The Molecular and Cellular Basis of the Human Brain Evolution

Millions of years have passed since humans parted ways with our closest nonhuman primates on the evolutionary pathway. During this time, humans have developed languages and writing skills, harnessed fire and began cooking, created innovative technologies that now govern our daily lives, and even studied how life itself works. So why have no other nonhuman primates ever rivaled our level of cognitive ability?

In hopes of answering that very question, much debate among scientists today centers around the differences between the brain structures of humans and nonhuman primates. While some argue that the larger size of the human brain alone is responsible for higher-order thinking, others insist that there is more to the story. Perhaps in addition to increased size, the connections between cells and the different cells themselves provide a better explanation. André Sousa and Ying Zhu, researchers at the Yale School of Medicine, analyzed tissue samples from sixteen regions of the brain to further investigate the cellular and molecular differences between human and nonhuman primate brains. Examining individual gene expression differences in the brains of chimpanzees, macaques, and humans, these researchers discovered human-specific differences in the expression of the TH gene responsible for dopamine production and the MET gene that is related to Autism Spectrum Disorder, gaining insight into the basis of certain neurological and psychiatric disorders.

Our Closest Relatives

In order to determine human-specific differences in the brain structures, the researchers chose to study chimpanzees, our closest living relative, as well as the rhesus macaque, one of the most commonly studied nonhuman primates. “Ideally, the easiest way to study human brain evolution would be to analyze the brains of all extinct human species,” Sousa remarked. However, since the brain does not fossilize, he and his colleagues instead had to compare the human brain with the brains of our closest living relatives to determine which features are most likely human-specific. For ethical reasons, they could only use postmortem tissue for direct molecular experimentation.

The researchers particularly analyzed the upregulation or downregulation of genes, to correspondingly compare increased or decreased gene expressions in different parts of the brain in the different species studied. “What drives these differences in gene expression are often changes in regulatory non-coding regions,” explains Sousa. “Additionally, mutations in non-coding regions of DNA don’t change the protein product, but rather change when, where, and how much is produced.”

Because humans and chimpanzees diverged from a common ancestor more recently than they did from macaques, the researchers were able to use these three branches of a much more extensive evolutionary tree in order to narrow down the origins of a modified gene. For example, if a specific gene appeared to be upregulated in humans but downregulated in both chimpanzees and macaques, then this would indicate a human-specific change. Similarly, if a gene was upregulated in humans and macaques, but downregulated in chimpanzees, then this would demonstrate a chimpanzee-specific change. This gene regulation would then correspond to an increase or decrease in the production of proteins in cells and thus the trait, or phenotype, displayed by each species.

A Glance at Brain Structure

The human brain is about three times larger than the chimpanzee brain. The primary assumption is that a bigger brain should be able to hold more information and form more complex circuits between nerve cells. “We believe that instead of one big change in brain structure that accounts for a lot of differences, there are actually many small but distinct differences in human brains that add together to make big differences, for example, in cognition,” Sousa explained.

Uncertain of where they would find the most differences in the brains of the three species, the researchers approached this study without a main brain region of interest. Because the neocortex is known predominantly for its role in higher cognitive function, they hypothesized that the greatest number of differences across the species would be located in this region. Their data demonstrated that, as expected, most genes were similar and therefore conserved among humans, chimpanzees, and macaques. However, the most interspecies differences in changes in gene expression were actually discovered not in the neocortex but in the striatum, a region of the brain primarily involved in voluntary movement, planning, and reward. “This is likely because it is a transition station between the neocortex and other regions of the brain, so changes in this region may also lead to changes in the neocortex,” Zhu reasoned.

