A Tiny Gene Saves Male Birds by Balancing Sex Chromosomes
Researchers from Uppsala University, Heidelberg University, and the University of Edinburgh have discovered that this microRNA reduces the activity of key genes in males. When the microRNA was removed, male embryos failed to develop. The findings, published in Nature, reveal that birds have evolved their own unique way of balancing gene activity between the sexes.
“Sex chromosomes determine whether an animal develops as male or female. In mammals, females have two X chromosomes (XX) and males have one X and one Y (XY). In birds, it’s the opposite: males have two Z chromosomes (ZZ) and females have one Z and one W (ZW). Over millions of years, the Y chromosome in mammals and the W chromosome in birds have lost most of their genes. This creates an imbalance: some important genes exist in two copies in one sex but only one copy in the other, and these genes can malfunction if there is either too much or too little of them,” explains Dr Amir Fallahshahroudi, who co-led the study with Dr Sara Yousefi Taemeh; both are group leaders at Uppsala University.
In mammals, this imbalance was solved by boosting the activity of the single X chromosome in males. However, this overactivity also occurs in females, who have two X chromosomes, creating a new problem. To fix it, one X chromosome in females is almost completely switched off — leaving both sexes with one overactive X chromosome. How birds handle this challenge has remained a mystery.
Previous research identified a microRNA on the Z chromosome that is mainly active in male birds and suggested it might help balance Z-linked gene activity. MicroRNAs are tiny RNA molecules that act like dimmer switches, turning down the activity of specific target genes.
To test this, the team used gene editing to remove this microRNA in chickens. The result was striking: all male embryos lacking both copies of the microRNA on their Z chromosomes failed to survive. Females, missing their single copy of the microRNA, developed normally. This shows that having two copies of the microRNA is essential for male survival. Without it, key genes on the Z chromosome became overly active, halting development. The same microRNA was found in all bird species studied — but not in any other animals. “This is the only known microRNA essential for the survival of just one sex,” says Dr Yousefi Taemeh.
“The study also reveals how this solution evolved. When female birds lost genes from the W chromosome, this loss was compensated by increased activity of certain genes on their single Z chromosome. In males, who have two Z chromosomes, this led to excessive activity. Evolution’s elegant solution was to use the microRNA to tone down these genes — but only in males. This strategy is entirely different from the mammalian approach and highlights the unique evolutionary path birds have taken to balance gene activity between the sexes,” says Professor Henrik Kaessmann (Heidelberg University, Germany), who co-supervised the work with Professor Mike McGrew (The Roslin Institute, UK).
This work was supported by the Swedish Research Council (VR and Formas) and the European Research Council (ERC).
Original Publication
A. Fallahshahroudi, S. Yousefi Taemeh, L. Rodríguez-Montes, N. Trost, D. Frank, P. Lafrenz, J. Koubek, G. Tellez Jr., M. Ballantyne, A. Idoko-Akoh, L. Taylor, A. Sherman, M. Davey, C. Ma, E. Sorato, M. Johnsson, C. Grozou, Y. Xue, L. Liu, G. Kramer, CJ. Rubin, M. Cardoso Moreira, M.J. McGrew, H. Kaessmann: A male-essential microRNA is key for avian sex chromosome dosage compensation. Nature Kaessmann: A male-essential microRNA is key for avian sex chromosome dosage compensation. Nature (published online 16-07-2025), DOI: 10.1038/s41586-025-09256-https://www.nature.com/articles/s41586-025-09256-9
Amir Fallahshahroudi, Researcher
Uppsala University, Department of Medical Biochemistry and Microbiology
IMBIM, Box 582, 751 23 Uppsala
Email: amir.fallahshahroudi@imbim.uu.se
Mobile: +46 76 304 3306
Sara Yousefi Taemeh, Researcher
Uppsala University, Department of Medical Biochemistry and Microbiology
IMBIM, Box 582, 751 23 Uppsala
Email: sara.yousefi.taemeh@imbim.uu.se
Mobile: +46 76 038 4246