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bioRxiv · 10.1101/030270

Frequency and complexity of de novo structural mutation in autism

William M Brandler·Danny Antaki·Madhusudan Gujral·Amina Noor·Gabriel Rosanio·Timothy R Chapman·Daniel J Barrera·Guan Ning Lin·Dheeraj Malhotra·Amanda C Watts·Lawrence C Wong·Jasper A Estabillo·Therese E Gadomski·Oanh Hong·Karin V Fuentes Fajardo·Abhishek Bhandari·Renius Owen·Michael Baughn·Jeffrey Yuan·Terry Solomon·Alexandra G Moyzis·Stephan J Sanders·Gail E Reiner·Keith K Vaux·Charles M Strom·Kang Zhang·Alysson R Muotri·Natacha Akshoomoff·Suzanne M Leal·Karen Pierce·Eric Courchesne·Lilia M Iakoucheva·Christina Corsello·Jonathan Sebat
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Abstract

Genetic studies of Autism Spectrum Disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variation (SV) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping and de novo assembly to genome sequencing of 235 subjects, 71 cases, 26 sibling controls and their parents, we present an atlas of 1.2 million SVs (5,213/genome), comprising 11 different classes. We demonstrate a high diversity of de novo mutations, a majority of which were undetectable by previous methods. In addition, we observe complex mutation clusters where combinations of de novo SVs, nucleotide substitutions and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%). Genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs but not an elevated rate of genome rearrangement.

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William M Brandler, Danny Antaki, Madhusudan Gujral, Amina Noor, Gabriel Rosanio, Timothy R Chapman, Daniel J Barrera, Guan Ning Lin, Dheeraj Malhotra, Amanda C Watts, Lawrence C Wong, Jasper A Estabillo, Therese E Gadomski, Oanh Hong, Karin V Fuentes Fajardo, Abhishek Bhandari, Renius Owen, Michael Baughn, Jeffrey Yuan, Terry Solomon, Alexandra G Moyzis, Stephan J Sanders, Gail E Reiner, Keith K Vaux, Charles M Strom, Kang Zhang, Alysson R Muotri, Natacha Akshoomoff, Suzanne M Leal, Karen Pierce, Eric Courchesne, Lilia M Iakoucheva, Christina Corsello, Jonathan Sebat. 2015-10-30. Frequency and complexity of de novo structural mutation in autism. https://doi.org/10.1101/030270

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