Search

Summary One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase [ 1–4 ]. As the endocranium closely mirrors the outer shape of the brain, these differences might reflect altered neural architecture [ 4, 5 ]. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans [ 6, 7 ]. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1 , which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape. Highlights • We use fossil skull data to derive an index of endocranial shape in human MRI scans • In 4,468 Europeans, we screen introgressed Neandertal SNPs for association with the index • Lead SNPs consistently associate with reduced globularity in five separate subsamples • These SNPs affect neural expression of two genes linked to neurogenesis and myelination Gunz, Tilot et al. combine paleoanthropology, archaic genomics, neuroimaging, and gene expression to study biological foundations of the characteristic modern human endocranial shape. They find introgressed Neandertal alleles that associate with reduced endocranial globularity and affect expression of genes linked to neurogenesis and myelination. [ABSTRACT FROM AUTHOR]