A partial, duplicate copy of a gene appears to be responsible for critical features of our human brain that distinguish us from our closest primate relatives. The momentous gene duplication event occurred about two or three million years ago, at a critical transition in the lineage of human evolution, according to a pair of studies published early online in the journal Cell, a Cell Press publication, on May 3rd, 2018.
The studies are the first to explore the evolutionary history and function of a gene duplicate that is uniquely human. These "extra" genes are particularly interesting because they most likely provide the source of material used for our brain's adaptive evolutionary change. Until now, studying these genes has been technically challenging as they are nearly indistinguishable from each other.
"There are approximately 30 genes that were selectively duplicated in humans, using some of our most recent genomic innovations." explains Franck Polleux, an expert in brain development at The Scripps Research Institute.
Intriguingly, many of these  genes appear to play some role in the developing brain. Polleux along with Evan Eichler, a genome scientist at the University of Washington, focused their attention on one known as SRGAP2. A gene that has, in fact, been duplicated at least twice during human evolution. First - about 3.5 million years ago, and again about 2.5 million years ago.
The new research shows how the second, and more recent, duplication event only produced a partial copy of the SRGAP2 gene. This copy functions at exactly the same time and place as the original gene, allowing it to interact with and block the function of the ancestral gene.
Interestingly, the partial gene occurs just as the fossil record reflects a transition from human's small brained Australopithecus ancestors and the genus Homo (as in Homo sapiens) appears. Homo ancestors will eventually become modern humans. This is a time when our ancestors' brains begin to expand and dramatically change and cognitive abilities are likely to have expanded.
"This innovation couldn't have happened without that incomplete gene duplication," explains Eichler. "Our data suggests a mechanism where incomplete duplication of this gene created a novel function 'at birth'."
The researchers don't believe SRGAP2 is solely responsible for our brain expansion, but such genetic interference does have potential benefits. Polleux and colleagues induced the function of human-specific SRGAP2 duplication in mice and found loss of SRGAP2 function accelerated neurons' migration in the developing mice brains, possibly more efficiently helping neurons reach their final destination. Moreover, mice neurons with decreased SRGAP2 function — due to expression of human-specific SRGAP2 — displayed more knob-like extensions or spines on neural surfaces. These spines made the mouse neurons appear much more like those found in human brains. Such spines enable more connections between neurons.
In addition to gaining insight into origins of our modern human brain, is the insight gained into human neuro-developmental disorders. Humans are prone to autism, epilepsy and schizophrenia, brain issues where neuronal connections are affected during development. Researchers point out how the human brain can have symptoms traceable to disruptions of ancestral SRGAP2. Researchers will now search for people carrying defects in the human-specific 'granddaughter' copy of SRGAP2 as well.
If this gene duplication did indeed produce an immediate effect in our evolution as Eichler and Polleux suspect, there must have been a fascinating period in our history characterized by tremendous variation in hominid cognition and behavior. SRGAP2 and other human-specific gene duplicates might also explain big differences between humans and other primates, despite the few differences in our genome sequences.
Eichle: "We may have been looking at the wrong types of mutations to explain human and great ape differences. These episodic and large [gene] duplication events could have allowed for radical - potentially earth-shattering - changes in brain development and brain function."
Structural genomic variations represent a major driving force of evolution, and a burst of large segmental gene duplications occurred in the human lineage during its separation from nonhuman primates. SRGAP2, a gene recently implicated in neocortical development, has undergone two human-specific duplications. Here, we find that both duplications (SRGAP2B and SRGAP2C) are partial and encode a truncated F-BAR domain. SRGAP2C is expressed in the developing and adult human brain and dimerizes with ancestral SRGAP2 to inhibit its function. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. Expression of SRGAP2C phenocopies SRGAP2 deficiency. It underlies sustained radial migration and leads to the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. These results suggest that inhibition of SRGAP2 function by its human-specific paralogs has contributed to the evolution of the human neocortex and plays an important role during human brain development.
Cécile Charrier, Kaumudi Joshi, Jaeda Coutinho-Budd, Ji-Eun Kim, Nelle Lambert, Jacqueline de Marchena, Wei-Lin Jin, Pierre Vanderhaeghen, Anirvan Ghosh, Takayuki Sassa, Franck Polleux.
Authors: Megan Y. Dennis, Xander Nuttle, Peter H. Sudmant, Francesca Antonacci, Tina A. Graves, Mikhail Nefedov, Jill A. Rosenfeld, Saba Sajjadian, Maika Malig, Holland Kotkiewicz, Cynthia J. Curry, Susan Shafer, Lisa G. Shaffer, Pieter J. de Jong, Richard K. Wilson, and Evan E. Eichler.
We would like to thank Marie Rougié and Virginie Courchet for excellent technical support and management of the mouse colonies and members of the Polleux laboratory for useful discussions. We thank Maxime Camo for help with the initial characterization of the SRGAP2 KO, Daniel Choquet for providing HOMER1c expression plasmid, and Evan Eichler's lab for reagents and useful discussions. N.L. is a clinical scientist of the FNRS and P.V. is a Research Director of the FNRS. This work was partially supported by grants of the FNRS, Belgian Queen Elizabeth Foundation, Welbio and Excellence Programs of the Walloon Region (to P.V.), Fonds Erasme and the Belgian Kids' Fund (to N.L.), NIH RO1NS067557 (F.P.) and ADI-Novartis funds (F.P.), NIH F31NS061610 (J.d.M.), NIH F31NS068038 (J.C.-B.), by NSFC (No.31171033), and “973” Project (No.2011CB933101) (W.-L.J.). C.C., K.J., T.S. and F.P. conceived the experiments, and C.C., K.J., J.C.-B., J.d.M., T.S., N.L., and P.V. performed the experiments. W.-L.J. provided the anti-SRGAP2 antibodies. J.-E.K. and A.G. provided RNA from cultured human ES cells. C.C., K.J., and F.P. prepared the manuscript. A.G. is currently an employee of F. Hoffmann La Roche.
A human skull overlaid will illustration of human brain. Image credit: Fiddes et al; Cell magazine.