A Bioinformatic Investigation into a Unique Human FOXM1 Exon Variant and Its Relevance to Gyrencephaly

Gyrification is a shared phenotype of brain development across many species. The identification of human- and primate-specific genes is a topic of great research interest to uncover the genetic mechanisms that drive human gyrification. Here we investigated a human transcript variant of FOXM1 with a unique ninth exon proposed to have a crucial role in primate gyrification.

We performed comprehensive bioinformatic analyses, including several BLASTs and multiple sequence alignment, utilising available deposited sequencing data. We aimed to determine the degree of conservation of human FOXM1 exon 9 across a wide range of species, with a particular focus on gyrencephalic primates. Furthermore, we aimed to determine the degree of conservation of the remaining regions of FOXM1 across a subset of gyrencephalic and lissencephalic species.

Our results revealed that the exon is only partially detected in four other primates, challenging its presumed conservation in humans, apes, and other primates. The remaining regions of FOXM1 had a remarkably high level of conservation, and, given its role in regulating proliferation and differentiation, the results suggested that FOXM1 may be required for early brain development across all species. However, the sporadic presence of the exon 9 sequence even in other gyrencephalic primates raises questions about its indispensability in the process of gyrification.

Therefore, we conclude that the FOXM1 transcript variant comprising the exon 9 sequence in its entirety could be more appropriately reclassified as a human-specific cortical folding variant not found in other species. This research lays the foundation for further investigating the role of FOXM1 exon 9 in human gyrification and brain development.