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Whole-genome deep learning analysis reveals causal role of noncoding mutations in autism

Jian Zhou, Christopher Y. Park, Chandra L. Theesfeld, Yuan Yuan, Kirsty Sawicka, Jennifer C. Darnell, Claudia Scheckel, John J Fak, Yoko Tajima, Robert B. Darnell, Olga G. Troyanskaya
doi: https://doi.org/10.1101/319681
Jian Zhou
1Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America
2Graduate Program in Quantitative and Computational Biology, Princeton University, Princeton, New Jersey, United States of America
3Flatiron Institute, Simons Foundation, New York, New York, United States of America
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Christopher Y. Park
3Flatiron Institute, Simons Foundation, New York, New York, United States of America
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
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Chandra L. Theesfeld
1Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America
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Yuan Yuan
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
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Kirsty Sawicka
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
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Jennifer C. Darnell
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
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Claudia Scheckel
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
7Institute of Neuropathology, University of Zurich, CH-8091, Zurich, Switzerland
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John J Fak
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
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Yoko Tajima
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
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Robert B. Darnell
4Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA
5Howard Hughes Medical Institute
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Olga G. Troyanskaya
1Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America
3Flatiron Institute, Simons Foundation, New York, New York, United States of America
6Department of Computer Science, Princeton University, Princeton, New Jersey, United States of America
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Abstract

We address the challenge of detecting the contribution of noncoding mutations to disease with a deep-learning-based framework that predicts specific regulatory effects and deleterious disease impact of genetic variants. Applying this framework to 1,790 Autism Spectrum Disorder (ASD) simplex families reveals autism disease causality of noncoding mutations by demonstrating that ASD probands harbor transcriptional (TRDs) and post-transcriptional (RRDs) regulation-disrupting mutations of significantly higher functional impact than unaffected siblings. Importantly, we detect this significant noncoding contribution at each level, transcriptional and post-transcriptional, independently and after multiple hypothesis correction. Further analysis suggests involvement of noncoding mutations in synaptic transmission and neuronal development, and reveals a convergent genetic landscape of coding and noncoding (TRD and RRD) de novo mutations in ASD. We demonstrate that sequences carrying prioritized proband de novo mutations possess transcriptional regulatory activity and drive expression differentially, and highlight a link between noncoding mutations and IQ heterogeneity in ASD probands. Our predictive genomics framework illuminates the role of noncoding mutations in ASD, prioritizes high impact transcriptional and post-transcriptional regulatory mutations for further study, and is broadly applicable to complex human diseases.

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  • ↵* co-first authors

  • ↵† co-senior authors

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Posted August 03, 2018.
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Whole-genome deep learning analysis reveals causal role of noncoding mutations in autism
Jian Zhou, Christopher Y. Park, Chandra L. Theesfeld, Yuan Yuan, Kirsty Sawicka, Jennifer C. Darnell, Claudia Scheckel, John J Fak, Yoko Tajima, Robert B. Darnell, Olga G. Troyanskaya
bioRxiv 319681; doi: https://doi.org/10.1101/319681
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Whole-genome deep learning analysis reveals causal role of noncoding mutations in autism
Jian Zhou, Christopher Y. Park, Chandra L. Theesfeld, Yuan Yuan, Kirsty Sawicka, Jennifer C. Darnell, Claudia Scheckel, John J Fak, Yoko Tajima, Robert B. Darnell, Olga G. Troyanskaya
bioRxiv 319681; doi: https://doi.org/10.1101/319681

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