A male-essential miRNA is key for avian sex chromosome dosage compensation
Birds have a sex chromosome system in which females are heterogametic (ZW) and males are homogametic (ZZ)<sup>1</sup>. The differentiation of avian sex chromosomes from ancestral autosomes entails the loss of most genes from the W chromosome during evolution<sup>1,2</sup>. 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 compensation<sup>3</sup>. 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.
Authors
- Carl‐Johan Rubin (ORCID: https://orcid.org/0000-0001-8238-5052)
- Jiří Koubek (ORCID: https://orcid.org/0000-0002-5117-6570)
- Günter Krämer (ORCID: https://orcid.org/0000-0001-7552-8393)
- Margarida Cardoso-Moreira (ORCID: https://orcid.org/0000-0001-6639-3597)
- Maeve Ballantyne (ORCID: https://orcid.org/0000-0002-3388-6261)
- Diane E. Frank
- Alewo Idoko-Akoh (ORCID: https://orcid.org/0000-0001-5864-4915)
- Enrico Sorato (ORCID: https://orcid.org/0000-0002-5223-4496)
- Amir Fallahshahroudi (ORCID: https://orcid.org/0000-0001-8820-0098)
- Adrian Sherman
- Mike J. McGrew (ORCID: https://orcid.org/0000-0001-8213-4632)
- Pascal Lafrenz (ORCID: https://orcid.org/0000-0002-3791-3474)
- Martin Johnsson (ORCID: https://orcid.org/0000-0003-1262-4585)
- Nils Trost (ORCID: https://orcid.org/0000-0002-5171-018X)
- Henrik Kaessmann (ORCID: https://orcid.org/0000-0001-7563-839X)
- Sara Yousefi Taemeh (ORCID: https://orcid.org/0000-0001-7744-3414)
- Lorna Taylor (ORCID: https://orcid.org/0009-0002-1645-1140)
- Leticia Rodríguez-Montes (ORCID: https://orcid.org/0009-0002-6192-8497)
- Long Liu (ORCID: https://orcid.org/0000-0003-0875-060X)
- Cheng Ma (ORCID: https://orcid.org/0000-0002-4540-0089)
- Ying Xue
- Megan G. Davey (ORCID: https://orcid.org/0000-0003-0194-9229)
- Guillermo Tellez (ORCID: https://orcid.org/0000-0002-6295-7305)
- Christina Grozou
Institutions
- Uppsala University (SE)
- Roslin Institute (GB)
- Heidelberg University (DE)
- The Francis Crick Institute (GB)
- Swedish University of Agricultural Sciences (SE)
- University of Bristol (GB)
- DKFZ-ZMBH Alliance (DE)
- Reneco (United Arab Emirates) (AE)
- Yangzhou University (CN)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s41586-025-09256-9
- Citations
- 7
- Primary Topic
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 12.72