The Key is in Dopamine

All primates have dopamine, a crucial neurotransmitter responsible for motor control and emotional responses. The researchers discovered that the TH gene, responsible for the production of dopamine, was more expressed in the human striatum than in the striata of chimpanzees and macaques, which indicates that humans most likely have more dopamine in the striatum than in the other species studied. “There are two possible explanations for this observation,” Sousa said. “First—there are exactly the same number of TH cells among the three species, but each human cell is producing considerably more dopamine; or second—humans have more TH cells than chimpanzees and macaques.” Because these comparisons were made at the tissue-level, the researchers performed cellular-level analysis and were able to conclude that the latter case was true: humans have more TH cells in the striatum than the other two species. In fact, chimpanzees and the other non-human African great apes (bonobos and gorilas) have no TH cells at all in the neocortex. All primate species have dopamine production centralized in specialized structures of the midbrain.  However, it is a novel discovery that humans likely have another localized production of dopamine in the neocortex. “This is important because it is the first time we showed that cells in the neocortex are also able to produce dopamine,” Sousa commented.

Additionally, since TH was expressed less in the neocortex of both chimpanzees and gorillas, this suggests that the expression of the gene was absent in the most recent common ancestor of the African great apes and reappeared in humans somewhere recent along the evolutionary timeline.

Dopamine’s involvement in motor control, learning and memory, and the reward system therefore holds great relevance to human evolution and even modern neurological diseases. Parkinson’s disease, for example, a neurodegenerative disorder that particularly affects movement, is caused by a lack of dopamine from the death of dopamine producing cells. “This loss of cells may also be related to some form of intellectual impairment, but this is purely hypothesized right now,” Zhu commented.

Still Unraveling the Mystery

In addition to the TH gene, this study found small but distinct differences in other genes, including MET and ZP2. Specifically, the MET gene, which is associated with autism spectrum disorder, was enriched only in the human prefrontal cortex, an area of the brain related to very high cognitive functions. A potential area of research would involve studying whether this increase in MET levels in the prefrontal cortex makes humans more susceptible to autism.

As for the ZP2, this gene was found only in the human brain and not in chimpanzees or macaques. “What’s most surprising about this gene is its location,” Sousa said. This gene, which has been studied extensively in the context of the reproductive system, is crucial for the recognition and mediation of the sperm in the egg. Future research could also be directed at studying this particular gene in order to figure out what it is also doing in the brain and how it got there. With the discoveries of this study in mind, researchers could examines these specific genes to gain clearer insight into the genetic and molecular changes in evolution of the human brain.

Future Direction

“We believe that there is a cumulative effect of all of these small changes we found that helps explain the evolution of the human brain and differentiate it between the brains of nonhuman primates,” Sousa said. Human-specific differences have huge implications for the onset of neurological diseases, such as Parkinson’s disease, in which a depletion of TH+ cells in the neocortex could be detrimental to cognitive function. Additionally, this study focused solely on adult brains among the three species, but the researchers are interested in expanding their research to cover other human developmental stages in hopes of learning about the differences in how brains change over time.

A possible addition to future research would be to include a more extensive comparison including many more species. The interspecies comparisons between humans, chimpanzees, and macaques in this study already demonstrate substantial difference between humans and our closest nonhuman primates, which could then possibly affect the way we employ animal models to study human disorders or develop pharmaceutical drugs. “Although we have made a big step towards understanding cellular and molecular distinctions in the human brain, there is still much work to do,” both researchers conclude.

About the Author

Anna Sun is a prospective Molecular, Cellular and Developmental Biology major in Pierson College ‘21. She is very interested in bioinformatics and plans to spend this summer in a laboratory conducting genetics research. In addition to writing for the Yale Scientific Magazine, she is involved in the MCDB Student Advisory Committee at Yale and loves to spend time with her friends discovering the food scene in New Haven.


The author would like to thank Dr. Sousa and Dr. Zhu for sharing their time and enthusiasm about their research.


  1. Interview with Dr. Sousa, Yale School of Medicine, interview on 1/25/18
  2. Interview with Dr. Zhu, Yale School of Public Health, interview on 1/29/18