Unveiling the Brain: How Human Cell Types Evolve to Become More Specialized Beyond Just Numbers

Our brain is likely the organ that most sets humans apart from other primates. Its unmatched size, intricacy, and abilities significantly surpass those of any other species on Earth. Nonetheless, humans share over 95% of our genome with chimpanzees, our closest living relatives.

Professor Soojin Yi from UC Santa Barbara, alongside her doctoral student Dennis Joshy and collaborator Gabriel Santepere from Hospital del Mar Medical Research Institute in Barcelona, recently set out to investigate how genes in different categories of brain cells have progressed when compared to those in chimpanzees. They discovered that while our genes encode for nearly all the same proteins as other apes, many of our genes are considerably more active than those of other primates.

Their findings, published in the Proceedings of the National Academy of Sciences, underscore the significance of gene expression in the development and function of the human brain.

Decoding nature’s blueprints

Each gene instructs a cell to produce a particular molecule, but this task is not carried out by the DNA itself. Instead, the information is transmitted to cellular machinery via a molecule known as messenger RNA. Scientists quantify gene expression by assessing the volume of mRNA generated by a specific gene.

As researchers began to grasp the genome’s role as the blueprint of life, they speculated that the human genome might account for our distinctive characteristics. However, a comprehensive comparison with chimpanzees conducted in 2005 revealed that we share 99% of our genes (though this figure has since been modified by scientists). This validated earlier findings based on a limited number of genes that indicated a minimal difference between human and chimpanzee genomes.

Currently, biologists hypothesize that gene expression could underlie these disparities. Consider the monarch butterfly: the adult possesses the same genome as when it was a caterpillar. The astonishing discrepancies between the two life stages stem solely from gene expression. Activating and deactivating various genes, or having them produce more or less mRNA, can profoundly influence an organism’s characteristics.

Illuminating the landscape

Past investigations have revealed variations in gene expression between humans and chimpanzees, with human cells typically exhibiting heightened gene expression. However, the picture remained unclear. The brain comprises numerous types of cells. Historically, scientists classified brain cells into two primary categories: neurons and glial cells. Neurons transmit electrochemical signals, similar to the copper wiring within a structure. Glial cells perform the majority of other functions, such as insulating the wires, sustaining the structure, and clearing debris.

Until recently, researchers could only examine composite tissue samples comprising various cell types. However, over the last decade, it has become feasible to analyze individual cell nuclei one at a time. This advancement enables scientists to differentiate between cell types, and often subtypes as well.

Yi, Joshy, and Santepere utilized datasets derived from a device with a very narrow channel to separate each nucleus into its own chamber within an array. They then categorized the cells by type before conducting statistical evaluations.

The team gauged gene expression by measuring the amount of mRNA generated by a specific gene in humans, chimpanzees, and macaques. An upregulated gene yields more mRNA in a particular species when compared to others, whereas a downregulated gene produces less. By comparing the two apes against macaques, the researchers could determine whether the differences between chimpanzees and humans arose from changes in chimpanzees, changes in humans, or a combination of both.

The authors noted differences in the expression of approximately 5–10% of the 25,000 genes analyzed in the study. Generally, human cells presented more upregulated genes compared to chimpanzees. This constitutes a significantly larger percentage than what researchers observed when unable to compartmentalize the analysis by cell type. The percentage increased to 12–15% when the authors began to account for cell subtypes.

“Now we can observe that individual cell types have their own evolutionary trajectories, becoming extremely specialized,” Yi stated.

Beyond neurons

The complexity of our neural pathways is unparalleled in the animal kingdom. Yet, Yi posits that our unique intelligence may not stem solely from this factor. Human glial cells make up over half of the cells in our brains, a significantly larger percentage than in chimpanzees.

Within the glial cell population, oligodendrocytes exhibited the most notable differences in gene expression. These cells provide the insulation that encases neurons, facilitating faster and more efficient electrical signal transmission. In a collaborative study released the preceding year, the team observed that humans possess a higher ratio of precursor to mature oligodendrocytes in comparison to chimpanzees. Yi speculates this may be linked to the extraordinary neural plasticity and gradual development of human brains.

“The heightened complexity of our neural network likely didn’t evolve in isolation,” Yi remarked. “It could not have come into being unless all these additional cell types had also developed, allowing for an expansion of neuron diversity, the quantity of neurons, and the intricacy of the networks.”

This research only examined cells from a select few regions of the brain. However, the cells in one specific brain area may vary from their equivalents in other regions. Yi intends to investigate the mechanisms underlying differences in gene expression and how genes correspond to various traits.

She also plans to trace differential gene expression

even earlier in our evolutionary timeline by including baselines from even more distantly related species. She is also keen on examining genetic variances between us and other ancient humans, such as Neanderthals and Denisovans.

Evolution encompasses more than simply altering genes. “The variation in gene expression is fundamentally how human brains developed,” Yi mentioned.