Another Genetic Battle of the Sexes: Imprinting

Shirley Tilghman says genomic imprinting is rapidly evolving.
Kay Chernush

The genetic power struggle between the sexes extends beyond the X and Y chromosomes to the level of individual genes.

Called genomic imprinting, this intricately orchestrated give-and-take plays out within a developing embryo, although the stage is set much earlier, when sperm and eggs are formed. About 40 genes have now been identified that are distinctively marked, or imprinted, so that the embryo will recognize its parental origin. As the embryo grows, the genes act differently depending on whether they came from the mother or the father.

Embryonic genes interact like performers in a jazz ensemble. A pianist introduces a passionate melody, the bassist starts up a few bars later and the saxophonist and drummer slip in, embellishing harmony and tempo. The genes from both mother and father cooperate with one another to create a perfect embryo. Imprinted genes, in contrast, go solo, such that only one copy is expressed, while the same gene inherited from the other parent remains mute because of chemical silencers, known as methyl groups, on the DNA. But, unlike musicians playing together, the genes are not cooperating with one another: They are at war, with the maternal genes trying to slow down growth and the paternal genes trying to promote it.

Sometimes, an imprinted gene misses a cue and either toots its own horn inappropriately or remains silent at the wrong time. Since there's no backup to fill in for the aberrant gene, the slip-up can result in a devastating disease such as Prader-Willi or Angelman syndrome. "We've become slightly more vulnerable because of this imprinting process," says Marisa S. Bartolomei, an HHMI investigator at the University of Pennsylvania. Bartolomei did her postdoctoral studies in the laboratory of another HHMI investigator, Shirley M. Tilghman of Princeton University, a leading expert in genomic imprinting.

Genomic imprinting certainly did not catch Gregor Mendel's attention in the mid-19th century when he was experimenting with crossing garden peas. His peas in a pod inherited their traits in a predictable pattern, helping Mendel figure out how genes are transmitted between generations. Mendel concluded that crosses are the same whether a dominant trait is maternal or paternal in origin. Perhaps he should have studied mammals and used his leisure time for gardening—a pastime that Tilghman throws herself into, but not for genetic insights.

Scientists didn't recognize the phenomenon of mammalian imprinting until the 1980s. In 1991, Bartolomei says, the concept of imprinting underwent a molecular revolution when scientists discovered that the gene for insulin-like growth factor 2 (Igf2) is imprinted. Scientists had previously conducted experiments to show that genetic imprinting occurs, but now they had actual genes responsible for the process, genes whose molecular mechanisms they could study. Additional genes have since been identified, and researchers have discovered that these tend to cluster together. But investigators in the field are still trying to answer some fundamental questions: What purpose does imprinting serve? Why are so few genes imprinted? Exactly how does an imprinted gene silence its complement?

A Genetic Arms Race

David Haig of Harvard University compares gene imprinting to a genetic arms race in polyandrous species, including certain types of mice, in which females mate with several partners within the same litter. According to Haig's theory, paternal genes that are expressed and lobby for fetal growth duke it out with maternal genes that limit growth. In evolutionary terms, such a parental tug-of-war is good for a species. While large offspring put more of a strain on the mother's resources, they have a better chance of survival. But the mother has a worthy argument for smaller offspring: Females need to conserve their nutritional resources within one litter to ensure that they themselves will survive to produce more litters.

Tilghman and colleagues sought to test Haig's theory about polyandrous mammals in monogamous species in which both parents have an equal interest in the offspring's survival. They chose Peromyscus polionotus, a wild breed of mouse. Imprinting, they found, occurs in this monogamous species—an observation that didn't fit with Haig's theory. Moreover, when crossed with Peromyscus maniculatus, a distant polygamous relative, the hybrids failed to imprint. Tilghman's team concluded that imprinting is rapidly evolving and could contribute to a high rate of speciation in mammals.

The same researchers published a study in the May 2000 issue of Nature Genetics that provides more insight into what happens when closely related species are crossed. "What my recent paper shows is that imprinting can contribute to the rapid acquisition of genetic incompatibilities between two related species that are no longer breeding," Tilghman says.

What end, then, does imprinting serve? Tilghman suggests that it may be that imprinting did not arise to benefit mammals. Rather, genomic imprinting is the consequence of the differences in parental strategies that optimize the number and fitness of their offspring.

Preventing the expression of a gene makes the most sense in the X chromosome, which in fact carries the greatest number of clusters of imprinted genes. Females inherit two X chromosomes while males get an X and a Y. If both X chromosomes were expressed, females would get a double dose of the protein encoded by the genes. Males would get only half the amount because they have only one X. Gene expression, however, logically should be at the same levels in both sexes of a species. Thus, jettisoning one of the female's sex chromosomes would allow for equality of the sexes.

Investigators would like to find the genetic switch that shuts off one copy of a gene for life and lets the other one replicate often and at a very active rate. Tilghman is studying six imprinted genes residing in one chromosomal region. DNA methylation is acting as a genetic muffler in one of these genes, but not in the others. She and Bartolomei have suggested that the imprinting of one gene,

Igf2, depends on the methylation of another gene, H19, rather than on its own methylation. H19, which encodes a highly expressed RNA and not a protein, is expressed in embyronic and neonatal tissues, but its function is unclear. "The bottom line is that there is not a single mechanism for silencing genes in imprinting," Tilghman says.

She and her fellow researchers in this field are hard at work trying to understand the various genes that seek solos during embryonic development. The arrangement works nicely, to be sure—but its driving force and ultimate purpose remain unclear.

- DKC