The genetic etiology of Autism Spectrum Disorders (ASDs) reflects of the nature of genome instability. Based in part on studies of copy number variation (CNV) from the first phase of this project, it is now widely recognized that de novo or recent mutations in the germline are important contributors to risk for ASDs. Mutations that confer high risk for autism are located within regions of hypermutability (ROHs). Examples include large >500 kb regions at 1q21.1, 15q11-13 and 16p11.2, where local genomic architecture predisposes to frequent recurrent rearrangements. All told, de novo CNVs contribute in approximately 5-10% of cases. It is likely that other classes of de novo mutation (DNM), in exons and in non-coding regions, contribute to ASD. As a field, we have a limited knowledge of global patterns of germline mutation in humans, and we have an incomplete understanding of how DNM contributes to risk for disease. Based on the knowledge above, and based on key findings that have emerged from our preliminary genome sequencing studies in autism, we hypothesize that, regions of hypermutability (ROHs), primarily consisting of nucleotide substitution hotspots, play a major role in ASDs. In the new phase of our project, we will apply a whole genome sequencing-based approach to determine the role of ROHs in ASD. We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims:
Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in a sample of 120 trios (60 ASD and 60 controls) and determine the parent of origin of DNMs.
Specific Aim 2 will investigate the role of ROHs in ASD. We will identify ROHs based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of ROHs with ASD in the discovery sample and in exome and CNV datasets from an independent sample of 2700 cases and 2700 controls.
Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

Public Health Relevance

Based on CNV and exome-sequencing studies of autism spectrum disorders (ASD) it has been established that de novo germline mutation is an important contributor to risk, and ASD risk alleles have particularly high mutation rates. We hypothesize that, as a general principle, genes that contribute high risk for ASD lie within genomic regions of hypermutability. We will apply a whole-genome sequencing approach to identify genomic regions of hypermutability and determine the association of mutational hotspots with disease in a large independent sample. We will investigate intrinsic characteristics of the genome and extrinsic factors such as parental age that influence rates of germline mutation. The findings of this study will yield fundamental insights into the genetic basis of ASD and the interplay between genes and environment.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Addington, Anjene M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Corominas, Roser; Yang, Xinping; Lin, Guan Ning et al. (2014) Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nat Commun 5:3650
Malhotra, Dheeraj; Sebat, Jonathan (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148:1223-41
Nord, Alex S; Roeb, Wendy; Dickel, Diane E et al. (2011) Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Eur J Hum Genet 19:727-31
Malhotra, Dheeraj; McCarthy, Shane; Michaelson, Jacob J et al. (2011) High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72:951-63
Vacic, Vladimir; McCarthy, Shane; Malhotra, Dheeraj et al. (2011) Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471:499-503
McCarthy, Shane E; Makarov, Vladimir; Kirov, George et al. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41:1223-7
Yoon, Seungtai; Xuan, Zhenyu; Makarov, Vladimir et al. (2009) Sensitive and accurate detection of copy number variants using read depth of coverage. Genome Res 19:1586-92
Sebat, Jonathan; Levy, Deborah L; McCarthy, Shane E (2009) Rare structural variants in schizophrenia: one disorder, multiple mutations;one mutation, multiple disorders. Trends Genet 25:528-35
Alarcon, Maricela; Abrahams, Brett S; Stone, Jennifer L et al. (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150-9
Kusenda, M; Sebat, J (2008) The role of rare structural variants in the genetics of autism spectrum disorders. Cytogenet Genome Res 123:36-43

Showing the most recent 10 out of 11 publications