Publication Date

2016-03-22

Availability

Embargoed

Embargo Period

2017-03-22

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2016-02-26

First Committee Member

Mohammad Faghihi

Second Committee Member

Eleonore Beurel

Third Committee Member

Vance Lemmon

Fourth Committee Member

Pantelis Tsoulfas

Fifth Committee Member

Gavin Rumbaugh

Abstract

Autism is a highly prevalent neurodevelopmental disorder that affects 1 in every 68 children in the US. Autism comprises a spectrum of highly heterogeneous disorders defined by characteristic deficits of communication and by presence of repetitive and stereotyped behavior. At the same time the disease is highly heritable and genetically heterogeneous, with hundreds of genetic variants that have been associated with it. Previous systems biology studies have provided first insights into convergence of various disease-associated genetic variants onto specific pathways, developmental windows and cell types in the brain. Additionally, transcriptomic and epigenetic studies have identified genes and pathways affected by common molecular pathology in autism. However, previous studies lacked special resolution, have not investigated commonalities and differences in transcriptomic and epigenetic changes across specific brain regions in autism, have not linked epigenetic changes to transcriptional regulation in the disease and have not looked at other levels of transcriptional control rather than gene expression, such as alternative splicing and expression of long noncoding RNAs. In my dissertation I attempt to fill in these gaps by performing analysis of antisense RNA expression in the autistic brain and by performing RNA sequencing and DNA methylation analysis of 6 different cortical regions of autism patients and controls. I demonstrate that many autism-associated genomic loci express antisense noncoding RNAs, with some of them upregulated in the cortex of autism patients. I have also developed an automated user-friendly tool to perform RNA sequencing data analysis and applied it to a large cohort of RNA-seq samples to identify differentially expressed protein-coding genes and long noncoding RNAs, with many genes and pathways recurring in multiple regions and patient cohorts. Finally, I identify convergence of transcriptomic changes of the frontal cortical regions in autism on common genes and pathways and a divergent effect of the pathology on gene expression and alternative splicing in the prefrontal and frontoinsular cortices in autism. The results of the study prompt to investigate dysfuntion of the insular cortex in autism and provide high-confidence autism gene candidates for further functional studies.

Keywords

Autism; RNA-seq; transcriptomics; epigenetics; insular cortex; prefrontal cortex

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