# Expanding the accessible genetic architecture of autism by single molecule sequencing

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $856,867

## Abstract

Project Summary
Within the last decade, major progress has been made in understanding the genetic basis of Autism Spectrum
Disorders (ASDs). Based on exome sequencing studies and microarray-based genotyping, it is recognized that
the genetic architecture of ASD consists of rare mutations of large effect, including structural variants (SVs)
and de novo point mutations that impact genes, as well as a significant contribution from common polygenic
variation. However, a majority of the genetic risk for ASD remains unexplained. A proportion of the missing
heritability of ASD could be attributable to genetic variation that remains inaccessible to today’s high
throughput sequencing platforms including a majority of structural variants (SVs) and sequence variation that
occurs within repetitive sequences in the genome. A systematic analysis of these novel classes of genetic
variation could close a significant gap in our knowledge of ASD genetics. The development of new single-
molecule sequencing platforms now enables direct sequencing of long DNA fragments (average read lengths
>5,000 bp). These technologies have enable sequence assembly and variant calling within complex and
repetitive regions of the genome and have dramatically increased the proportion of structural and tandem
repeat (TR) variation that can be captured by whole genome sequencing (WGS). The application of long read
WGS to ASD family samples could greatly expand knowledge of the genetic causes of autism. This study will
investigate the contribution of complex genetic variants to risk for ASD using a combination of long-read and
short-read technologies. (1) We will characterize global patterns of genetic variation in a primary sample of
ASD families (N=373 cases, 127 sibling controls and their parents) by WGS using the Pacific Biosciences
(SEQUEL) platform, and these data will be combined with an existing WGS dataset of Illumina short reads on
the same samples. (2) We will investigate the genetic association of novel classes of SVs and TRs in genes
and in regulatory elements that control gene expression, and novel findings will be replicated in Illumina WGS
data on 2600 ASD families from the Simons Simplex Collection (SSC) (3) We will then investigate the influence
of novel risk alleles on clinical phenotype in families and experimentally confirm the effects of mutations on
gene function. Our proposed study will expand our knowledge of the genetic architecture of ASD and identify
novel risk alleles and genetic mechanisms underlying disease risk.

## Key facts

- **NIH application ID:** 10216962
- **Project number:** 5R01MH113715-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jonathan Sebat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $856,867
- **Award type:** 5
- **Project period:** 2017-09-06 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216962

## Citation

> US National Institutes of Health, RePORTER application 10216962, Expanding the accessible genetic architecture of autism by single molecule sequencing (5R01MH113715-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10216962. Licensed CC0.

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