The Evolution of Human Cortical Development

Of all the traits that separate humans from their cousins, few draw as much fascination as our unusually large brain. How does it work? Why did it evolve? Those are big questions, and, as usual, the best way to answer them is one piece at a time, hoping that the partial answers will eventually coalesce into a coherent whole. Thanks to a team of researchers at Yale, we now have one more piece of the puzzle — a list of genes which have evolved to be more active during the development of the human cortex.

To identify these genes, the researchers mapped the genetic regulators active in the developing cortex of human, rhesus macaque, and mouse embryos. They began by looking for epigenetic changes linked to increased activity ("epigenetic gains") and compared their findings in the three species to identify genes which are more active in human cortical development. According to their analysis, these epigenetic gains weren't associated with with human-specific changes in the genetic sequence, but they did find "hotspots of epigenetic gains" — that is, genomic regions with an unusually high density of epigenetic gains. I'd love to know more about how and why these hotspots came to be; it wouldn't be the first time that the physical conformation of a genome has an evolutionary impact.

Next, the team wanted to understand the biological importance of these genes, which have evolved to be more active during human cortical development. Rather than going through the list of roughly 11,000 genes, they compared it with a gene coexpression network of the human brain. The network consists of 96 modules of genes with correlated expression during cortical development. By comparing their list with the network, the team could pick out the modules that have become more active during our evolution. They found 17 modules which are enriched in epigenetic gains — in other words, 17 modules which have evolved increased activity in the developing human cortex — associated with processes such as cortical patterning or controlling the number of cortical cells. The module with the strongest enrichment contains genes involved with the extracellular matrix, which plays a role in neuronal migration and maintaining the self-renewal of progenitor cells. "Building a more complex cortex likely involves several things: making more cells, modifying the functions of cortical areas, and changing the connections neurons make with each other. And the regulatory changes we found in humans are associated with those processes," said James Noonan, senior author of the study, in a press release.

By identifying genes and genetic modules that have been important during human cortical evolution, this paper provides a valuable resource to researchers striving to understand the human brain, from how it evolved to how it works today. To me, it's also intriguing to see how much of this evolution — a hallmark of our lineage — involved changes in genetic regulation rather than genetic novelties. A few years ago, I wrote about a pair of studies which showed that alternative splicing — encoding different versions of a protein in a single gene — has played an important role in mammalian evolution. Though quite different, these studies are linked by an underlying theme, the idea of evolution mixing and matching the bits and pieces at its disposal to come up with interesting new combinations. I'll close by quoting this paper's lead author, Steven Reilly: "While we often think of the human brain as a highly innovative structure, it's been surprising that so many of these regulatory elements seem to play a role in ancient processes important for building the cortex in all mammals. However, this is often a hallmark of evolution, tinkering with the tools available to produce new features and functions."

Ref
Steven K. Reilly, SK, Yin, J, Ayoub, AE, et al. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science 347:6226 (1155-1159). (2015) doi:10.1126/science.1260943

Image credits
The image (of a chimpanzee brain) is by Flickr user Gaetan Lee and is distributed by Wikimedia Commons under a CC-BY license.