Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

Xiaowei Zhu; Bo Zhou; Reenal Pattni; Kelly Gleason; Chunfeng Tan; Agnieszka Kalinowski; Steven Sloan; Anna-Sophie Fiston-Lavier; Jessica Mariani; Dmitri Petrov; Ben Barres; Laramie Duncan; Alexej Abyzov; Hannes Vogel; Alexander Urban; Christopher Walsh; Javier Ganz; Mollie Woodworth; Pengpeng Li; Rachel Rodin; Robert Hill; Sara Bizzotto; Zinan Zhou; Alice Lee; Alissa D’gama; Alon Galor; Craig Bohrson; Daniel Kwon; Doga Gulhan; Elaine Lim; Isidro Cortes; Joe Luquette; Maxwell Sherman; Michael Coulter; Michael Lodato; Peter Park; Rebeca Monroy; Sonia Kim; Yanmei Dou; Andrew Chess; Attila Jones; Chaggai Rosenbluh; Schahram Akbarian; Ben Langmead; Jeremy Thorpe; Jonathan Pevsner; Rob Scharpf; Sean Cho; Flora Vaccarino; Liana Fasching; Simone Tomasi; Nenad Sestan; Sirisha Pochareddy; Andrew Jaffe; Apua Paquola; Daniel Weinberger; Jennifer Erwin; Jooheon Shin; Richard Straub; Rujuta Narurkar; Anjene Addington; David Panchision; Doug Meinecke; Geetha Senthil; Lora Bingaman; Tara Dutka; Thomas Lehner; Taejeong Bae; Laura Saucedo-Cuevas; Tara Conniff; Diane Flasch; Trenton Frisbie; Jeffrey Kidd; Mandy Lam; John Moldovan; John Moran; Kenneth Kwan; Ryan Mills; Sarah Emery; Weichen Zhou; Yifan Wang; Kenneth Daily; Mette Peters; Fred Gage; Meiyan Wang; Patrick Reed; Sara Linker; Ani Sarkar; Aitor Serres; David Juan; Inna Povolotskaya; Irene Lobon; Manuel Solis; Raquel Garcia; Tomas Marques-Bonet; Gary Mathern; Jing Gu; Joseph Gleeson; Laurel Ball; Renee George; Tiziano Pramparo; Aakrosh Ratan; Mike Mcconnell; Carol Tamminga; Douglas Levinson

doi:10.1038/s41593-020-00767-4

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Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

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Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

Xiaowei Zhu, Bo Zhou, Reenal Pattni, Kelly Gleason, Chunfeng Tan, Agnieszka Kalinowski, Steven Sloan, Anna-Sophie Fiston-Lavier, Jessica Mariani, Dmitri Petrov, …

Nature Neuroscience, Vol.24(2), pp.186-196

11/01/2021

DOI: https://doi.org/10.1038/s41593-020-00767-4

Résumé

Schizophrenia

Neuronal development

Neurodevelopmental disorders

Machine learning

Glial development

Active retrotransposons in the human genome (L1, Alu and SVA elements) can create genomic mobile element insertions (MEIs) in both germline and somatic tissue1. Specific somatic MEIs have been detected at high levels in human cancers2, and at lower to medium levels in human brains3. Dysregulation of somatic retrotransposition in the human brain has been hypothesized to contribute to neuropsychiatric diseases4,5. However, individual somatic MEIs are present in small proportions of cells at a given anatomical location, and thus standard whole-genome sequencing (WGS) presents a difficult signal-to-noise problem, while single-cell approaches suffer from limited scalability and experimental artifacts introduced by enzymatic whole-genome amplification6. Previous studies produced widely differing estimates for the somatic retrotransposition rates in human brain3,6–8. Here, we present a highly precise machine learning method (RetroSom) to directly identify somatic L1 and Alu insertions in <1% cells from 200× deep WGS, which allows circumventing the restrictions of whole-genome amplification. Using RetroSom we confirmed a lower rate of retrotransposition for individual somatic L1 insertions in human neurons. We discovered that anatomical distribution of somatic L1 insertion is as widespread in glia as in neurons, and across both hemispheres of the brain, indicating retrotransposition occurs during early embryogenesis. We characterized two of the detected brain-specific L1 insertions in great detail in neurons and glia from a donor with schizophrenia. Both insertions are within introns of genes active in brain (CNNM2, FRMD4A) in regions with multiple genetic associations with neuropsychiatric disorders9–11. Gene expression was significantly reduced by both somatic insertions in a reporter assay. Our results provide novel insights into the potential for pathological effects of somatic retrotransposition in the human brain, now including the large glial fraction. RetroSom has broad applicability in all disease states where somatic retrotransposition is expected to play a role, such as autoimmune disorders and cancer.

