Olduvai domain expression downregulates mitochondrial pathways: implications for human brain evolution and neoteny.

Encoded by the NBPF gene family, Olduvai (formerly DUF1220) protein domains have undergone the largest human lineage-specific copy number expansion of any coding region in the genome. Olduvai copy number shows a linear relationship with several brain size-related measures and cortical neuron number among primates and with normal and disease-associated (micro- and macrocephaly) variation in brain size in human populations. While Olduvai domains have been shown to promote proliferation of neural stem cells, the mechanism underlying such effects has remained unclear. Here, we investigate the function of Olduvai by transcriptome and proteome analyses of cells overexpressing , a gene encoding 7 Olduvai domains. Our results from both RNAseq and mass spectrometry approaches suggest a potential downregulation of mitochondria. In our proteomics study, a Gene Ontology (GO) enrichment analysis for the downregulated proteins revealed a striking overrepresentation of the biological process related to the mitochondrial electron transport chain ( value: 1.81e-11) and identified deregulation of the NADH dehydrogenase activity ( value: 2.43e-11) as the primary molecular function. We verify the reduction of apparent mitochondria via live-cell imaging experiments. Given these and previous Olduvai findings, we suggest that the Olduvai-mediated, dosage-dependent reduction in available energy via mitochondrial downregulation may have resulted in a developmental slowdown such that the neurogenic window among primates, and most extremely in humans, was expanded over a greater time interval, allowing for production of greater numbers of neurons and a larger brain. We further suggest that such a slowdown may extend to other developmental processes that also exhibit neotenic features.