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Moms and dads often argue over parenting, but, unbeknownst to them, they actually started the fight when their offspring was still in the womb.

In this prenatal skirmish, the leading theory states, paternal genes act to increase the nourishment the fetus receives while maternal genes act to restrict fetal nourishment and growth. The theory, called the "intergenomic conflict" hypothesis, grew from the discovery in the mid-1980s of imprinted genes. Such genes are unusual in that they are expressed (i.e. produce RNA and proteins) only from the father's copy of the gene or the mother's copy, but not from both.

Dr. Benjamin Tycko, professor of pathology, and Dr. Dale Frank, assistant professor of clinical pathology, have found more support for the controversial conflict hypothesis in a maternal gene that is expressed in the placenta. The findings, published in the May 28 Proceedings of the National Academy of Sciences, also help explain how pregnant females keep placenta size under control.

The conflict hypothesis, as it was originally proposed, predicts that in promiscuous species the male has an evolutionary advantage if his offspring are big and can drain resources from the female, who could nourish a competing male's offspring. The female, on the other hand, can spread her genes in the population if she can restrict the growth of any one fetus, to conserve resources for her offspring with other males.

The hypothesis developed as an explanation for imprinting because the first imprinted genes discovered control growth. In 1991, Dr. Argiris Efstratiadis, Higgins Professor of Genetics & Development, discovered that a growth-promoting gene, Igf2, is turned off in the chromosome inherited from the mother and is expressed only from the chromosome inherited from the father. Knocking out this gene in mice led to stunting of both placental and fetal growth.

Since then, other growth-enhancing genes have been discovered that also are turned off by the mother, along with growth-restricting genes turned off by the father. But several of the other imprinting genes that have conformed to the predictions of the conflict model work through the same pathway as Igf2. Since the conflict hypothesis was built partly on the discovery of Igf2, discovery of an independent pathway would help bolster evidence for the theory.

Drs. Tycko and Frank now have found a gene that works through an independent biochemical pathway. The gene, called Ipl (for Imprinted in Placenta and fetal Liver), is turned off in the father's genome and was first discovered by the two researchers, with graduate student Naifeng Qian, about five years ago. The conflict hypothesis predicts the gene's normal function should restrict placental or fetal growth or both.

In the PNAS paper, Dr. Frank reports that in knockout mice missing the Ipl gene, which lacked the growth-restricting presence of Ipl, one layer of the placenta, the spongiotrophoblast, grew abnormally large. The greater placental growth, however, did not increase the size of the fetus. The placenta, while necessary for reproduction, also is parasitic on the mother. So Dr. Frank's findings suggest a modification of the conflict theory, in which some genes that are expressed only from the maternal copy may have become imprinted specifically to keep the placenta under control.

The researchers also found the gene works to restrict placental growth without using the Igf2 pathway, lending additional support to the intergenomic hypothesis. When the Igf2 gene was knocked out, the Ipl gene was still able to restrict growth of the placenta.

Dr. Tycko cautions the Ipl findings are not definitive proof of the conflict theory, and that some imprinted genes appear to be "growth-neutral." Other theories to explain imprinting have been put forward over the years, including one that suggests imprinting might exist to prevent a sexually reproducing species from cloning itself. Still, Dr. Tycko notes that in more than 10 different imprinted genes that do control growth the evidence shows every one expressed from the maternal copy inhibits growth, while every example expressed from the paternal copy is growth promoting.

But regardless of the reason for imprinting's existence, the new data about Ipl and other imprinted genes may help explain placental growth and function. "This gene has an isolated effect on placental growth," Dr. Frank says. "Not many other genes are known to play such a tightly restricted role in the life of this organ. Genes like Ipl allow one to more carefully evaluate the role of the placenta during fetal development. Ultimately, one would like to identify whether abnormalities in genes like Ipl play a role in human disease, to see what effect placental development has on the fetus."

More work will be needed to test whether over-expression of the human Ipl gene may underlie some placental and fetal growth failure. Imprinted genes may even play a role in the health of the fetus after birth. "Low birth-weight babies have higher rates of hypertension, coronary heart disease, and diabetes when they become adults," Dr. Tycko says. "We may be able to understand the connection better if we understand the genetic factors that control placental function."

Grants from the National Institutes of Health and the Human Frontiers Science Project supported the research.


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