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Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder

Esther R. Berko, Masako Suzuki, Faygel Beren, Christophe Lemetre, Christine M. Alaimo, R. Brent Calder, Karen Ballaban-Gil, Batya Gounder, Kaylee Kampf, Jill Kirschen, Shahina B. Maqbool, Zeineen Momin, David M. Reynolds, Natalie Russo, Lisa Shulman, Edyta Stasiek, Jessica Tozour, Maria Valicenti-McDermott, Shenglong Wang, Brett S. Abrahams, Joseph Hargitai, Dov Inbar, Zhengdong Zhang, Joseph D. Buxbaum, Sophie Molholm, John J. Foxe, Robert W. Marion, Adam Auton, John M. Greally
doi: https://doi.org/10.1101/004853
Esther R. Berko
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Masako Suzuki
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Faygel Beren
2Stern College for Women, Yeshiva University, New York, NY 10016, USA
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Christophe Lemetre
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Christine M. Alaimo
3The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children’s Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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R. Brent Calder
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Karen Ballaban-Gil
4Department of Neurology, Children’s Hospital at Montefiore, Bronx, NY 10467, USA.
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Batya Gounder
2Stern College for Women, Yeshiva University, New York, NY 10016, USA
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Kaylee Kampf
2Stern College for Women, Yeshiva University, New York, NY 10016, USA
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Jill Kirschen
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Shahina B. Maqbool
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Zeineen Momin
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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David M. Reynolds
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Natalie Russo
3The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children’s Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
5Department of Psychology, The College of Arts and Sciences, Syracuse University, Syracuse, NY 13244, USA.
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Lisa Shulman
6Children’s Evaluation and Rehabilitation Center, Department of Pediatrics, Albert Einstein College of Medicine. Bronx, NY 10461, USA.
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Edyta Stasiek
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Jessica Tozour
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Maria Valicenti-McDermott
6Children’s Evaluation and Rehabilitation Center, Department of Pediatrics, Albert Einstein College of Medicine. Bronx, NY 10461, USA.
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Shenglong Wang
7Information Technology Services, New York University, New York, NY 10003, USA.
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Brett S. Abrahams
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
8Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Joseph Hargitai
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Dov Inbar
9Child Development and Rehabilitation Institute, Schneider Children’s Medical Center, Petach Tikvah, Israel.
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Zhengdong Zhang
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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Joseph D. Buxbaum
10Seaver Autism Center for Research and Treatment, Departments of Psychiatry, Neuroscience, and Genetics and Genomic Sciences, and the Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10023, USA.
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Sophie Molholm
3The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children’s Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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John J. Foxe
3The Sheryl and Daniel R. Tishman Cognitive Neurophysiology Laboratory, Children’s Evaluation and Rehabilitation Center, and Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Robert W. Marion
6Children’s Evaluation and Rehabilitation Center, Department of Pediatrics, Albert Einstein College of Medicine. Bronx, NY 10461, USA.
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Adam Auton
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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John M. Greally
1Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Department of Neuroscience, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA
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  • For correspondence: john.greally@einstein.yu.edu
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ABSTRACT

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested an homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

AUTHOR SUMMARY Older mothers have a higher than expected risk of having a child with an autism spectrum disorder (ASD). The reason for this increased risk is unknown. The eggs of older mothers are more prone to abnormalities of chromosome numbers, suggesting this as one possible mechanism of the increased ASD risk. Age is also associated with a loss of control of epigenetic regulatory patterns that govern gene expression, indicating a second potential mechanism. To test both possibilities, we sampled cells from the same developmental origin as the brain, and performed genome-wide tests looking for unusual chromosome numbers and DNA methylation patterns. The studies were performed on individuals with ASD and typically developing controls, all born to mothers at least 35 years of age at the time of birth. We found the cells from individuals with ASD to have changes in DNA methylation at a number of loci, especially near genes encoding proteins known to interact with those already implicated in ASD. We conclude that epigenetic dysregulation occurring in gametes or early embryonic life may be one of the contributors to the development of ASD.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
Esther R. Berko, Masako Suzuki, Faygel Beren, Christophe Lemetre, Christine M. Alaimo, R. Brent Calder, Karen Ballaban-Gil, Batya Gounder, Kaylee Kampf, Jill Kirschen, Shahina B. Maqbool, Zeineen Momin, David M. Reynolds, Natalie Russo, Lisa Shulman, Edyta Stasiek, Jessica Tozour, Maria Valicenti-McDermott, Shenglong Wang, Brett S. Abrahams, Joseph Hargitai, Dov Inbar, Zhengdong Zhang, Joseph D. Buxbaum, Sophie Molholm, John J. Foxe, Robert W. Marion, Adam Auton, John M. Greally
bioRxiv 004853; doi: https://doi.org/10.1101/004853
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Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
Esther R. Berko, Masako Suzuki, Faygel Beren, Christophe Lemetre, Christine M. Alaimo, R. Brent Calder, Karen Ballaban-Gil, Batya Gounder, Kaylee Kampf, Jill Kirschen, Shahina B. Maqbool, Zeineen Momin, David M. Reynolds, Natalie Russo, Lisa Shulman, Edyta Stasiek, Jessica Tozour, Maria Valicenti-McDermott, Shenglong Wang, Brett S. Abrahams, Joseph Hargitai, Dov Inbar, Zhengdong Zhang, Joseph D. Buxbaum, Sophie Molholm, John J. Foxe, Robert W. Marion, Adam Auton, John M. Greally
bioRxiv 004853; doi: https://doi.org/10.1101/004853

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