Olduvai domains downregulate mitochondrial pathways to promote human brain evolution and neoteny

Abstract

Olduvai (formerly DUF1220) protein domains, encoded by the NBPF gene family, have undergone the greatest human lineage-specific copy-number expansion of any coding sequence in the genome and strongly correlate with brain size and neuron number across primates. Here we show that Olduvai domains act in a dosage-dependent manner to suppress mitochondrial metabolism. Transcriptomic, proteomic, and live-cell imaging analyses of cells overexpressing NBPF1 (which encodes seven Olduvai domains) reveal pronounced downregulation of mitochondrial pathways, including electron transport chain components and NADH dehydrogenase activity, as well as reduced mitochondrial abundance. By limiting energy availability, this suppression delays cellular maturation and developmental timing. We propose that the resulting prolongation of neurogenesis increases neuron production, providing a mechanistic link between Olduvai copy number expansion and the evolutionary enlargement of the human brain. This dosage-sensitive mitochondrial regulation may also contribute to broader neotenic features of human development, offering a unifying molecular mechanism for brain expansion and the neotenic traits that distinguish humans from other primates.