Autism spectrum disorder is complex; it presents differently in different patients, and the causes are still unclear, even though hundreds of small changes in gene sequences have been linked to an increased risk of developing the condition. Scientists have now developed a genetic map that focused on eight distinct genetic mutations that have all been associated with autism spectrum disorder (ASD), to reveal how these various mutations may be connected. This network map shows that these various mutations converge on the same pathways, and affect the early stages of brain development.
This research, which was reported in Nature, can provide new insights into the causes of ASD, which could eventually help scientists create new preventive or treatment options. The work has illustrated that while certain genetic mutations may initially have very disparate effects, these effects start to overlap more and more as the brain progresses through developmental stages.
Autism risk genes are particularly active during the earliest stages of fetal brain development, so it is crucial to study the effects of these genes during these stages, when they are probably having their biggest impact.
However, it is very challenging to study human brains during this time; and they cannot be analyzed directly. Even when postmortem brain tissue can be examined, it is usually long after these very early developmental stages.
The researchers had to turn to simplified, miniature versions of human brains kwon as brain organoids, to study the effects of the mutations. The investigators created brain organoids using cell samples taken from ASD patients who carried autism-linked genetic mutations; ASD patients with no known genetic susceptibility; and unaffected individuals.
This work showed that different genetic mutations create certain molecular characteristics at first. But as the organoids grew and developed over 100 days, the different genetic mutations slowly began to have very similar effects. The mutations tended to affect the formation of synapses, and the maturation of neurons.
“Think of it like different routes leading to similar destinations," said senior study author Dr. Daniel Geschwind, a distinguished professor at UCLA. . “The mutations start by affecting different aspects of early brain development, but they end up impacting overlapping pathways.”
A gene network related to chromatin remodeling (or the packaging of DNA in cells) and gene expression seemed to be crucial to how the influence of these distinct mutations eventually came together. When the activity of these genes was reduced, the researchers found that many genes previously linked to autism were affected.
The organoids from people without a genetic link to ASD did not display these molecular changes. These researchers noted that the genetic underpinnings of ASD are likely particularly complex in people who do not carry major ASD-linked mutations.
“This work demonstrates how stem cell models can help us understand neurodevelopmental conditions during the developmental periods most relevant to disease origins,” Geschwind added.
Sources: University of California, Los Angeles; Nature
