UCSF researchers have discovered a human gene that can be traced back through the mouse to the fly, illuminating a molecular nugget from ancient times that may play a crucial role in male fertility - and infertility.
The researchers suspect that the gene, known as BOULE, participates in the creation of sperm at a stage of development known as meiosis (which occurs only in the development of sperm and egg). When the like gene is deleted in the fly, a process similar to meiotic function is disrupted, preventing sperm development, and thereby causing male infertility.
"We think that the identification of genes like BOULE that are required for meiotic function is going to be very important clinically, because some 30 percent of infertile men have meiotic arrest during sperm development, and this is very similar to what you see in flies that have mutations in this gene," says the lead author of the study, Eugene Yujun Xu, PhD, a postdoctoral fellow in the laboratory of senior author Renee A. Reijo Pera, PhD, a leading researcher on sperm-related infertility in men and a UCSF assistant professor of obstetrics-gynecology and reproductive sciences.
The researchers are now examining whether deletions in the equivalent gene in mice cause meiotic arrest in the animals' developing sperm. They also are investigating whether the BOULE gene is altered in infertile men whose sperm have various developmental defects, particularly those with indications of meiotic arrest in the testes.
If a defect in BOULE does prove to be a cause of male infertility, it might be possible, says Xu, to treat the condition by introducing a normal copy of the gene into the testes through a nontoxic vector, where it could then replicate. The testis, unlike brain or heart, is located outside the main human body, limiting the possibility that the gene therapy approach would damage other tissues of the body, he says.
While the clinical implications of the finding are tantalizing, the discovery of the BOULE gene also offers a dazzling insight into the evolutionary process. The BOULE gene appears to be the "grandfather" of two more recently evolved genes that are also associated with sperm development - but with different functions. The development of the class of genes, known as DAZ, discovered by Reijo Pera several years ago, illuminates the way in which genes evolve within and between species, taking on distinct functions in the process.
BOULE, located on chromosome 2, and the Boule gene in the fly probably evolved, the researchers say, from a common ancestor. The fly Boule gene plays a critical role in meiotic function, and developed at least a half billion years ago. The human BOULE gene resembles Boule in sequence, and the meiotic expression pattern of the BOULE protein is identical to the fly Boule protein. (Meiosis is a relatively late step in reproductive cell development, when a cell doubles its DNA and then divides twice, to produce the one share of chromosomes that will merge with the germ cell of the other sex. In merging, the germ cells thus create the full set of DNA of the new organism.)
The researchers believe BOULE is the "father" of DAZL, a gene located on human chromosome 3. DAZL arose in early vertebrate some 120-200 million years ago and has been shown in the frog to be required for development of the earliest step in the development of both female and male germ cells (reproductive cells) - the creation of germ stem cells. The gene's role in humans is not known. DAZL, in turn, is believed to be the father of the DAZ gene, which arose 30-40 million years ago, is located on the Y chromosome in humans. Mutations in DAZ are associated with 13 percent of cases of human male infertility.
The DAZ gene is believed to be involved in a very early stage of sperm cell development known as spermatogonia, which follows the formation of the germ stem cells. But while some men with DAZ mutations do not have any fully developed sperm, other men produce sperm - just not enough to beat the odds required for fertilization. In other words, while the DAZ gene's role in fertility is important, its role in the actual development of sperm appears to be important - but not essential.
In tracing the DAZ gene's genetic heritage, however, the researchers have discovered in BOULE a gene that may be essential for sperm development. Their finding also suggests, they say, that the DAZ gene itself is at an interim stage in its evolution.
"History tells us more about what's going on now, and how we got to this point," says Xu. Some evidence suggests, he says, that the DAZ gene is evolving faster than do most genes. And this, he says, is consistent with the researchers' hypothesis.
"If you think in terms of evolution, reproductive success is at the crux in determining success of a species," he says. "It could be that millions of years from now DAZ will have evolved into an essential function in sperm development."
The emergence of the DAZ genes on different chromosomes reflects the random "duplication" of genes that occurs during evolution. At times an organism will duplicate its entire content of genomic material, or genome; at other times, it will duplicate a small segments of a single chromosome.
"Nature's pretty smart," says Xu. "Rather than creating a new gene from scratch, it duplicates it, and over time the new gene evolves into a novel function with minimal variation on the original."
The other co-author of the study was Frederick L. Moore, a graduate student in the Department of Biochemistry and Biophysics at UCSF.
The study was funded by a National Research Service Award, Ford Foundation and Woodrow Wilson Foundation fellowship and grants from the National Institutes of Health, the Searle Foundation and the Sandler Family Foundation.