One Gene’s Slow Rise May Explain How Primate Brains Grew Big and Folded

The human brain owes much of its power to two features that separate primates from most other mammals: sheer size and elaborate folding. The cerebral cortex, the wrinkled sheet of tissue responsible for perception, language and abstract thought, expanded gradually over tens of millions of years of primate evolution, and its surface became increasingly convoluted to pack more of it into the skull. Yet the molecular machinery driving that gradual transformation has remained stubbornly elusive. Now a study published in Nature Genetics points to a single gene, cyclin B1 interacting protein 1, or CCNB1IP1, whose expression rose step by step along the primate lineage in lockstep with the growth and folding of the cortex.

The research team, led by Lei Shi of the Kunming Institute of Zoology at the Chinese Academy of Sciences, exploited an unusual comparative tool: the tree shrew. This small, squirrel-like mammal is not a primate, but it sits close enough to the primate branch on the evolutionary tree to serve as an outgroup, a reference point that allows scientists to distinguish what is genuinely primate-specific from what is shared more broadly among mammals. By comparing the developing brains of humans, macaques, tree shrews and mice, the researchers could trace which genetic changes coincided with the expansion of cortical territory that defines our order.

Their first discovery was that CCNB1IP1, a gene that had little or no activity in the developing brains of other mammals, acquired expression in the primate brain. More strikingly, the level of that expression climbed progressively across the evolutionary ladder, from lower primates through monkeys to apes and finally humans. That gradient mirrored the gradient in cortical size and gyrification, the technical term for the degree of cortical folding, suggesting a quantitative relationship rather than a simple on-off switch. Statistical analysis confirmed that both the gyrification index and brain weight correlate with evolutionary divergence time across species, consistent with a gradual, cumulative process rather than a sudden leap.

Where did the increased expression come from? The answer, according to the study, lies not in the protein-coding sequence of the gene itself but in its regulatory DNA. Comparative analysis of cis-regulatory elements, the short stretches of DNA near a gene that control when and how strongly it is transcribed, revealed evolutionary changes that ratcheted up CCNB1IP1 activity. The researchers focused on two candidate regulatory regions, CRE1 and CRE2, and examined histone modifications such as H3K4me3 and H3K27ac, chemical tags on chromatin that mark active regulatory elements in human neural progenitor cells. Sequence alignments across twenty mammalian species highlighted sites that changed specifically in the human lineage, and one region, CRE1, contained sub-elements associated with the gradual expression increase during primate evolution.

To test whether the gene could actually reshape a brain, the team turned to experiment. When they overexpressed CCNB1IP1 in the embryonic mouse cortex using in utero electroporation, they saw a cascade of cellular effects: more cells entering DNA synthesis, an expanded pool of basal progenitors, and increased neuronal output. Basal progenitors are the self-amplifying stem cells of the subventricular zone, a germinal layer that is disproportionately well developed in primates and is widely regarded as the engine of cortical expansion. In the human fetal cortex, single-cell analysis showed that CCNB1IP1 is expressed most strongly in neural progenitor cells, and higher in basal progenitors than in apical progenitors at the peak of neurogenesis, precisely where extra rounds of cell division would matter most.

The mechanistic heart of the paper concerns what CCNB1IP1 actually does inside those cells. The researchers demonstrated that it represses E2F1, a transcription factor that drives the cell cycle, by targeting it for ubiquitin-mediated degradation, the cellular waste-disposal pathway that tags proteins for destruction by the proteasome. By damping E2F1, CCNB1IP1 alters the tempo of the cell cycle in neural progenitors. Slower, differently timed cycles are a long-standing theme in cortical evolution: since the classic work of Pasko Rakic and others, developmental biologists have argued that small changes in the duration and timing of progenitor cell divisions, repeated over thousands of rounds, can yield enormous differences in final neuron number. CCNB1IP1 offers a concrete molecular handle on that process.

The most dramatic experiment came next. Using CRISPR-Cas9, the team created conditional knock-in mice carrying the human CCNB1IP1 gene at the Rosa26 locus, activated in the excitatory neuronal lineage via Emx1-Cre. Ordinary mice have smooth, lissencephalic brains; their cortices lack the folds seen in humans and other gyrencephalic species. Remarkably, the knock-in mice developed recognizable cortical folding, along with an expanded cortical area, an increased proportion of upper-layer neurons, and measurable gains in cognitive performance on behavioral tests such as novel object recognition and the Morris water maze. In effect, a single regulatory change was sufficient to push a rodent brain partway toward a primate-like architecture.

The findings fit into a broader and increasingly rich picture of human brain evolution. Previous work has identified other human-specific genetic innovations that expand cortical progenitors, including the NOTCH2NL gene family, which enhances Notch signaling, and ARHGAP11B, a human-specific gene that promotes basal progenitor amplification and can even induce folding in mouse embryos. What distinguishes the new study is its emphasis on gradualism. Rather than a single human-specific invention, CCNB1IP1 shows a stepped increase in expression across the primate tree, implying that the enlargement and folding of the cortex were built incrementally, species by species, through cumulative regulatory tweaks rather than one dramatic mutation.

It is also a study in methodological craft. The authors combined laser microdissection of individual cortical layers in tree shrew embryos, bulk and single-cell transcriptomics across species, comparative genomics of regulatory elements, protein interaction assays, and transgenic mouse modeling into a single coherent argument. Data from brain organoids derived from humans, chimpanzees, bonobos and gorillas reinforced the expression gradient, and postnatal expression data from public brain atlases showed that the gene’s activity persists across multiple brain regions during development. All sequencing data have been deposited in public repositories, allowing other groups to scrutinize and extend the results.

Caveats remain, as they always do. Correlation between gene expression and cortical complexity across species does not by itself prove causation for every step of primate evolution, and the knock-in mouse, while striking, models only one component of a process that surely involved many genes. CCNB1IP1 has also been implicated in other contexts, including cancer biology, where it modulates ubiquitination of proteins such as MYCN, so its functions are likely broader than neurodevelopment alone. Still, the study delivers something rare: a gene whose evolutionary upregulation tracks the growth of the primate cortex, a plausible molecular mechanism linking it to progenitor behavior, and proof that boosting it can fold a smooth brain. In the long story of how our ancestors’ minds swelled and wrinkled into their modern form, CCNB1IP1 now stands as one of the clearest characters yet identified.

Subject of Research: Evolutionary changes in CCNB1IP1 gene regulation and their role in primate cortical expansion and folding

Article Title: CCNB1IP1 regulatory evolution underlies gradual increases in cortical size and folding in primates

Article References: Hu, T., Ma, P., Kong, Y., Tan, Y., Sun, X., Wang, J., Xiang, K., Mao, B., Wu, Q., Yi, S. V., & Shi, L. (2026). CCNB1IP1 regulatory evolution underlies gradual increases in cortical size and folding in primates. Nature Genetics. https://doi.org/10.1038/s41588-026-02773-x

Image Credits: AI Generated

DOI: 10.1038/s41588-026-02773-x

Keywords: CCNB1IP1, primate evolution, cortex, cortical folding, neurogenesis, basal progenitors, cis-regulatory elements, E2F1, ubiquitin degradation, tree shrew, knock-in mice, brain evolution