X and Y Chromosomes Concern More Than Reproduction

Editor's Note: This is the third article in a series on sex-based differences in the biology of males and females. Future articles in the series will cover sex-based differences in autoimmunity, drug metabolism, and life expectancy. While responses to "What's the difference between men and women?" might evoke answers about reproductive plumbing and hormones, researchers are unearthing some subtle, genomic reasons for the differences. So far, the linchpins to finding these genomic variations seem to involve X-chromosome inactivation, Y chromosome genetics, and genetic imprinting. Lisa Damiani Sherry Marts, scientific director for the Society for Women's Health Research, thinks these areas will be focal points. "We're looking at this as the start of a new field of research," she says. "In another 10 years [sex-based differences] is going to be like neuroscience, where it started out as a few physiologists and a few biochemists, and pretty soon you've got a core group that's really moving the field forward. Then folks start to realize that this is actually something you can build a career on." Carmen Sapienza, professor of pathology at Temple University School of Medicine, Philadelphia, and an Institute of Medicine (IOM) 1 study panel member comments, "There will be lots of biochemical differences that are genetic between males and females that may not have anything to do with hormones." X Versus Y The fact that females have two X chromosomes while males have an X and Y is the stuff of Genetics 101. But how that simple truth may affect biology beyond sex determination is the subject of a nascent sub-field. One dynamic area is X inactivation. Each female somatic cell has one, randomly inactivated X chromosome. Most, but not all, of the genes on this X chromosome are mute. The inactivated X deteriorates, ending up as a Barr chromatin body in a corner of the nucleus. What's more, the active genes, comprising up to 10% to 15% of X-chromosome-linked genes, may be expressed in differing amounts between men and women. Biologist Sharon P. Shriver, Pennsylvania State University, studies the gene gastrin-releasing peptide receptor (GRPR), which codes for a growth factor receptor. Shriver and colleague Jill Siegfried, at the University of Pittsburgh, have found intriguing connections between GRPR and X-inactivation. GRPR is activated in early fetal development in human lungs. Once the lungs have matured, the receptor normally remains inactive in adult lung tissue. GRPR, however, becomes reactivated in lung tumors. Siegfried examined normal lung tissue in smokers and found that GRPR was triggered in both males and females, and surmised that it could be an early carcinogenic change associated with smoking. After learning that GRPR is located on the X chromosome, the researchers analyzed their data by sex2 and found that in normal lung tissue of non-smokers, 55% of women express GRPR; no male non-smokers did. With light smokers, 75% of women express the gene in normal, non-tumorous lung tissue, versus 20% of men. But with heavy smokers, "men catch up," she says. In this group, about 75% of both sexes express the gene. Courtesy of Sharon P. ShriverNo Longer Silent: GRPR (gastrin-releasing peptide receptor) occurs at a significantly higher frequency in female nonsmokers and light smokers than in men with similar smoking histories. After more than 25 pack-years of smoking, no significant difference was found in the frequency of GRPR expression between men and women. The researchers also showed that GRPR could be expressed from a woman's inactive X chromosome. Thus, the gene has the potential to appear in higher amounts in women because females have two copies of the gene that can be activated, compared to one in men. Add this data to statistics showing that women are two to three times more likely to develop lung cancer than men, as well as sooner, and that non-smokers with this disease are three times more apt to be female, and the indication is that GRPR presents a good case for a sex-specific mechanism. "Our hypothesis is that having two potentially active copies of the gene might explain the observations that women express the gene in response to less smoking than men, and this may be responsible for the increased risk of women for lung cancer," concludes Shriver. Housekeeping and the Y Chromosome While most genes on the Y chromosome are related to reproduction and sex determination, some have housekeeping roles. For example, the gene RPS4Y encodes the ribosomal protein S4, and is only expressed in male cells. RPS4Y is different from its counterpart on the X chromosome, RPS4X. RPS4 is just one of many housekeeping proteins that are encoded as slightly different forms by the X and Y chromosome, differing by a few amino acids, says David Page, professor of biology at Massachusetts Institute of Technology's Whitehead Institute and a Howard Hughes Medical Institute (HHMI) investigator.3 This means that male ribosomes come in two types, an X and a Y, and females have ribosomes with RPS4 from just the X chromosome. "The $64 million question is do they differ functionally," says Page. "It's an interesting question about which to speculate and we have zero information. RPS4X and RPS4Y can functionally replace each other in a cultured cell in a dish. But in the context of something more complex like an animal, are they functionally distinct?" Sapienza stresses, "These are not genes that necessarily respond to hormone difference. I think [researchers] are