Date of Award

Spring 4-10-2023

Embargo Period

4-19-2023

Document Type

Thesis

Degree Name

Master of Biomedical Science

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Stefano Berto

Second Advisor

Patrick Mulholland

Third Advisor

Richard Drake

Fourth Advisor

Ewoud Schmidt

Fifth Advisor

Onder Albayram

Abstract

Neuropsychiatric disorders have a significant impact on modern society. These disorders affect a large percentage of the population: schizophrenia has a world-wide prevalence of 1% and autism spectrum disorders (ASD) affects 1 in 59 school-aged children in the US. There is substantial evidence that most neuropsychiatric disorders have a genetic component. Thus, with the advent of high throughput sequencing much effort has gone into identifying genetic variants associated with these disorders. The emerging picture from these studies is a complex one where hundreds of genes with small effects interact with a varied landscape of common variants to result in disease. Despite this complexity, individual disease-associated genes have been identified but studies of the functional role of each of these genes in brain development and function have only just begun. In addition to efforts designed to identify disease-relevant genetic variants, large consortia have been formed to generate other genomic datasets (e.g., bulk, or single cell RNA expression) to uncover both cell-type specific and tissue-specific transcriptional networks where disease-associated genes are involved.

This study integrated several types of bulk tissue datasets with single-cell datasets to investigate the cortical distribution, cell-type specificity, and developmental trajectories of two ASD-linked genes: IL1RAPL1 and its paralog IL1RAPL2. Genetics studies linked IL1RAPL1 and IL1RAPL2 with ASD and intellectual disabilities (ID) and both are strong ASD risk gene candidates with a SFARI score of two. Even though IL1RAPL1 has been shown to have a role in synaptic development and synaptic strength, little is known about IL1RAPL2. Therefore, whether or how IL1RAPL2 functions in synapse development is a significant gap in knowledge and given the role of cortical excitatory neurons in ASD and intellectual ability, IL1RAPL2 is highly likely to serve a critical role. Recently, IL1RAPL2 has been identified as a hub gene in an ASD module associated with memory oscillations and it is strongly co-expressed with other ASD-risk genes. These data further confirm the potential role of IL1RAPL2 in neuronal etiology and ASD.

To further gain insights into the role of these genes in the human brain and ASD, we analyzed the transcriptomic landscapes of IL1RAPL1 and IL1RAPL2 in cortical region and cell types of the human brain. We hypothesized that IL1RAPL1 and IL1RAPL2 gene expression significantly differs within cortical regions involved in higher order cognitive function, both at cell-type level and during development.

This project took advantage of publicly available genomic data from PsychENCODE, Allen Institute, and Lister Lab. We analyzed bulk RNA-seq from neurotypical and ASD patients (N = 103) identifying gene expression and co-expression differences between IL1RAPL2 and IL1RAPL1 in 11 cortical regions. We next used a time series bulk RNA-seq data from neurotypical subjects (N = 39) to infer the developmental trajectories of IL1RAPL2 and IL1RAPL1 in 11 cortical regions. Finally, by using single cell RNA-seq data, we uncovered the cell-type gene expression distribution differences between IL1RAPL2 and IL1RAPL1 in multiple regions and cortical-layers in human and mice samples, and to find differences in expression across development.

In summary, this comprehensive genomic project highlighted significant differences between IL1RAPL1 and IL1RAPL2 in specific brain regions, cell-types, and developmental trajectories across the human lifespan. The identified differences provide preliminary evidence that IL1RAPL1 and IL1RAPL2 might play a different role in human cortical development and cell-type.

Rights

Copyright is held by the author. All rights reserved.

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