A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development

The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression 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 a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable number tandem repeat that is longer in chimpanzees compared to humans, and variable in the human population. Thus, this work provides mechanistic insight into how a cis-acting structural variation establishes a regulatory network that affects human brain evolution. [Display omitted] •ZNF558 is uniquely expressed in human but not chimpanzee forebrain progenitors•ZNF558 has been co-opted to control the expression of a single gene, SPATA18•ZNF558 plays a role in mitochondrial homeostasis and brain development•ZNF558 expression is controlled by the size of a downstream VNTR Johansson et al. identify ZNF558, a KRAB-ZFP expressed in human but not chimpanzee forebrain progenitors, where it regulates its target SPATA18. The expression of ZNF558 is controlled by the size of a VNTR that is longer in chimpanzees compared to humans, demonstrating a role for structural variations in human brain evolution.