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What Makes Our Brain Human? The Search for Answers

Posted on by Dr. Francis Collins

The Thinker

“The Thinker” by Auguste Rodin (photo by Brian Hillegas)

Humans’ most unique traits, such as speaking and abstract thinking, are rooted in the outer layer of our brains called the cerebral cortex. This convoluted sheet of grey matter is found in all mammals, but it is much larger and far more complex in Homo sapiens than in any other species. The cortex comprises nearly 80 percent of our brain mass, with some 16 billion neurons packed into more than 50 distinct, meticulously organized regions.

In an effort to explore the evolution of the human cortex, many researchers have looked to changes in the portion of the genome that codes for proteins. But a new paper, published in the journal Science [1], shows that protein-coding DNA provides only part of the answer. The new findings reveal that an even more critical component may be changes in the DNA sequences that regulate the activity of these genes.

In the study, a team led by Steven Reilly and James Noonan at Yale University, New Haven, CT, compared the development of the cortex in human, rhesus macaque, and mouse. Instead of focusing on protein-coding DNA, the researchers set their sights on tracking the activity of regulatory elements in the genome. Specifically, they looked at two key types of regulatory elements: promoters, which are DNA signals that generally lie just upstream of protein-coding genes; and enhancers, which are DNA regions that can be located some distance away, but modulate a gene’s output, rather like the dimmer function on a light switch.

Assessing activity of promoters and enhancers can be done by looking at specific chemical modifications of the proteins, called histones, that the DNA is wrapped around. Using two of these so-called “epigenetic marks” that are correlated with regulatory activity, the researchers identified 22,139 promoters and 52,317 enhancers that were active in human embryonic brain tissue between 7 to 12 weeks after conception—the time period during which distinctly human aspects of the cortex begin to appear. When this map was compared to similar maps from rhesus and mouse, nearly 12,000 regulatory elements stood out as being more active in humans than in the other mammals, suggesting they may be involved in the evolutionary changes that allowed the human cortex to develop substantially more complexity than those of other species.

To learn more about how these regulatory differences related to the biology of the developing cortex, researchers turned to the BrainSpan project, an NIH-supported atlas of gene expression in the human brain from early development to adulthood. They overlaid their new human-specific list of regulatory elements and target genes onto the BrainSpan atlas of all genes with roles in brain development. From there, they could narrow down the list further to those promoters and enhancers that regulate genes known to play pivotal roles in human brain development.

Indeed, researchers found a marked convergence between their new map of regulatory elements and the BrainSpan map of gene expression. Combining both datasets pointed to 17 common biological processes and pathways—including cortical patterning, renewal of progenitor cells, and migration of neurons—as being crucial for the development of the human cortex. Taken together, these findings suggest that evolutionary changes in regulatory activity may have been instrumental in shaping the human cortex.

Finally, it’s important to note that this work demonstrates the power of comparing maps of regulatory elements with maps of gene expression. Not only does this “epigenomic” approach enable scientists to look more systematically at biological processes in the brain, it may prove valuable in studying other organ systems as well.


[1] Evolutionary changes in promoter and enhancer activity during the human corticogenesis.  Reilly SK, Yin J, Ayoub AF, Emera D, Leng J, Cotney J, Sarro R, Rakic P, Noonan JP. Science. 2015 March 6;347 (6226):1155-1159.


Brain Basics: Know Your Brain (National Institute of Neurological Disorders and Stroke/NIH)

Noonan Lab (Yale School of Medicine, New Haven, CT)

BrainSpan: Atlas of the Developing Brain (a joint effort of the Allen Institute for Brain Science and researchers supported by the National Institute of Mental Health/NIH)

Epigenomics (National Human Genome Research Institute/NIH)

NIH Support: National Institute of General Medical Sciences; National Institute on Drug Abuse; National Institute of Neurological Disorders and Stroke


  • martyn strong says:

    The human parts of my brain get taken offline due to too much video viewing. Some parts of video (the cuts, pans and zooms etc.) trigger my reflex response in the brain stem or in the reptilian parts of the brain, that can take the parts of the more human parts of the brain offline. These are hard coded reflexes and they reduce the overall amount of resources that the brain uses. The cuts and pans etc. produce primitive visual signals that are similar to those signals that are produced by predators. Tests need to be done to see how long the areas of the brain stay offline.

  • José Eduardo de Salles Roselino says:

    To search for the difference that makes us humans by the study of the most clear anatomical difference seems to be the simplest way to address this problem. However, it must be considered that what we have as great difference today did not have appeared from on night to the following day in the life of our ancestors. The point that is highlighted by Martyn Strong calls for a functional aspect that must be taken into account. How our cortex works in conjunction with more primitive parts of our brains may have had a small functional difference that over the long period of time have lead to the great anatomical difference observed today.

  • Structure of Human Brain and Function says:

    The exploration of what sets the human brain apart is a captivating journey into our uniqueness. The intricate interplay of neural networks and cognitive abilities gives rise to our profound emotions, complex thoughts, and remarkable creativity. From the development of advanced language skills to our capacity for introspection, our brain’s remarkable evolution has paved the way for our species to thrive in a dynamic world. Understanding the distinctive features that make our brain human not only sheds light on our origins but also fuels our aspirations to unlock its full potential. A thought-provoking read that highlights the essence of our cognitive identity.

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