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Paternal Genes (blue) are found in the hypothalamus maternal cells in the cortex.

Imprinted Genes Suggest your Cortex may derive from your Mother
Gail Vines New Scientist 3 May 1997

"WE could produce remarkable children," a beautiful actress once cooed to the cerebral Irish playwright George Bernard Shaw. "Ah yes," he replied, quick as a flash, "but what if they had my looks and your brains?" A simple joke about vanity and the vagaries of sexual reproduction, perhaps. But Shaw's quip may be more apt than he could ever have guessed. Pioneering work on mice suggests that a mother's genes play the dominant role in the development of the parts of her offsprings' brains that are responsible for intelligence. The father's genes, on the other hand, may shape not his offsprings' looks so much as the parts of their brains that influence emotional make-up. Safe to say, it won't just be the textbooks that suffer a major shake-up if the astonishing new findings hold true for humans. Women seeking intelligent children might decide that a trip to the Nobel prizewinners' sperm bank is a waste of time, and instead choose easy-going husbands over intellectual high-flyers. Men interested in the IQ of their offspring might suddenly find smart wives more appealing. Eugenics could resurface in a new guise as repressive regimes allow only brainy women to have babies. The strange genes that threaten even greater social ferment than cloning are "imprinted" genes. Genes exist in pairs, one from the mother and one from the father. Most of the time one can't be told from the other-the two are equally active. But imprinted genes are different. They carry a biochemical label that reveals their parental origin and determines whether or not they are active inside the cells of the offspring (see "The silence of the genes", p 36). Some imprinted genes work only if they come from the mother. The same gene is silenced if it is inherited via the sperm, rather than the egg. Other imprinted genes operate the other way round and are only switched on if they are inherited from the father. Genomic imprinting was unequivocally demonstrated for the first time in mice in 1984. Many found the idea that genes behaved differently depending on their parentage almost impossible to believe. But the discovery also grabbed the attention of some of the world's top geneticists. By 1990, the first imprinted gene had been pinpointed in mice and humans-a gene for a growth hormone called insulin-like growth factor-II. Since then, researchers have found another 15 or so imprinted genes in mice, along with their human equivalents. But even conservative estimates put the true number in the hundreds. There could be far, far more-albeit ones that may prove very difficult to find. Some imprinted genes are likely to be silent for only the briefest periods during development, or only in some tissues. Other genes may produce an array of different products, only some of which are affected by the gene's original gender. Missing or malfunctioning imprinted genes have even been implicated in human diseases, ranging from heritable obesity to childhood cancers ("Why genes have a gender", New Scientist, 22 May 1993, p 34). But even these surprises pale in comparison with the new finding that imprinted genes may play a role in the healthy functioning of the organ that is most closely linked with what it means to be human-the brain. Two University of Cambridge researchers, Eric "Barry" Keverne, who works on the co-evolution of brain and behaviour in primates, and Azim Surani, who did the original genomic imprinting experiments in 1984, have evidence that in the mouse the mother's genes contribute more to the development of the "thinking", or "executive", centres of the brain, while paternal genes have a greater impact on the development of the "emotional" limbic brain. Whether imprinted genes have the same effect on the development of the human brain is as yet unknown, although two human diseases suggest they could. "We will have to wait and see," Surani says. Wherever the new research leads and it has already gripped the imagination of researchers in disciplines ranging from genetics to psycho-Darwinism-"it is incredibly exciting", says David Skuse, director of behavioural studies at the Institute of Child Health in London. The story began back in 1984 when Surani and his Cambridge colleagues made peculiar sorts of mouse embryos that bore only the father's genes, or only the mother's. The idea was to discover why mammals cannot reproduce parthenogenetically, that is from an unfertilised egg, the way other animals do. Instead, the researchers ended up demonstrating the existence of imprinting. To create "androgenetic" embryos that bore only paternal genes, they transferred the DNA from two sperm into an egg which had already had its DNA removed. To create the "gynogenetic" equivalent bearing only maternal genes, they united the chromosomes from two unfertilised eggs.

So far so good. These embryos should, on the face of it, have developed normally because they had the right number of genes. Yet when they were transferred to a mouse's womb, the embryos died within a few days. The androgenetic embryos died because certain vital genes had been switched off by the ; father in each of the two copies, while the gynogenetic embryos had a different set of equally vital genes switched off by the mother. Surani went on to show that the imprinted genes that are switched on only when inherited from the mother are vital for the early development of the embryo proper, while the father's genetic legacy is essential for the normal development of the tissues that become the placenta. It is because of this genetic imprinting that mammals-unlike, say, green fly are incapable of parthenogenesis. But if imprinted genes play such crucial, and distinctly different roles in the first few days of an embryo's life, they might also be doing something important later on in development-perhaps even in the brain-reasoned Surani and Keverne. Suspicions were strong. The problem was how to prove it, given that embryos endowed with a double dose of only one parent's genes perish just a few days into the pregnancy.

