Summary: Researchers have linked a previously overlooked portion of the human genome to greater severity of autism symptoms.
Source: University of Colorado
University of Colorado Anschutz Medical Campus scientists have identified a highly duplicated, largely unexamined region of the human genome as being associated with the severity of autism symptoms—an insight that could guide future research into the biology of autism and, ultimately, clinical approaches.
The team focused on a genomic region that has been difficult to study with standard methods because of its complexity and high degree of duplication. This region encodes most copies of the Olduvai protein domain family (formerly DUF1220), a set of sequences present in roughly 300 copies across the human genome. Olduvai sequences have been previously linked to human brain evolution and to various cognitive conditions.
Led by James M. Sikela, PhD, professor in the Department of Biochemistry and Molecular Genetics at the CU School of Medicine, the research group analyzed whole genome sequence data from individuals with autism and found a dose-dependent relationship: as the number of Olduvai copies increased, measures of autism symptom severity also increased.
Sikela’s group has reported similar trends in earlier work, but widespread follow-up by other groups has been limited because the Olduvai family is technically challenging to measure. The CU team developed improved, higher-resolution measurement methods and applied them to an independent sample in order to strengthen the evidence for the association.
“It took us several years to develop accurate methods for studying these sequences, so we fully understand why other groups have not joined in,” Sikela said. “By replicating the association in multiple independent datasets and improving measurement precision, we hope other autism researchers will examine this complex gene family.”
The study addresses a persistent challenge in autism genetics: while autism is known to have a strong genetic component, many conventional genetic studies have failed to account for that contribution fully. The authors suggest this may be because important contributors lie in highly duplicated, variable regions of the genome—areas that standard approaches often overlook.
The results were published in the American Journal of Psychiatry. CU Anschutz co-authors included Jonathan M. Davis, PhD, and Ilea Heft, PhD. The study was carried out in collaboration with Dr. Stephen Scherer of The Hospital for Sick Children (SickKids) and the University of Toronto, and used whole genome sequences provided by the Autism Speaks MSSNG open-science project.
Funding: The research was supported by grants from the National Institute of Mental Health (NIMH) and the Simons Foundation for Autism Research (SFARI).
Publication and research details: The paper, titled “A Third Linear Association Between Olduvai (DUF1220) Copy Number and Severity of the Classic Symptoms of Inherited Autism,” reports replication of a copy-number association using a refined measurement approach and an independent cohort. The work appeared in the American Journal of Psychiatry on February 15, 2019 (doi: 10.1176/appi.ajp.2018.18080993).
The investigators compared Olduvai CON1 subtype copy number with standardized measures of autism symptom severity derived from the Autism Diagnostic Interview–Revised. Using whole genome sequence data from 215 individuals in the MSSNG project and a modified read-depth technique to estimate copy number, the team applied linear mixed-effects models to test associations.
Results showed a significant linear relationship between CON1 copy number and both social diagnostic score (SDS) and communicative diagnostic score (CDS). When combined with earlier datasets for a total sample of 524 individuals, the authors observed robust associations between CON1 dosage and symptom severity. The analysis also implicated specific Olduvai subtypes located in the genes NBPF1 and NBPF14, accounting for a portion of explained variance (R2 ≈ 6.2%). Associations were stronger in multiplex families (those with more than one affected individual) than in simplex families.
In conclusion, the study reports a third independent dose-dependent association between Olduvai copy number and the classic behavioral symptoms of inherited autism. Because Olduvai sequences are highly duplicated and typically underexamined by conventional genomic analyses, these findings highlight an underexplored genomic component that may play an important role in inherited forms of autism.
University of Colorado. Hidden Genes May Underlie Autism Severity. Neuroscience News. February 15, 2019. DOI: 10.1176/appi.ajp.2018.18080993.