The SSC-ASC Whole-Genome Sequencing Consortium has been established to discover de novo and inherited genomic variation that increase risk for ASD. In project one of four linked projects, Stephan Sanders will reprocess existing whole-genome sequencing data from thousands of ASD families using a common standardized pipeline to identify noncoding variants associated with ASD.
William Moody plans to test the hypothesis that disruptions in neonatal sleep-wake cycles, which are known to occur in autism spectrum disorder, cause abnormalities in early electrical activity which, in turn, result in neurodevelopmental changes associated with this condition.
The abundance of mutations in chromatin regulatory proteins in ASDs highlights the significance of chromatin structure in brain development. Kavitha Sarma and colleagues plan to study whether RNA-containing chromatin structures called R-loops are molecular drivers of deregulated gene expression in ASDs. They will also test the possibility of targeting R-loops for future therapy in ASDs.
Exploring the consequences of 16p11.2 deletion in diverse species is key to understanding conserved pathophysiological mechanisms that underly the condition in humans. In the current project, Yann Herault plans to develop a new rat model corresponding to the deletion of the 16p11.2 homologous region in the Long-Evans strain. Comparing similarities and differences between rat and mouse models and humans with 16p11.2 deletion syndrome should not only provide a better understanding of the condition, but also has the potential to foster the development of novel therapeutic approaches.
Shrikanth Narayanan, in collaboration with Somer Bishop, plans to develop ‘transcription-free’ audio analytics based on signal processing and machine-learning techniques that will help support the analysis of speech and language abilities in children with autism.
The Autism Inpatient Collection provides a comprehensive registry of biological and clinical data on over 1,400 youth with autism spectrum disorder (ASD) that can be used by approved researchers to increase inclusion of those who are severely affected by ASD in research. The goal of the current project is twofold. Firstly, it is to further expand this collection to ultimately include data from 1,600 youth. Secondly, Matthew Siegel and colleagues plan to test their ability to use physiological signals obtained through wearable biosensors to predict the imminent onset of aggressive behaviors, which may open a new window for intervening before a challenging behavior occurs.
Mark Zylka plans to evaluate the extent to which molecular phenotypes worsen with age in Chd8V986*/+ heterozygous mice, which harbor a loss-of-function autism-linked mutation. Results from this study are expected to highlight the importance of expanding the age range over which autism model mice are evaluated, with the ultimate aim of better understanding neuropathological changes in older individuals with ASD.
The neuron-specific potassium-chloride co-transporter, KCC2, is involved in the regulation of excitatory and inhibitory neuronal activity. It has been identified as a promising therapeutic target for autism. In the current project, Charles Craik’s laboratory and collaborators plan to determine the high-resolution structure of KCC2 with the intention of developing strategies to regulate its activity.
In this project, Karen Parker and her colleagues aim to determine whether the lower vasopressin levels that were observed in the cerebrospinal fluid of adult monkeys with naturally occurring social deficits are also found in “at-risk” infant monkeys. They also plan to test whether these infants exhibit poor social cognition abilities in multiple domains relevant to autism. The identification of biomarkers at an early developmental stage is a critical next step towards early pharmacological intervention in “at-risk” young monkeys, and ultimately, young children at risk for social challenges.
Stephanie Bielas plans to study an Asxl3 null mouse model to better understand the role that Asxl3-dependent deubiquitination activity plays in specifying neural progenitor cell transcriptional programs that regulate cortical neuronal fate.