Brain wiring and supragranular-enriched genes linked to protracted human frontal cortex development.
The human frontal cortex is unusually large compared with many other species. The expansion of the human frontal cortex is accompanied by both connectivity and transcriptional changes. Yet, the developmental origins generating variation in frontal cortex circuitry across species remain unresolved. Nineteen genes, which encode filaments, synapse, and voltage-gated channels (e.g., NEFH, SYT2, VAMP1) are especially enriched in the supragranular layers of the cerebral cortex in humans relative to mice. The increased expression of these genes suggests enhanced cortico-cortical projections emerging from layer III in humans. We confirm that the expression of these supragranular-enriched genes is preferentially expressed in frontal cortex layer III in humans relative to mice. We demonstrate a concomitant expansion in cortico-cortical pathways projecting within the frontal cortex white matter in humans with diffusion MR tractography. To identify developmental sources of such variation, we compare frontal cortical white matter growth and developmental trajectories of transcriptional profiles of supragranular-enriched genes in humans and mice. We also use temporal changes in gene expression during postnatal development to control for variation in developmental schedules across species. The growth of the frontal cortex white matter and transcriptional profiles of supragranular genes are both protracted in humans relative to the timing of other transformations. These findings demonstrate that an expansion of projections emerging from the human frontal cortex is achieved by extending the duration of cortical circuitry development. Integrating RNA sequencing with neuroimaging level phenotypes is an effective strategy to assess deviations in developmental programs leading to variation in connections across species.