Autism spectrum disorder (ASD) affects each individual differently. Scientists have identified more than one thousand genes associated with ASD, but no single gene explains the majority of cases. This has left researchers with a persistent question: How can such diverse genetic changes give rise to the same condition and affect each person so differently?
A new study by researchers from A*STAR's Genome Institute of Singapore (A*STAR GIS), in collaboration with A*STAR's Bioinformatics Institute (A*STAR BII), offers a new perspective. Published in Nature Communications, the study suggests that ASD may arise not only from which genes are affected but also from where and how changes unfold as the brain develops.
To investigate this question, researchers generated brain organoids from induced pluripotent stem cells donated by individuals with and without ASD. These three-dimensional cellular models recreate key stages of fetal brain development that cannot be studied directly in humans. They then combined mapping of gene activity in individual cells with advanced computational analysis to identify individual cell types, map their locations and track how they assemble during brain development.
Using these approaches, the researchers observed notable differences between brain organoids from donors with and without ASD. Organoids from donors without ASD formed the typical ordered layers of the developing cerebral cortex, the brain's outer layer. In organoids from donors with ASD, this stratified structure often became disorganised in distinct patches, whilst nearby areas developed normally. The distribution and extent of these disorganised patches differed between individuals, suggesting that ASD does not arise through a single uniform developmental process but through distinct spatial patterns of brain development.
The researchers traced these structural changes to radial glial cells, the neural stem cells that act as architects and scaffolding of the developing brain. Normally, these cells remain tightly connected as they guide newly born neurons towards their appropriate positions. In organoids with ASD, these connections were disrupted. As a result, the supporting scaffold became disorganised and neurons failed to organise into their normal stratified structure. Dr Liu Jinyue, principal scientist at A*STAR GIS and corresponding co-author of the study, noted that "by observing how brain cells assemble into tissues, we can better understand why autism presents so differently from one person to another".
The study brought together A*STAR GIS's expertise in spatial genomics and stem cell biology with A*STAR BII's expertise in computational biology. These complementary strengths enabled the team to reconstruct early brain development at individual cell resolution. Dr Wan Yue, executive director of A*STAR GIS, indicated that "understanding biology is not just about what cells are present, but also where they are and how they interact. By adding the spatial dimension and combining diverse expertise, we can study not only autism but also other complex human diseases in entirely new ways".
