DUF1220 copy number and the evolutionary expansion of primate cerebral cortex

When compared to brains of other primates, the most striking feature of the human brain is its exceptional size. This size difference is mainly due to a massively expanded cerebral cortex and, thus, a higher number of brain... [ view full abstract ]

When compared to brains of other primates, the most striking feature of the human brain is its exceptional size. This size difference is mainly due to a massively expanded cerebral cortex and, thus, a higher number of brain neurons. The growth of the primate cortex has however not been uniform, with a set of key regions in lateral temporal, parietal and prefrontal association cortex showing disproportionally high expansion. Extreme gene duplication has been suggested as a possible evolutionary mechanism underlying the rapid cortical expansion seen in the primate lineage. The NBPF gene family has received particular interest as it contains sequences encoding DUF1220, a protein domain (of unknown function) showing more human lineage specific copy number increases than any other protein encoding sequence in the human genome. DUF1220 copy number has been linked to differences in brain size and neuron number across primates. Furthermore, variations in DUF1220 copy number across humans has been used to predict head circumference, and associations with micro/macrocephaly have been reported.

Taking advantage of gene expression maps made available in the Allen Human Brain Atlas (AHBA), we tested whether variations in NBPF expression (i.e., DUF1220 dosage) across the cortex was associated with the evolutionary expansion of a given cortical region. Interestingly, in the AHBA sample of 6 adult brains we found low levels of NBPF expression in evolutionary high-expanding parts of cortex and high expression in low-expanding parts. This negative correlation was replicated in another gene, TBC1D3, which shares similar human-specific copy-number increases as NBPF. Investigating an atlas of the developing human brain (BrainSpan), however, we found high levels of NBPF/TBC1D3 expression globally across the brain during the gestation period and early childhood, followed by reduced expression levels in late childhood and adolescence. The results suggest that DUF1220/TBC1D3 dosage may play a role in proliferation during human neurogenesis, but contribute to growth suppression in adulthood.