A normal healthy baby is the dream of every pregnant woman – and, fortunately, in most cases this dream comes true. Occasionally, however, women have 'molar' pregnancies, where a vastly overgrown placenta develops; the pregnancy either miscarries or is terminated. Most of these molar pregnancies arise because the fetus has inherited an extra set of the father's chromosomes. Studies of these pregnancies will help us understand the mysteries of early human development, and should give pause for thought to those contemplating cloning adult humans.

Molar pregnancies arise when fertilisation goes awry, for example if two sperm enter the egg at the same time. "A partial mole has two sets of paternal chromosomes and one set of maternal chromosomes," says Rosemary Fisher, a Senior Research Fellow at Imperial College School of Medicine, who has recently been awarded a Wellcome Trust project grant to study the mechanisms underlying molar pregnancies. "The fetus develops for a while, although it's abnormal, and the placenta overgrows and forms a cluster of fluid-filled cysts. These look like grapes, completely different to the normal tiny finger-like projections – the chorionic villi – of the placenta which implant into the wall of the uterus. In the complete mole, which has no maternal chromosomes at all, you never see anything that looks like a fetus – that's how they are diagnosed at ultrasound."

Hydatidiform moles like these are actually relatively common, affecting about 1 in every 700–800 pregnancies. Although this incidence is similar to that of Down's syndrome, moles are less well known as they miscarry or are terminated early. As they are associated with a risk of cancer, any woman in the UK who has a molar pregnancy is registered on databases held in London, Sheffield or Dundee. "Moles are a form of proliferative disease," says Dr Fisher, "and there is a significant risk of the mole progressing to a malignant tumour of the placenta that persists after the pregnancy is terminated. Our unit at Charing Cross Hospital is particularly concerned with monitoring and following up patients with molar pregnancies, as these cancers are life-threatening."

Instead of two sets of paternal chromosomes, sometimes two sets of maternal chromosomes come together, with no paternal genome. In this case, the outcome is very different. "Instead you get a benign cystic tumour," says David Bonthron, Professor of Molecular Paediatrics at St James's University Hospital, Leeds, who is collaborating with Dr Fisher. "This ovarian teratoma usually sits in the ovary and grows, remaining benign, and no placenta develops. The hydatidiform mole and the ovarian teratoma are the opposite in terms of the origins of the chromosomes, and you see very characteristic differences in the kinds of tissue that develop."

A difference of sex

Why should the effects of the extra sets of chromosomes depend on their origins? An embryo needs two sets of genes to develop – why does it matter where they come from? The answer appears to lie in an unusual phenomenon known as 'imprinting', discovered about 20 years ago.

Imprinting involves the modification of particular key genes, generally by the addition of methyl groups to the DNA, which affects whether they are active or inactive. Because patterns of methylation are different in the maternal and paternal chromosomes, genes retain a memory or 'imprint' of their parental origin. In an embryo, an otherwise identical gene might therefore be active if inherited from the mother or inactive if inherited from the father. Because of these imprints, development will occur normally only if each parent contributes one set of chromosomes to the embryo.

The biological logic behind imprinting is far from clear. One appealing theory is that it reflects a conflict between the goals of the mother's and father's genes: the genomes have different agendas and are, in fact, 'at war' – the battlefield being the fetus growing within the mother.

The idea is that the genes from the father are trying to drive the fetus to be big and strong by extracting as many nutrients as possible from the mother – for example by maximising the size of the placenta. Meanwhile the maternal genome is defensive, taking care of the fetus developing now but safeguarding the mother to produce and feed further offspring. The characteristics of the hydatidiform mole – a massively proliferating placenta – are consistent with two sets of paternal genes furiously driving development without the balance of the maternal genome.

The biparental mole

New light is being shed on this fascinating area by the study of an unusual subset of hydatidiform moles. While searching through the London database of molar pregnancies, Dr Fisher came across a group of women who only ever have moles. "One lady has had six molar pregnancies and no normal pregnancies," says Dr Fisher. Interestingly, these extremely rare cases had some unusual features. "The mole pregnancies of these ladies have exactly the same appearance – pathologically – as those that have two sets of paternal chromosomes. But genetically they have one set of chromosomes from the mother and one set from the father – they are biparental complete moles."

