Imaging genomics reveals genetic architecture of the globular human braincase

Abstract

Compared with our fossil ancestors and Neandertal kin, modern humans have evolved a distinctive skull shape, with a rounder braincase and more delicate face. Competing explanations for this rounder skull have either linked it to changes in brain organisation, or seen it as a byproduct of gracilization (evolution of thinner and lighter skeletal anatomy). Here, we combined palaeoanthropological data from hominin fossils and imaging genomics data from living humans to gain insight into evolutionary and developmental mechanisms shaping this uniquely modern human phenotype. We analysed endocranial globularity from magnetic resonance imaging (MRI) brain scans and genetic data of more than 33,000 adults. We discovered 28 genomic loci significantly associated with endocranial globularity. There was genetic overlap with the brain's ventricular system, white matter microstructure, and sulcal morphology, and with multivariate genetic analyses of reading/language skills, but not with general cognition. The associated genes exhibited enriched expression in the brain during prenatal development and early childhood. The connection to the ventricular system hints at a role for cerebrospinal fluid pressure in shaping the endocranium during development. Genes linked to endocranial globularity also showed enhanced expression in the cardiovascular and female reproductive systems. This finding suggests coevolutionary pathways whereby changes impacting factors such as energy needs, pregnancy, or fertility concurrently shape the brain and its structure. 1 bioRxiv preprint doi: https://doi.org/10.1101/2024.03.20.585712; this version posted March 22, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. 40 Main Text: 41 42 43 44 45 46 47 During foetal and infant development, the growing brain leaves an impression inside the skull. Such endocranial imprints (endocasts) in fossil skulls document evolutionary changes in brain volume, folding patterns, and brain shape. Modern humans have a distinct endocranial shape, that is more globular than the elongated endocrania seen in all other fossil hominins and apes1,2. This endocranial globularity involves increased parietal bulging and an enlarged posterior cranial fossa, which houses the cerebellum (Fig. 1A). …