Abstract

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.

Original languageEnglish
Pages (from-to)52-69.e8
JournalCell Stem Cell
Volume29
Issue number1
Early online date2021
DOIs
Publication statusPublished - 2022

Bibliographical note

Copyright © 2021 The Author(s). Published by Elsevier Inc.

Subject classification (UKÄ)

  • Genetics
  • Neurosciences
  • Medical Genetics

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