Findings may yield insight on potential male infertility treatment
In two related studies, NICHD-funded researchers discovered that only three genes are required for the development of healthy sperm in mice. To the researchers' surprise, the male, or Y, chromosome is not needed at all to produce fertile sperm precursors called spermatids. In a study published in Science, the team found that the Y chromosome's sperm-producing function may be replaced by two genes from the X chromosome, called Sox9 and Eif2s3x—at least for the development of viable spermatids. In another study published in PLOS Genetics, the same researchers discovered that only a single Y chromosome gene, called Zfy2, is needed for spermatids to develop into mature sperm cells.
The X and Y chromosomes determine sex, and the Y chromosome is unique to males. Males have an X and a Y chromosome, while females have two X chromosomes. Many genes on the Y chromosome are involved in male sex determination and development. Many others are believed to be involved in male fertility. However, information linking a particular gene to a specific reproductive process is limited. Identifying the minimum genetic sequences needed for producing healthy sperm may lead to information useful for treating infertility.
Researchers led by NICHD grantee, Monika Ward, Ph.D., from the University of Hawai'i, previously found that only two genes from the Y chromosome, called Sry and Eif2s3y, are needed for male mice to make healthy spermatids. The mice had other reproductive defects, so the researchers selected the healthiest spermatids and successfully produced offspring using an experimental assisted reproductive technology called round spermatid injection, or ROSI.
"Knowledge of the minimal genetic requirements for the production of sperm can help in developing new assisted reproductive technologies that may improve outcomes for couples trying to conceive."
- Susan Taymans, Ph.D.,
Fertility and Infertility Branch, NICHD
Taking these findings further, the study authors explored potential backup mechanisms for these genes on the X chromosome. In the new Science study, they replaced the entire Y chromosome with extra copies of the X chromosome genes Sox9 and Eif2s3x. These two genes were selected because Sry functions by regulating Sox9, and Eif2s3x is nearly identical to its counterpart on the Y chromosome, Eif2s3y. Through ROSI, the researchers produced offspring from the genetically modified male mice, showing for the first time that the Y chromosome is not required for reproduction in mammals.
In the PLOS Genetics study, the researchers identified the role of a Y chromosome gene called Zfy2. In mouse experiments, they found that Zfy2 triggers the complex process that turns immature spermatids, which are not always fertile, into mature sperm. Additionally, they showed that only 3 genes—Zfy2, Sry, Eif2s3y—are needed to make mature sperm for intracytoplasmic sperm injection (ICSI), a process frequently used in fertility clinics.
Infertility is a common problem, affecting approximately 7% of men (4.7 million) and 11% of women (6.7 million) of reproductive age in the United States. Identifying genes required for healthy sperm development, such as Zfy2, Sry, and Eif2s3y, may lead to new treatments for male infertility.
"Experimental procedures, such as ROSI, work in animal studies, but are still considered experimental in people because of safety concerns. Knowledge of the minimal genetic requirements for the production of sperm can help in developing new assisted reproductive technologies that may improve outcomes for couples trying to conceive," said Susan Taymans, Ph.D., a program director in NICHD's Fertility and Infertility Branch.
Yamauchi Y, Riel JM, Ruthig VA, Ortega EA, Mitchell MJ, and Ward MA. Two genes substitute for the mouse Y chromosome for spermatogenesis and reproduction . Science (2016)
Yamauchi Y, Riel JM, Ruthig V, and Ward MA. Mouse Y-encoded transcription factor Zfy2 is essential for sperm formation and function in assisted fertilization . PLOS Genetics (2015)
Yamauchi Y, Riel JM, Ruthig VA, Stoytcheva Z, and Ward MA. Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse . Science (2014)