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What Makes Our Brain Human? The Search for Answers

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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.

Reference:

[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.

Links:

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

Posted In: Science

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