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Monika Ward in her lab.
University of Hawaiʻi at Mānoa scientists have uncovered a direct link between a missing Y chromosome gene and male infertility. Their new research reveals that deleting this single gene in mice not only caused infertility but also disrupted hundreds of other genes vital for healthy sperm. The findings, published August 27 in Cell Death and Differentiation, offer significant implications for understanding reproductive health.
The role of Zfy
The study, led by Monika Ward of UH Mānoa’s John A. Burns School of Medicine and the Yanagimachi Institute for Biogenesis Research (YIBR), focused on the Zfy gene, found on the Y chromosome in both humans and mice. In mice, there are two versions of this gene: Zfy1 and Zfy2.
Monika Ward, left, with her research team.
Using CRISPR gene-editing, the team created mice missing one or both versions. Males without both, known as Zfy double knockouts, were completely infertile, with severely abnormal or absent sperm.
“This work really pushes forward our understanding of how this important Zfy gene works,” said Ward. “We identified pathways and other genes that are affected and we can now study how exactly Zfy regulates them.”
To continue investigations, the researchers turned to assisted reproduction techniques pioneered at UH, including intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI). This allowed them to examine the molecular consequences of Zfy loss.
When one gene disrupts hundreds
The results revealed that without Zfy, hundreds of genes became misregulated—some too active, others too weak. Many of these genes are responsible for sperm production, DNA packaging, and cell survival.
As a result, sperm precursor cells in the testes died off early, and the sperm that did form carried fragile DNA that wasn’t properly condensed.
Student-assisted research
Ward also highlighted the contributions of students. The study’s first author, Hayden Holmlund, completed his PhD at UH and is now a postdoctoral fellow in California. Undergraduate student Benazir Yarbabaeva also played a role and has since joined the graduate program to continue her research.
The project highlights YIBR’s collaborative mission, with contributions from colleagues in France and England.
