As the nascent brain develops, genes scattered throughout the brain begin to express themselves, to define their future roles, and to interplay with others — not unlike adolescents milling through a locker-lined hallway at school. Now, investigators from the University of California, Los Angeles, say they’ve developed a map describing genetic variants — "risk genes" — associated with the development of autism spectrum disorder (ASD), in addition to those implicated in neural disturbances unrelated to the disorder.
Although sharing common risk genes, the disorder and the more generalized “intellectual disability” develop distinctly as genes express themselves, copying data from DNA to RNA, says Daniel Geschwind, a neurologist at UCLA.
"Identifying gene variants that boost risk is only the first step of unraveling a disease," Geschwind said in a statement. "We need to figure out where genetic changes appear in the brain, at what stages during development, and which biological processes they disrupt. Only then will we understand how mutations cause autism."
For their study, Geschwind and his colleagues became the first to report mapping groups of autism-risk genes by function, and to identify behavioral roles in early brain development. Just as important, however, the team isolated those expressive behaviors from others, leading to generalized learning disability distinct from ASD.
Using the online atlas BrainSpan, the investigators followed genetic activity in the developing brain before birth, as genetic information is copied.
Investigator Neelroop Parikshak said that the team found gene variants expressing themselves in the developing brain as cells that determined their future roles in the neural circuitry. “Changes made in the genes influence the brain’s wiring by altering the synapse, and shaping how neurons transmit signals to each other.”
Those gene variants, or mutations, also interfered with larger-scale functioning of the brain, interfering with communication among layers and hemispheres, a phenomenon confirmed by previous study of the autistic brain, according to Geschwind.
"We discovered gene-related disruption of circuits that connect the autistic brain's layers and hemispheres to each other," explained Geschwind, who leads the university’s Center for Autism Research and Treatment. "Our finding suggests that the mutated genes caused the miswiring; it's not a result of having the disease itself."
Parikshak emphasized that ASD should be considered distinct on the molecular level from intellectual disability, even though they share common risk genes. "Genes linked to intellectual disability influence many biological processes in the body," he added. "But genes tied to autism tend to affect specific functions, such as the connections between brain regions that are essential to many human-specific behaviors, such as speech and language."
With this discovery, investigators at the university plan to expound on the work by sequencing the genomes of several thousand people, studying genetic mutations linked to ASD and intellectual disability.
Source: Geschwind, Daniel H., Parikshak, Neelroop N., Luo, Rui, Zhang, Alice, Won, Hyejung, et al. Integrative Functional Genomic Analyses Implicate Specific Molecular Pathways and Circuits in Autism. Cell. 2013.