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Titre: Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia
Créateurs - sans rôle: Xiaowei Zhu - Palo Alto University
Bo Zhou - Stanford University
Reenal Pattni - Stanford University
Kelly Gleason - The University of Texas Southwestern Medical Center
Chunfeng Tan - The University of Texas Southwestern Medical Center
Agnieszka Kalinowski - Stanford University
Steven Sloan - Emory University
Anna-Sophie Fiston-Lavier - Université de Montpellier, Institut des Sciences de l'Evolution - Montpellier - ISEM
Jessica Mariani - Yale University
Dmitri Petrov - Palo Alto University
Ben Barres - Stanford University
Laramie Duncan - Stanford University
Alexej Abyzov - Mayo Clinic in Arizona
Hannes Vogel - Palo Alto University
Xiaowei Zhu - Stanford University
Bo Zhou - Stanford University
Alexander Urban - Stanford University
Christopher Walsh - Boston Children's Hospital
Javier Ganz - Boston Children's Hospital
Mollie Woodworth - Boston Children's Hospital
Pengpeng Li - Boston Children's Hospital
Rachel Rodin - Boston Children's Hospital
Robert Hill - Boston Children's Hospital
Sara Bizzotto - Boston Children's Hospital
Zinan Zhou - Boston Children's Hospital
Alice Lee - Harvard University
Alissa D’gama - Harvard University
Alon Galor - Harvard University
Craig Bohrson - Harvard University
Daniel Kwon - Harvard University
Doga Gulhan - Harvard University
Elaine Lim - Harvard University
Isidro Cortes - Harvard University
Joe Luquette - Harvard University
Maxwell Sherman - Harvard University
Michael Coulter - Harvard University
Michael Lodato - Harvard University
Peter Park - Harvard University
Rebeca Monroy - Harvard University
Sonia Kim - Harvard University
Yanmei Dou - Harvard University
Andrew Chess - Icahn School of Medicine at Mount Sinai
Attila Jones - Icahn School of Medicine at Mount Sinai
Chaggai Rosenbluh - Icahn School of Medicine at Mount Sinai
Schahram Akbarian - Icahn School of Medicine at Mount Sinai
Ben Langmead - Kennedy Krieger Institute
Jeremy Thorpe - Kennedy Krieger Institute
Jonathan Pevsner - Kennedy Krieger Institute
Rob Scharpf - Kennedy Krieger Institute
Sean Cho - Kennedy Krieger Institute
Flora Vaccarino - Yale University
Liana Fasching - Yale University
Simone Tomasi - Yale University
Nenad Sestan - Yale University
Sirisha Pochareddy - Yale University
Andrew Jaffe - Lieber Institute for Brain Development
Apua Paquola
Daniel Weinberger - Lieber Institute for Brain Development
Jennifer Erwin - Lieber Institute for Brain Development
Jooheon Shin - Lieber Institute for Brain Development
Richard Straub - Lieber Institute for Brain Development
Rujuta Narurkar - Lieber Institute for Brain Development
Anjene Addington - Lieber Institute for Brain Development
David Panchision - National Institute of Mental Health
Doug Meinecke
Geetha Senthil - National Institute of Mental Health
Lora Bingaman - National Institute of Mental Health
Tara Dutka - National Institute of Mental Health
Thomas Lehner - National Institute of Mental Health
Alexej Abyzov - Mayo Clinic in Arizona
Taejeong Bae - Mayo Clinic in Arizona
Laura Saucedo-Cuevas - Rockefeller University
Tara Conniff - Rockefeller University
Diane Flasch - University of Michigan
Trenton Frisbie - University of Michigan
Jeffrey Kidd - University of Michigan
Mandy Lam - University of Michigan
John Moldovan - University of Michigan
John Moran - University of Michigan
Kenneth Kwan - University of Michigan
Ryan Mills - University of Michigan
Sarah Emery - University of Michigan
Weichen Zhou - University of Michigan
Yifan Wang - University of Michigan
Kenneth Daily - Sage Bionetworks
Mette Peters - Sage Bionetworks
Fred Gage - Salk Institute for Biological Studies
Meiyan Wang - Salk Institute for Biological Studies
Patrick Reed - Salk Institute for Biological Studies
Sara Linker - Salk Institute for Biological Studies
Ani Sarkar - Salk Institute for Biological Studies
Aitor Serres - Salk Institute for Biological Studies
David Juan - Universitat Pompeu Fabra
Inna Povolotskaya - Universitat Pompeu Fabra
Irene Lobon - Universitat Pompeu Fabra
Manuel Solis - Universitat Pompeu Fabra
Raquel Garcia - Universitat Pompeu Fabra
Tomas Marques-Bonet - Universitat Pompeu Fabra
Gary Mathern - University of California, Los Angeles
Jing Gu - University of California San Diego
Joseph Gleeson
Laurel Ball
Renee George
Tiziano Pramparo
Aakrosh Ratan
Mike Mcconnell
John Moran - University of Michigan
Flora Vaccarino - Yale University
Carol Tamminga
Douglas Levinson
Alexander Urban - Palo Alto University
Détails de publication: Nature Neuroscience, Vol.24(2), pp.186-196
Identifiants: 99153211709311
Unité académique: Institut des Sciences de l'Evolution - Montpellier - ISEM
Langue: English
Type de ressource: Journal article
Champs locaux: hal-04954735