 individuals from 51 families with unsolved cases. We applied read- and assembly-based strategies to facilitate comprehensive characterization of de novo mutations, structural variants (SVs), and DNA methylation. Using LRS pangenome controls, we efficiently filtered >97% of common SVs exclusive to 87 offspring. We find no evidence of increased autosomal SV burden for probands when compared to unaffected siblings yet observe a suggestive trend toward an increased SV burden on the X chromosome among affected females. We establish a workflow to prioritize potential pathogenic variants by integrating autism risk genes and putative noncoding regulatory elements defined from ATAC-seq and CUT&Tag data from the developing cortex. In total, we identified three pathogenic variants in TBL1XR1 , MECP2 , and SYNGAP1 , as well as nine candidate de novo and biallelic inherited homozygous SVs, most of which were missed by short-read sequencing. Our work highlights the potential of phased genomes to discover complex more pathogenic mutations and the power of the pangenome to restrict the focus on an increasingly smaller number of SVs for clinical evaluation.
Article Details
Authors (228)
Yang Sui
Jiadong Lin
Michelle D. Noyes
Youngjun Kwon
Isaac Wong
Nidhi Koundinya
William T. Harvey
Mei Wu
Kendra Hoekzema
Katherine M. Munson
Gage H. Garcia
Jordan Knuth
Julie Wertz
Tianyun Wang
Department of Medical Genetics, School of Basic Medical Sciences, Neuroscience Research Institute, Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Peking University
Kelsey Hennick
Druha Karunakaran
Rafael A. Polo Prieto
Rebecca Meyer-Schuman
Fisher Cherry
Davut Pehlivan
Bernhard Suter
Jonas A. Gustafson
Danny E. Miller
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
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
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
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
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
Edward A. Belter
Jonathan LoTempio
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
Tianjie Liu
Glennis A. Logsdon
Ryan Lorig-Roach
Hailey Loucks
Jane E. Loveland
Jianguo Lu
Shuangjia Lu
Julian K. Lucas
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
David Porubsky
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
DongAhn Yoo
Wenjin Zhang
Ying Zhou
Xiaoyu Zhuo
Giulia Zunino
Hanna Berk-Rauch
Tomasz J. Nowakowski
Aravinda Chakravarti
Center for Human Genetics and Genomics, New York University Grossman School of Medicine
Huda Y. Zoghbi
Evan E. Eichler