With one set of genes from each parent, the embryo should develop normally. Why do they end up as moles? The answer probably lies in defective imprinting. "The biparental complete moles appear to run in families," says Professor Bonthron, "so we think that it is likely that there is an inherited defect causing a global failure in imprinting the genome in the egg."

Funded by the Wellcome Trust, Dr Fisher and Professor Bonthron are tackling the causes of the biparental mole from two directions. The first approach will look at how imprinting is affected in the moles, while the second will try to find the faulty gene that is disrupting imprinting in the egg.

"We know of about 30–40 imprinted genes in mammals," says Professor Bonthron, "and it's estimated that there are about a few hundred imprinted genes in the genome overall. So the first part of the project will be examining the known genes: if we know the way a particular imprinted gene behaves normally, and whether it is methylated, we can look to see whether the imprinting is disrupted in the mole."

The major difficulty with this part of the project is not the analysis, it is the material. "The condition is very rare, and for most of the cases we don’t have much tissue," says Dr Fisher. "We've had a lot of experience of looking at archival tissue, developing new techniques for DNA analysis, so our experience in microdissection of thin sections of tissue will work well with David's experience in methylation studies."

The second part of the project will work on identifying the gene that is defective in the affected women. The condition is inherited in an autosomal recessive manner (two mutant copies are needed for an effect to be seen), so Dr Fisher and Professor Bonthron will be looking for patches of the genome that are identical in affected individuals to home in on the region of the genome responsible. "We think that the gene may, in some way, be involved in setting the imprinted status of multiple genes on different chromosomes," says Dr Fisher. "This gene could be a master controller."

Imprinting is a fascinating, still relatively new area, and one that clearly has a significant impact. "You can't mess with imprinting," says Professor Bonthron,“and the biparental moles are an extreme reflection of that. We're looking at a very rare clinical condition, but these biparental complete moles could tell us something very fundamental about human development and the differing roles of the maternal and paternal genome."

The research is also a shot across the bows of those considering human cloning – attempting to generate a new individual with two sets of chromosomes from one parent. As the case of the biparental complete mole illustrates, the early development of the human being is a complex, finely controlled and exquisitely sophisticated process. We are only just beginning to understand it.

External links

• Department of Cancer Medicine at Imperial College School of Medicine: Dr Fisher research interests
• St James's University Hospital: Professor Bonthron research interests

Further reading

Professor David Bonthron
Hayward B E, Kamiya M, Strain L, Moran V, Campbell R, Hayashizaki Y, Bonthron D T (1998). The human GNAS1 gene is imprinted, and encodes distinct paternally and biallelically expressed G proteins. Proc. Natl. Acad. Sci. USA 95: 10038-10043.

Hayward B E, Moran V, Strain L, Bonthron D T (1998). Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally and biallelically derived proteins. Proc. Natl. Acad. Sci. USA 95: 15475-15480.

Kamiya M, Judson H, Okazaki Y, Takada S, Arima T, Muramatsu M, Kusakabe M, Murakami K, Satomura K, Hermann R, Takagi N, Wake N, Bonthron D T, Hayashizaki Y (2000). The cell cycle control gene ZAC/PLAGL1 is imprinted - a strong candidate gene for transient neonatal diabetes. Hum. Mol. Genet. 9: 453-460.

Hayward B E, Bonthron D T (2000). An imprinted antisense transcript at the human GNAS1 locus. Hum. Mol. Genet. 9: 835-841.

Hayward B E, Barlier A, Korbonits M, Grossman A B, Jacquet P, Enjalbert A, Bonthron D T (2001). Imprinting of the Gs alpha gene GNAS1 in the pathogenesis of acromegaly. J. Clin. Invest.107: R31-R36.

Dr Rosemary A Fisher
Fisher R A, Newlands E S (1998). Molecular and genetic studies of gestational trophoblastic disease. J. Reprod. Med. 43: 53-59.

Helwani M N, Seoud M, Zahed L, Zaatari G, Khalil A, Slim R (1999). A familial case of recurrent hydatidiform molar pregnancies with biparental genomic contribution. Hum. Genet. 105: 112-115.

Moglabey Y B, Kircheisen R, Seoud M, Mogharbel N E, Van den Veyver I, Slim R (1999). Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum. Molec. Genet. 8: 667-671.

Fisher R A, Khatoon R, Paradinas F J, Roberts A P, Newlands E S (2000). Repetitive complete hydatidiform mole can be biparental in origin and either male or female. Hum. Reprod. 15: 594 -598.