Pity the poor autism researcher. Recent studies have linked hundreds of gene mutations scattered throughout the brain to increased autism risk. Where do you start?
UCLA neuroscientists may have an answer. They are the first to map groups of autism-risk genes by function, and to identify where and when these genes normally play major roles in early brain development.
In addition, they discovered disturbances in neural circuits that define key pathways between parts of the cerebral cortex. The research suggests that these early disruptions are created by mutations in genes during fetal brain development and are not a result of autism itself.
Published in the Nov. 21 edition of Cell, the findings will help scientists understand how genetic changes cause autism on a molecular level and prioritize targets for future studies.
"Identifying gene variants that boost risk is only the first step of unraveling a disease," explained lead author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, professor of neurology at the David Geffen School of Medicine at UCLA and professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior. "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."
Using an online atlas called BrainSpan, the authors charted gene activity in the developing brain before birth. In particular, they examined what happens during gene expression --when genes copy data from DNA to RNA in order to create proteins.
Geschwind and his colleagues found high activity in risk genes during two processes critical to early brain development.
"We found that gene variants are expressed in the developing brain when cells define their future identities and roles in neural circuits," first author Neelroop Parikshak, a graduate student researcher in Geschwind's lab. "Therefore, changes in the genes influence the brain's wiring by altering the synapse and shaping how neurons transmit signals to each other."
The mutated genes also interfered with how the brain's layers and halves relate to one another, a phenomenon confirmed by previous imaging studies of the autistic brain.