going to start paying attention to this." Studying the Imprint Genetic imprinting, a relatively new investigative area, may also turn up some sex-specific health differences related to genetics. Gene expression depends on the sex of the transmitting parent. There is, for example, increased severity of neurofibromatosis when the gene for it comes from the mother. About 45 such genes have been identified, most of them residing on the autosomes. So far, a handful of rare disorders have been related to imprinted genes. For example, Angelman's syndrome is associated with a maternal lineage gene. Children with Angelman's are born with severe mental retardation and with little or no verbal skills. If the maternal copy of the UBE3A gene associated with the syndrome is mutated, children develop the disease; however, if the paternal copy is mutated, it doesn't affect the child because this nonimprinted gene is effectively silenced. "Think about it this way," suggests Marisa Bartolomei, HHMI assistant investigator, and associate professor of cell and developmental biology, University of Pennsylvania School of Medicine, "You can get certain diseases depending if the disease-related gene is on the maternal- or paternal-imprinted chromosome. So it's not the sex of the person with the disease that matters, rather the lineage of the chromosome." In the extra-embryonic regions of mice, which include the placenta, X-inactivation is imprinted, with the male X inactivated and the female X turned on. Terry Magnuson, the Sarah Graham Kenan professor of genetics at the University of North Carolina, Chapel Hill School of Medicine, reported last August4 that the eed gene has a role in the inactivation of the paternal X chromosome and in maintaining its silencing. eed helps to keep genes turned off, so it is critical in preserving proper imprinting. Another role for eed is regulating developmental patterning, which ensures embryos develop in the proper sequence from head to tail. Without eed or with one that's mutated, hox genes, also important in patterning, get expressed in the wrong places, setting up skeletal and tumorgenetic problems for male and female mice later on. On the other hand, female mice in which the paternal X is activated die in utero. Inside the Uterus The environment inside the mammalian uterus, especially the type and amount of hormones the developing embryo experiences, can have a profound effect on later physiology and behavior. Peter Nathanielsz, professor of reproductive medicine in the Laboratory for Pregnancy and Newborn Research at Cornell University, says, "We pass more biological milestones before we're born than we ever do in life." Studying human sex differences in fetal programming is still in its early days, with more clear-cut examples from animal studies. John Vandenbergh, professor of zoology, North Carolina State University, Raleigh and a member of the IOM study panel, studies physiology and the influence of hormones on murine fetal development and post-natal behavior. In large litters, females situated in utero between two males are exposed to testosterone for a short period of time during male differentiation. These females become slightly masculinized, anatomically, physiologically, and behaviorally. This area, called the intra-uterine position effect, was primarily worked out by Fred vom Saal at the University of Missouri, says Vandenbergh. One of Vandenbergh's students, Andrew Hotchkiss, now a postdoc in the psychology department at Ohio State University, recently completed a project with rats that demonstrates altered play in neonatally androgenized females that were injected with testosterone. These females play more like their roughhousing male counterparts. The upshot of Vandenbergh and colleagues' work is that the hormonal environment during fetal development and after contributes to differences seen later in life, even in highly inbred strains of lab-reared mice. Tentative findings in fraternal human male and female twins hint at human analogues to the intra-uterine position effect in mice. Dennis McFadden at the University of Texas, Austin has shown that the spontaneous otic emission, a clicking sound emitted by the cochlea and used as one measure of hearing competency, is generally slower in males than females.5 But the click rate of girls in utero with brothers is about halfway between the average male and average female click rate. Says Vandenbergh, "So [these twin girls] have been partly masculinized in this sexually dimorphic trait and it does not seem to be related to reproduction." Karen Young Kreeger (kykreeger@aol.com) is a contributing editor. References 1. Institute of Medicine, Exploring the Biological Contributions to Human Health: Does Sex Matter? T.M. Wizemann, M. Pardue, eds., Washington, D.C.: National Academy Press, 2001. 2. S. Shriver et al., "Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer," Journal of the National Cancer Institute, 92:24-33, 2000. 3. M. Watanabe et al., Functional equivalence of human X- and Y-encoded isoforms of ribosomal protein S4 consistent with a role in Turner syndrome," Nature Genetics, 4:268-71, 1993. 4. J.B. Wang et al., "Imprinted X inactivation maintained by a mouse Polycomb group gene," Nature Genetics, 28[4]:371-5, Aug. 1, 2001. 5. D. McFadden, "A masculinizing effect on the auditory systems of human females having male co-twins," Proceedings of the National Academy of Sciences, 90:11900-04, 1993.

X and Y Chromosomes Concern More Than Reproduction

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