The Masculinization of the X Chromosome: Many Genes for Early Male Sperm Production Reside on the X Chromosome

CAMBRIDGE, Mass. — In an entirely counterintuitive result, scientists have found that nearly half of all genes related to the earliest stages of sperm production reside not on the male sex (Y) chromosome as expected, but on the X chromosome, a chromosome universally thought of as the female sex chromosome.

The finding, published in the April issue of Nature Genetics, comes as a big surprise and is causing scientists to rethink the "gender identity" of the X chromosome.

"Scientists and non-scientists alike are comfortable thinking about the Y chromosome as a specialist in male characteristics. By default, we’ve traditionally thought of the X chromosome as sexually neutral or as a specialist in female characteristics. Our findings indicate that the X chromosome has a specialty in sperm production much like the Y chromosome does," says David Page, who is lead author on the paper and a researcher at the Whitehead Institute for Biomedical Research and Howard Hughes Medical Institute.

The finding also raises the speculation that infertility due to low sperm production may be an X-linked disorder, passed on to male children through their mothers, much like color-blindness or hemophilia.

In this study, the Page lab researchers and their colleague John McCarrey at Southwest Foundation for Biomedical Research, in San Antonio, Texas, sought to study the genetic underpinnings of spermatogonia—stem cells in the testes that give rise to sperm. Spermatogonia are "the mother of all sperm cells," but unlike other stem cells, such as blood stem cells, which have been the subject of intense study, sperm stem cells have remained largely unexplored. So Jeremy Wang, a postdoctoral fellow in the Page lab, and his colleagues conducted a systematic search for genes that are active exclusively in sperm stem cells in mice.

The researchers found 25 genes, including 19 new ones, that were expressed exclusively in mouse sperm stem cells. They found that of these, only 3 were linked to the Y chromosome and 10 were linked to the X chromosome.

"This was a big surprise because if the genes had been distributed randomly in the genome, we would have expected none, or at the most a couple, of these sperm-specific genes to be X-linked," says Page.

This finding is yet another chapter in the 300 million year story of the X and the Y chromosomes, adds Page whose research is unfolding, chapter by chapter, the odyssey of the sex chromosomes that began their lives as autosomes (or non-sex chromosomes) but have since become specialized.

Aside from the intellectual surprise, this finding has enormous implications for future scientific investigation, and it opens up a whole new territory scientifically, says Page.

"The X chromosome is one of the most intensely studied chromosomes, and the X-linked mode of inheritance is a textbook classic—it is one of the three modes of inheritance that we study in medical genetics," says Page.

In this mode of inheritance, a genetic defect on the X chromosome may cause a disease (for example color blindness or hemophilia). The mother, who has a defective gene on one of her two X chromosomes, is protected against the disease because women have two copies of the X, and her normal X makes up for the defective one. Her sons have a 50 percent chance of inheriting the defective X and succumbing to the disease. Her daughters have a 50 percent chance of inheriting the defective X and becoming carriers.

The finding that sperm-specific genes are found on the X chromosome suggests a new avenue for study, says Page. One obvious possibility is that X chromosome plays a role in some forms of male infertility that results from low sperm counts. Thus far, researchers have combed the Y chromosome looking for the genetic underpinnings of low sperm counts. But in these cases, the defects on the Y may tell only part of the story. The researchers will have to do further studies to see if they can find the other part of the story in the X chromosome.

Finally, this study spurs researchers to ask if infertility can be inherited, just like color blindness and hemophilia. Previous research from the Page lab had suggested that the genetic defect underlying low sperm count can be inherited by sons from their fathers when infertile father use intracytoplasmic sperm injection (ICSI) to have children.

"Now it appears that we may face the possibility that genetic defect underlying low sperm count can be inherited through mothers," says Page.