RT Journal Article SR Electronic T1 Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder JF bioRxiv FD Cold Spring Harbor Laboratory SP 004853 DO 10.1101/004853 A1 Esther R. Berko A1 Masako Suzuki A1 Faygel Beren A1 Christophe Lemetre A1 Christine M. Alaimo A1 R. Brent Calder A1 Karen Ballaban-Gil A1 Batya Gounder A1 Kaylee Kampf A1 Jill Kirschen A1 Shahina B. Maqbool A1 Zeineen Momin A1 David M. Reynolds A1 Natalie Russo A1 Lisa Shulman A1 Edyta Stasiek A1 Jessica Tozour A1 Maria Valicenti-McDermott A1 Shenglong Wang A1 Brett S. Abrahams A1 Joseph Hargitai A1 Dov Inbar A1 Zhengdong Zhang A1 Joseph D. Buxbaum A1 Sophie Molholm A1 John J. Foxe A1 Robert W. Marion A1 Adam Auton A1 John M. Greally YR 2014 UL http://biorxiv.org/content/early/2014/05/06/004853.abstract AB 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.