Gene expression study reveals human brain cell types becoming more specialized, not just more numerous

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Our human genome is most similar to that of chimpanzees, our nearest living relatives.

A researcher at UC Santa Barbara, Soojin Yi from the Ecology, Evolution, and Marine Biology Department, collaborated with her student Dennis Joshy and Gabriel Santepere from Hospital del Mar Medical Research Institute in Barcelona. They wanted to find out how genes in different kinds of brain cells have evolved by comparing ours to those of chimpanzees. The study concluded that, despite our genes coding for almost all the same proteins as other apes, many of our genes are much more productive than those of other primates.

Emphasize the significance of gene expression in shaping the evolution and functioning of the human brain.

Interpreting nature's blueprints

Each gene sends instructions to a cell to produce a specific molecule, but it doesn't do so directly through the DNA. Instead, the instructions are passed along through a molecule called messenger RNA. Researchers measure the production of a gene by counting the amount of mRNA made by it.

As scientists started to grasp the significance of the genome as life's blueprint, they thought it might explain our distinctive characteristics. However, a detailed comparison with chimpanzees in 2005 showed we share 99% of our genes (although scientists have since reevaluated this figure). This validated earlier studies based on limited numbers of genes, which had previously indicated a relatively small difference between the human and chimpanzee genomes.

Experts in the field of biology believe that the differences in form and function between the various life stages of an organism may be attributed to variations in how certain genes are expressed. For instance, a monarch butterfly undergoes a remarkable transformation from a caterpillar to an adult, all while retaining the same genetic makeup. The striking differences between these two life stages can be primarily attributed to the differing ways genes are turned on and off, or those that produce varying levels of messenger RNA, end resultantly altering the organism's characteristics.

Getting a clearer picture

Previous studies have discovered varying levels of gene activity between humans and chimpanzees, with human cells generally exhibiting more gene expression, yet the outcomes were unclear. The brain consists of numerous cell types. Historically, researchers classified brain cells into two primary categories: neurons and glial cells. Neurons transmit electrical and chemical signals, somewhat akin to electrical wiring in a building. Glial cells handle most other functions, such as insulating the signal-transmitting neurons, providing structural support, and removing waste.

Until recently, scientists were limited to studying samples made up of many different types of cells. However, over the past decade, it's become possible to test individual cell nuclei, one at a time. This allows researchers to distinguish between cell types and often identify subtypes as well.

Scientists Yi, Joshy, and Santepere used data from a device with a narrow outlet to separate each nucleus into its own compartment in a container. Next, they sorted the cells by type, followed by a statistical analysis.

The team measured the expression of a specific gene in humans, chimpanzees, and macaques by looking at the amount of genetic material (mRNA) each produced. An increase in mRNA indicated a gene was upregulated (produced more) in a particular species compared to the others. By contrast, a decrease in mRNA suggested a gene was downregulated, producing less. By comparing chimpanzees and humans to macaques, the researchers could determine if differences between the two humans and chimpanzees were due to changes in the chimpanzees themselves, changes in the humans themselves, or a combination of both.

The researchers identified variations in the expression of approximately 5-10% of the 25,000 genes studied. Overall, human cells had a larger number of genes that were increased compared to chimpanzees, a much higher percentage than what was found when the analysis was not broken down by cell type. This gap increased to 12-15% when the authors examined specific cell subtypes.

"All of us can see that each cell type has its own evolutionary path and has really specialized," Yi said.

Not just neurons

The complexity of our brain's neural pathways is unmatched in the animal world. However, Yi believes that our distinct intelligence isn't due solely to this sophistication. Human glial cells make up more than half of the cells in our brains, a larger proportion than even in chimpanzees.

last year, a team found that humans tend to have more precursors versus mature target brain cells compared with chimpanzees, which Yi believes could be linked to the outstanding neural flexibility and prolonged development of human brains.

Our neural network is more intricate than it should be," Yi stated. "It likely wasn't solely responsible for evolving that complexitysolo; it probably wouldn't have existed without the development of other cell types that enabled the increase in neuron diversity, the number of neurons, and the complexity of these neural networks.

This study focused on a limited number of brain regions. Nevertheless, cells from one brain area might have distinct characteristics compared to those from other areas. Yi intends to investigate the underlying causes of variations in gene expression and how genes correspond to specific traits.

She also plans to track how gene expression differs across time in our evolutionary history by referencing information from more remotely related animals. Additionally, she's interested in comparing genomics between us and other archaic human species, such as Neanderthals and Denisovans.

Evolution is about more than just modifying genes. "Differential gene expression is actually how the human brain evolved," Yi said.

DOI: 10.1073/pnas.2411918121

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