Evolutionary conservation and divergence of the human brain transcriptome.

Area of Science:

• Neuroscience
• Genomics
• Evolutionary Biology

Background:

• Mouse models are crucial for studying genetic influences on brain phenotypes.
• However, the extent to which human-specific neurological or psychiatric traits can be modeled in mice remains unclear.

Purpose of the Study:

• To compare gene co-expression conservation across humans, mice, and non-human primates.
• To identify species-specific divergence in brain gene expression patterns and cell types.

Main Methods:

• Analysis of 116 independent datasets from human, mouse, and non-human primate brains (>15,000 samples).
• Comparison of gene co-expression modules, focusing on regional and cell-type-specific variations.
• Investigation of cis-regulatory and protein-coding sequence divergence.

Main Results:

• Human lineage shows greater co-expression changes than mouse, with the cerebral cortex being the most diverged region.
• Glial cells (microglia, astrocytes, oligodendrocytes) exhibit significantly more divergence than neurons.
• Divergence in cis-regulatory sequences contributes to co-expression changes; loss-of-function intolerant genes are enriched in neuronal modules.
• Dozens of human neuropsychiatric/neurodegenerative disease risk genes show high co-expression divergence between mice and humans.
• 3D human brain organoids partially recapitulate in vivo co-expression modules.

Conclusions:

• Robust co-expression modules reflect brain-wide and regional gene expression patterns.
• Cell-type-specific modules, particularly glial ones, are most divergent between species.
• Findings provide a resource for interpreting and guiding human disease modeling in non-primate species.