A male-essential miRNA is key for avian sex chromosome dosage compensation

Amir Fallahshahroudi (), Sara Yousefi Taemeh, Leticia Rodríguez-Montes, Nils Trost, Dana Frank, Pascal Lafrenz, Jiri Koubek, Guillermo Tellez, Maeve Ballantyne, Alewo Idoko-Akoh, Lorna Taylor, Adrian Sherman, Megan Davey, Cheng Ma, Enrico Sorato, Martin Johnsson, Christina Grozou, Ying Xue, Long Liu, Guenter Kramer, Carl-Johan Rubin, Margarida Cardoso-Moreira, Mike J. McGrew () and Henrik Kaessmann ()
Additional contact information
Amir Fallahshahroudi: Heidelberg University
Sara Yousefi Taemeh: Uppsala University
Leticia Rodríguez-Montes: Heidelberg University
Nils Trost: Heidelberg University
Dana Frank: Heidelberg University
Pascal Lafrenz: Heidelberg University
Jiri Koubek: Heidelberg University
Guillermo Tellez: University of Edinburgh
Maeve Ballantyne: University of Edinburgh
Alewo Idoko-Akoh: University of Bristol
Lorna Taylor: University of Edinburgh
Adrian Sherman: University of Edinburgh
Megan Davey: University of Edinburgh
Cheng Ma: Uppsala University
Enrico Sorato: Reneco International Wildlife Consultants
Martin Johnsson: Swedish University of Agricultural Sciences
Christina Grozou: Uppsala University
Ying Xue: Yangzhou University
Long Liu: Yangzhou University
Guenter Kramer: Heidelberg University
Carl-Johan Rubin: Uppsala University
Margarida Cardoso-Moreira: Francis Crick Institute
Mike J. McGrew: University of Edinburgh
Henrik Kaessmann: Heidelberg University

Nature, 2025, vol. 645, issue 8079, 148-157

Abstract: Abstract Birds have a sex chromosome system in which females are heterogametic (ZW) and males are homogametic (ZZ)1. The differentiation of avian sex chromosomes from ancestral autosomes entails the loss of most genes from the W chromosome during evolution1,2. However, the extent to which mechanisms evolved that counterbalance this substantial reduction in female gene dosage remains unclear. Here we report functional in vivo and evolutionary analyses of a Z-linked microRNA (miR-2954) with strong male-biased expression, previously proposed to mediate avian sex chromosome dosage compensation3. We knocked out miR-2954 in chicken, which resulted in early embryonic lethality in homozygous knockout males, probably driven by specific upregulation of dosage-sensitive Z-linked target genes. Evolutionary gene expression analyses further revealed that these dosage-sensitive target genes underwent both transcriptional and translational upregulation on the single Z in female birds. Altogether, this work unveils a scenario in which evolutionary pressures following W gene loss drove transcriptional and translational upregulation of dosage-sensitive Z-linked genes in females but also their transcriptional upregulation in males. The resulting excess of transcripts in males, resulting from the combined activity of two upregulated dosage-sensitive Z gene copies, was in turn offset by the emergence of a highly targeted miR-2954-mediated transcript degradation mechanism during avian evolution. This study uncovered a unique sex chromosome dosage compensation system in birds, in which a microRNA has become essential for male survival.

Date: 2025
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DOI: 10.1038/s41586-025-09256-9

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