Patchwork embryo

The two researchers came up with an ingenious solution. They discovered that mouse embryos could survive to around term in surrogate mouse mothers so long as at least half their cells were normal embryonic cells with genes from both female and male. The rest of the embryo's cells could be tailored to test the hunch that imprinted genes are important for later development. All they had to do was judiciously mix the, specially made androgenetic or gynogenetic embryos with normal embryos when each was only a few cells, and create a genetic patchwork embryo known as a chimera. Even the precise ratio didn't matter-the important thing was to watch what happened to the chimera, and to the androgenetic or gynogenetic cells it contained, as it grew from an embryo into a fully-developed fetus. The results were mind-blowing. Surani and Keverne found that although many s of the chimeras lived until term-about three weeks in a mouse-they didn't all look the same. Embryos with an extra dose of maternal genes grew into fetal mice with big heads (and brains) perched on small bodies. By contrast, embryos with an extra dose of the father's genes grew into fetuses with huge bodies but tiny brains. Although the mice were strikingly abnormal and never survived for long, the results confirmed Surani and Keverne's hunch that imprinted genes are essential for normal mouse development way beyond the early days of gestation. What's more, it looked as if the genes that are only active if they come from e mothers build bigger brains, while e genes that are only active if inherited m the father build bigger bodies. To find out more, the researchers mapped the fate of cells inside the brains of the chimeras. They had made the chimeras using androgenetic and gynonetic embryos that carried a genetic marker in every cell-either one thousand copies of the beta globin gene, or the lac Z transgene. Surani, Keveme and their colleagues made thin sections rough the brains of the chimeras and then counted the cells that contained the two markers. In that way, they identified the number of cells containing only maternal genes or only paternal genes in six different parts of the brain that are known to control a whole gamut of cognitive functions from feeding behaviour to memory.

A tale of two brains

For the first few days of development, any cell could turn up anywhere in the embryos' brains. But as the embryos matured to become almost fully developed mice, cells that carried only paternal genes accumulated in clusters scattered throughout the "emotional" brain-the hypothalamus, the amygdala, the preoptic area, and the septum. These areas make up part of the limbic system that is important for behaviours that ensure survival, such as sex, eating and aggression. The researchers found none of the paternally derived cells in the "executive" brain-that is in the cortex, which is the site of advanced brain functions such as memory and conscious thought and an area below called the striatum that initiates and controls fine movement. Just the opposite happened in the embryos that were a mix of ordinary and maternal cells. in these embryos, the cells containing only maternal genes were absent from the emotional brain. Instead, they selectively accumulated in the brain's executive regions. As the embryos got older and cells proliferated, their brains contained more and more of either the maternal or the paternal cells in their favoured sites. Conversely, the numbers, of androgenetic and gynogenetic cells that had ended up in the "wrong" regions fell as they failed to produce a lineage or were eliminated. Keverne and Surani are quick to point out that it is not possible to draw a precise picture of what is going on because the chimeras are abnormal in at least two respects: they have a deficiency of one parent's imprinted genes and an excess dose of the other parent's. In truth, the chimeric mice can only hint at the normal role of the imprinted genes, by revealing what happens when they are pushed out of balance. The researchers have yet to follow the fate of the paternal and maternal cells in other parts of the mouse embryos, so they do not yet know why the androgenetic chimeric mice had such big bodies. Still, one conclusion seems clear: in addition to the hundreds or thousands of non-imprinted genes that are needed to build a normal brain, an embryo needs a carefully concocted balance in the activity of the genes it receives from its mother and father. in the normal mouse and human-that balance is most likely achieved by imprinting, that is silencing, certain genes when they are inherited from one parent. "It is very important work, and very, very promising," says Wolf Reik, who works on imprinting at the Babraham Institute near Cambridge. He admits, however, that no one yet knows what the full implications of the findings will be. "Everyone is a little bit lost as to what it really means." One tantalising possibility is that the human mother's genes make the biggest contribution to the part of the brain that society values most-the cortex. In humans, the cortex is responsible for highly sophisticated intellectual skills such as language and the ability to plan ahead. It is also exceptionally large in humans and our close primate relatives. Fathers, on the other hand, appear to have drawn the short straw. Their genes contribute more to the evolutionarily ancient, "primitive" brain parts. These areas regulate more instinctual behaviours such as feeding, fighting and reproduction, and in primates, including humans, they have withered relative to the size of the cortex over evolutionary time. TWo rare human diseases that are caused by defects in imprinted genes provide circumstantial evidence that imprinted genes do indeed affect the development of the human brain in a way not dissimilar to the mouse. one condition, Angelman syndrome, arises when a baby is born missing the function of an imprinted gene (or genes) on chromosome 15. The region is silenced in the father and so it must be inherited from the mother. The maternal gene can be lost either through a tiny genetic deletion or by an accident that causes both copies of chromosome 15 to come from the father. The result is mental retardation, jerky movements, and speech difficulties-defects in activities that are controlled by the cortex and striatum. The second condition, Prader-Willi syndrome, typically results in brain disorders that cause over-eating, obesity, a placid nature and an underdeveloped sexual drive-defects in behaviours that are largely under the control of the brain's primitive regions. The genes responsible are usually silenced in the mother, and must be inherited from the father. People with Prader-Willi lack the imprinted gene or genes because of a mutation in the vital stretch of DNA or, again, because their two copies of chromosome 15 both come from the same parent, but this time from the mother. These diseases are "only the tip of the iceberg", says Reik, who suspects that many psychiatric disorders will turn out to be influenced by imprinted genes. one psychoanalytically inclined academic has even claimed Keverne and Surani's "astonishing discovery" for Freud. Christopher Badcock, author of Psycho-Darwinism, speculates that the father's genes build the "id"-the unconscious, emotive, instinctive component of the psyche, while the "ego", which is the conscious, cognitive and inhibiting part is a creation of the mother's genome. During development, Badcock speculates, "maternal and paternal genes competed for control of behaviour, culminating in a mind divided into two conflicting parts strikingly similar to Freud's ego and id". Back in Cambridge, the hunt is on to identify the genes that affect brain development in the mouse.

