Topographic Axes of Wiring Space Converge to Genetic Topography in Shaping Human Cortical Layout

Abstract

Genetic factors have involved the gradual emergence of cortical areas since the neural tube begins to form, shaping the specialization of neural circuits in the human brain. Informed by invasive tract-tracing measurements, the cortex exhibits marked interareal variation in connectivity profiles, yet how this spatial variation is encoded in genetics remains unclear. Instead of considering a complex one-to-one mapping between genetic coding and interareal connectivity variation, we hypothesized the existence of a more efficient way that the organizing principles are embedded in genetic profiles to underpin the configuration of connectivity across the human cortex. Specifically, we found that a noninvasive neuroimaging measure, i.e., global connectopy derived from diffusion-weighted MRI tractography, reliably indexes the organizing principles of interareal connectivity variation, and it captures three dominant topographic patterns along the dorsoventral, rostrocaudal, and mediolateral axes of the cortex. We further found that the global connectopies converge to the gradients of vertex-by-vertex genetic correlation matrix on the phenotype of cortical morphology and the cortex-wide spatiomolecular gradients. Moreover, we found the critical role of genes related to brain morphogenesis in scaffolding the global connectopies. Our findings identify a common space linking genetic profilings and interareal connectivity variation, which may contribute to the accurate formation of cortical connections and arealization.

Comparative Analysis of Human-Chimpanzee Divergence in Brain Connectivity and its Genetic Correlates

“…The connectivity divergence and its underlying genetic associations were further investigated. The filtered genes identified by PLSR using the AHBA dataset are implicated in synapse and axon-related processes and neuronal projections, which are at the basis of macroscale anatomical connections 25,100 . Several genes, including EFCAB1 , C2CD4C, and SYT17 , were predicted to enable calcium ion binding 101,102 , which plays an important role in signal transduction and other cellular processes.…”

“…Recent studies have mapped chimpanzee brain connections using diffusion MRI and revealed substantial interspecies differences with humans 14,16,17,[20][21][22][23] . Moreover, understanding brain evolution requires a genetic perspective, as genetic factors strongly influence neural connectivity and uncover molecular mechanisms driving interspecies differences in brain connections, revealing insights into cognitive diversity and adaptation among primates 24,25 . However, comprehensive whole-brain connectional analyses and comparisons between chimpanzees and humans, coupled with genetic investigations into species differences in brain connections, are still lacking.…”