Human Brain Peeled Back to Its Transcriptional Core

The human brain has so many organizational layers that you might wonder whether there is, deep down, a core that we all share, however diverse our brains are in other respects. It turns out that there is a core, report scientists at the Allen Institute for Brain Science. This core, the scientists say, is transcriptional and surprisingly compact—just 32 gene-expression signatures.

The Allen Institute scientists decided that the highly stereotyped character of the human brain implied that a conserved molecular program was responsible for the brain’s development, cellular structure, and function. “So much research focuses on the variations between individuals, but we turned that question on its head to ask, what makes us similar?” explained Ed Lein, Ph.D., investigator at the Allen Institute for Brain Science. “What is the conserved element among all of us that must give rise to our unique cognitive abilities and human traits?”

Using a microarray profiling dataset from the Allen Human Brain Atlas, Dr. Lein and colleagues found that many genes showed highly consistent patterns of transcriptional regulation across brain regions as quantified using a metric called differential stability (DS). DS is the tendency for a gene to exhibit reproducible differential expression relationships across brain structures.

This approach allowed the investigators to identify molecular patterns that dominate gene expression in the human brain and appear to be common to all individuals. The investigators detailed their work November 16 in the journal Nature Neuroscience, in an article entitled, “Canonical genetic signatures of the adult human brain.”

“[We assessed] reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization,” wrote the authors. “The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations.”

“[These genes appear to] represent a functionally critical set whose transcriptional regulation is tightly controlled,” the authors continued. “Taking this concept of conserved patterning from genes to gene networks, we demonstrate the existence of a relatively small (32) set of consensus coexpression gene networks that explain most (90.1%, ρ > 0.4) transcriptional variation across adult brain regions.”

In other words, most of the patterns of gene usage across all 20,000 genes could be characterized by just 32 expression patterns. While many of these patterns were similar in human and mouse, the dominant genetic model organism for biomedical research, many genes showed different patterns in human. Surprisingly, genes associated with neurons were most conserved across species, while those for the supporting glial cells showed larger differences.

The most highly stable genes—the genes that were most consistent across all brains—include those that are associated with diseases and disorders like autism and Alzheimer’s and include many existing drug targets. These patterns provide insights into what makes the human brain distinct and raise new opportunities to target therapeutics for treating disease.

Finally, the investigators noted that highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity. According to the investigators, this suggests a link between conserved gene expression and functionally relevant circuitry.

“The human brain is phenomenally complex,” said Christof Koch, Ph.D., president and CSO at the Allen Institute for Brain Science. “There could easily have been thousands of patterns, or none at all. This gives us an exciting way to look further at the functional activity that underlies the uniquely human brain.”