A human-specific structural variation at the ZNF558 locus controls a gene regulatory network during forebrain development
Johansson, P. A.; Brattas, P. L.; Douse, C. H.; Hsieh, P.; Pontis, J.; Grassi, D.; Garza, R.; Jonsson, M. E.; Atacho, D. A. M.; Pircs, K.; Eren, F.; Sharma, Y.; Johansson, J.; Trono, D.; Eichler, E. E.; Jakobsson, J.
Show abstract
The human forebrain has expanded in size and complexity compared to that of chimpanzee despite limited changes in protein-coding genes, suggesting that gene regulation is an important driver of brain evolution. Here we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate the mitophagy gene SPATA18, supporting a link between mitochondrial homeostasis and cortical expansion. The unusual on-off switch for ZNF558 expression resides in a downstream variable number tandem repeat (VNTR) that is contracted in humans relative to chimpanzee. Our data reveal the brain-specific co-option of a transposon-controlling KRAB-ZFP and how a human-specific regulatory network is established by a cis-acting structural genome variation. This represents a previously undescribed genetic mechanism in the evolution of the human brain.
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