Fallahshahroudi Amir, Yousefi Taemeh Sara, Rodríguez-Montes Leticia, Trost Nils, Frank Dana, Lafrenz Pascal, Koubek Jiri, Tellez Guillermo, Ballantyne Maeve, Idoko-Akoh Alewo, Taylor Lorna, Sherman Adrian, Davey Megan, Ma Cheng, Sorato Enrico, Johnsson Martin, Grozou Christina, Xue Ying, Liu Long, Kramer Guenter, Rubin Carl-Johan, Cardoso-Moreira Margarida, McGrew Mike J, Kaessmann Henrik
Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany.
Department of Medical Biochemistry and Microbiology, Biomedical Center (BMC), Uppsala University, Uppsala, Sweden.
Nature. 2025 Jul 16. doi: 10.1038/s41586-025-09256-9.
Birds have a sex chromosome system in which females are heterogametic (ZW) and males are homogametic (ZZ). The differentiation of avian sex chromosomes from ancestral autosomes entails the loss of most genes from the W chromosome during evolution. 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. 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.
鸟类具有一种性染色体系统，其中雌性为异配性别（ZW），雄性为同配性别（ZZ）。鸟类性染色体从祖先常染色体的分化过程中，W染色体在进化过程中失去了大多数基因。然而，进化出的平衡雌性基因剂量大幅减少的机制的程度仍不清楚。在这里，我们报告了对一种Z连锁微小RNA（miR-2954）的体内功能和进化分析，该微小RNA具有强烈的雄性偏向性表达，此前被认为介导鸟类性染色体剂量补偿。我们在鸡中敲除了miR-2954，这导致纯合敲除雄性胚胎早期致死，可能是由剂量敏感的Z连锁靶基因的特异性上调驱动的。进化基因表达分析进一步表明，这些剂量敏感的靶基因在雌性鸟类的单条Z染色体上经历了转录和翻译上调。总之，这项工作揭示了一种情况，即W基因丢失后的进化压力驱动了雌性中剂量敏感的Z连锁基因的转录和翻译上调，但也驱动了雄性中的转录上调。由于两个上调的剂量敏感Z基因拷贝的联合作用，雄性中产生的转录本过量，反过来又被鸟类进化过程中出现的高度靶向的miR-2954介导的转录本降解机制所抵消。这项研究揭示了鸟类中一种独特的性染色体剂量补偿系统，其中一种微小RNA对雄性生存至关重要。
