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.

尽管蛋白质编码基因的变化有限，但与黑猩猩相比，人类前脑的大小和复杂性有所扩大，这表明基因表达调控是大脑进化的重要驱动力。在这里，我们确定了一种 KRAB-ZFP 转录因子 ZNF558，它在人类而非黑猩猩前脑神经祖细胞中表达。ZNF558 进化为 LINE-1 转座子的抑制因子，但已被选为调节单个靶标，即线粒体自噬基因SPATA18. ZNF558 在线粒体稳态中发挥作用，脑类器官的功能丧失实验表明 ZNF558 在人类大脑早期发育过程中影响发育时间。ZNF558 的表达受可变数量串联重复的大小控制，与人类相比，该可变数量串联重复在黑猩猩中更长，并且在人群中是可变的。因此，这项工作提供了对顺式作用结构变异如何建立影响人类大脑进化的调节网络的机制洞察力。