Surani and his colleagues have been systematically screening the mouse genome to find out whether healthy versions of the genes like those that are defective in Angelman and Prader-Willi syndromes might be the mysterious imprinted genes that regulate brain development in the mouse. In one set of experiments, they are comparing the genes that are active in normal mice embryo cells with the genes that are active in embryo cells that contain only genes from the mother. Then, using a process called subtraction hybridisation, they pull out the genes that are silent when inherited from the mother mouse and are active only when they come from the father. Surani has already found three or four new imprinted genes, and any one of these may be important for brain development. The next step is to find out what each gene does by creating "knock-out" mice, that is mice in which the imprinted gene is silenced no matter which parent it is inherited from. The first results will be published later this year. Once the mouse genes have been identified, it should be relatively easy to investigate the role of their equivalents in human males and females. Until that time, a word of warning: Angelman and Prader-Willi syndromes hint that, when it comes to imprinted genes and brain development, what's true for mother mice might also be true for human mothers. But the two species are different in some obvious and not so obvious ways. For instance, at least one gene that is known to be imprinted in mice is not imprinted in humans. Tempting as it might be, it's still a tad early for women to start celebrating a genetic monopoly on the intellectual wellbeing of the human species. F7

Further reading: "Genomic imprinting and the differential roles of parental genomes in brain development" by Eric B. Keverne and others, Developmental Brain Research, vol 92, p 91 (1996). "Primate brain evolution: genetic and functional considerations" by Eric & Keverne, Fran Martel and Claire Nevison, Proceedings ofthe Royal Society London B, vol 262, p 689 (1996). "Peg3 imprinted gene on proximal chromosome 7 encodes for a zinc finger protein" by Yoshimi Kuroiwo and others, Nature Genetics, vol 12, p 186 (1996). Genomic Imprinting: causes and consequences, edited by R. Ohisson, K Hall and M. Ritzen, Cambridge University Press (1995).

An imprinted gene behaves differently depending on whether it is inherited from a mother or from a father. Soehow it is shut off as it is passed through either the egg or the sperm; only one copy is active in offspring. The nature of such gene silencing is not certain, although "methylation" is clearly improtant. In this process DNA is silenced when it is surrounded with methyl groups attached to the DNA added by enzymes in the sperm or egg. Some geneticists think methylation may not be the primary imprint - instead some structural change in the DNA labels each chromosome with its parental roigin long before methylation takes place. The mysterious imprinting affects genes on any chromosome, not just those on the sex chromosomes. And it is fully reversible providing a neat on-off switch. At some point in each mammal's life cycle, the DNA is wiped clean of its inherited imprints, clearing the way for new imprints, probably during the final stages of egg and sperm development.

Are Parent's Genes at War?

The imprinted genes of a female mouse foster big brains and small bodies in her offspring, while paternal genes do the opposite That finding seems to support the popular "parental gene warfare" theory used to explain genetic imprinting - where genes are active only from a parent of a particular sex.

In 1991 David Haig of Harvard University and Tom Moore of the Babraham Institute nr Cambridge. The discovery of insulin-like growth factor genes one which is inherited only from the father and stimulates fetal growth and the other which is inherited only from the mother but codes a "false receptor" which mops up the IGF II. The rationale behind the arm race was that the father's genes code for a hungry placenta because he has no interest in furthering the mothers future reproduction against the growth of the child and the mother's codes for slowed development which will serve her continuing reproductive capacity. However such an arms race should lead to more rapid evolution as is the case in malaria and the immune system. However the evolutionary rates of imprinted genes turn out to be normal slow-evolving genes so the arms race theory is dented.