It is well known that the human cortex is expanded compared with other mammalian species, but the molecular mechanisms underpinning the evolution of human corticogenesis are not well understood. A new paper in Development takes a novel computational approach to screen for genetic changes that could have played an important role in human brain evolution. To learn more about the story behind the paper, we caught up with first author Juan Moriano and corresponding author Cedric Boeckx, a Research Professor at Catalan Institute for Research and Advanced Studies (ICREA).
Juan Moriano (left) and Cedric Boeckx (right)
Cedric, what questions are your lab trying to answer?
CB: We are fundamentally interested in human cognition, and language in particular. We'd like to understand the biological underpinnings of this remarkable capacity that humans have to develop a system of communication that is quite special. Like many, we think that this capacity relies, at least in part, on how the brain develops. So, we focus on what makes the human brain, well, human. This naturally takes us into the realm of evolution and comparative biology.
We focus on what makes the human brain, well, human. This naturally takes us into the realm of evolution and comparative biology.
Tell us about the background of the field that inspired your work
JM & CB: It's a wonderful time to be interested in the evolution of the human brain. There is a plethora of computational and experimental approaches being developed that collectively allow us to examine the many high-quality genomes of many species (including extinct species) and search for the intricate ways in which variation found in the genes impact the way in which brains develop differently, and how these developmental differences in turn push in different directions within phenotypic space.
Can you give us the key results of the paper in a paragraph?
JM & CB: We identified a zinc-finger transcription factor, KLF6, as a regulator of a cholesterol biosynthesis programme specifically in the route leading to outer radial glia cells. With our paleogenomic interrogation, we identified high-frequency regulatory variants derived in our species that, for example, further illuminate the KLF6 regulatory network.
In particular, we found a role for GLI3 and associated regulatory regions that show signals of positive selection in our lineage. Finally, we provide the code in an open access format to allow others to reproduce the analysis and implement the pseudotime-informed non-negative matrix factorisation method for learning the dynamics of gene expression programmes from single-cell datasets.
When doing the research, did you have any particular result or eureka moment that has stuck with you?
JM: I remember waiting with expectation for the results from several analyses to test the robustness of our findings. Of course, there was great excitement with our comparative genomic analyses, which helped us to identify prominent candidate genes for the recent evolution of the human brain.
There was great excitement with our comparative genomic analyses, which helped us to identify prominent candidate genes for the recent evolution of the human brain
Examining genetic differences between Homo sapiens (left) and Neanderthals (right) uncovers changes that may have helped drive the recent evolution of the human brain.
And what about the flipside: any moments of frustration or despair?
JM: The completion of this project was to some extent associated with the completion of my PhD, so I had some worries about having the final manuscript ready. Fortunately, everything went smoothly at the end and right on time to enjoy the summer vacation!
Why did you choose to submit this paper to Development?
JM & CB: We felt our manuscript aligned very well with previous research published in Development, and we really appreciate the efforts of the Journal and The Company of Biologists to support the community of developmental biologists at multiple levels, from Travelling Fellowships, to preLights, the Node or the Pathway to Independence Programme.
What is next for you after this paper?
JM: This paper was a central piece of my PhD thesis, which I defended this year (2024). Happily, soon after completing my PhD, I started a postdoctoral position at Professor Arnold Kriegstein's laboratory (University of California San Francisco) to investigate the questions we find most fascinating about the development and evolution of the human brain.
Where will this story take your lab next?
CB: Clearly the next step is functional validation. Together with our long-term collaborator, Giuseppe Testa, we have been seeking ways to exploit brain organoids to probe our computational predictions further, and hopefully figure out which (genetic) differences ended up making a (phenotypic) difference – impacting the course of human brain development.
JM & CB: Department of General Linguistics, University of Barcelona and University of Barcelona Institute of Complex Systems, 08007 Barcelona, Spain.
CB: University of Barcelona Institute of Neurosciences and Catalan Institute for Research and Advanced Studies (ICREA), 08007 Barcelona, Spain.
E-mail: [email protected]; [email protected]