A human-specific structural variation at the ZNF558 locus controls a gene regulatory network during forebrain development

Pia Annette Johansson; Per Ludvik Brattås; Christopher H. Douse; PingHsun Hsieh; Julien Pontis; Daniela A. Grassi; Raquel Garza; Marie E. Jönsson; Diahann A. M. Atacho; Karolina Pircs; Feride Eren; Yogita Sharma; Jenny Johansson; Didier Trono; Evan E. Eichler; Johan Jakobsson

doi:10.1101/2020.08.18.255562

GeneticsbioRxivAug 18, 2020

Preprint

A human-specific structural variation at the ZNF558 locus controls a gene regulatory network during forebrain development

Pia Annette Johansson iD, Per Ludvik Brattås iD, Christopher H. Douse iD, PingHsun Hsieh iD, Julien Pontis iD, Daniela A. Grassi iD, Raquel Garza iD, Marie E. Jönsson iD, Diahann A. M. Atacho iD, Karolina Pircs iD, Feride Eren iD, Yogita Sharma iD, Jenny Johansson iD, Didier Trono iD, Evan E. Eichler iD, Johan Jakobsson iD

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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