Comprehensive investigation of temporal and autism-associated cell type composition-dependent and independent gene expression changes in human brains

The functions of human brains highly depend on the precise temporal regulation of gene expression, and substantial transcriptome changes across lifespan have been observed. While cell type composition is known to be temporally variable in brains, it remains unclear whether it is the primary cause of age-related transcriptome changes. Here, taking advantage of published human brain single-cell RNA-seq data, we applied a two-step transcriptome deconvolution procedure to the public age series RNA-seq data to quantify the contribution of cell type composition in shaping the temporal transcriptome in human brains. We estimated that composition change contributed to around 25% of the total variance and was the primary factor of age-related transcriptome changes. On the other hand, genes with substantial composition-independent temporal expression changes were also observed, which had diverged expression properties, functions and regulators as genes with temporal expression changes related to composition. This indicates a second independent mechanism shaping the human brains temporal transcriptome properties, which is important for human brain functions.