THE battle of the sexes runs deeper than anyone realised. It has long been
thought that males and females compete to control the way their offspring
develop by chemically marking the genes they contribute. Now biologists in
Britain have shown that mammal eggs can wipe out such marks on the father鈥檚
genes鈥攁 discovery that could have important implications for cloning.
Although embryos receive two copies of every gene, one each from the mother
and father, the two are not always equally active. That is because many genes
carry an 鈥渋mprint鈥�, a series of chemical marks known as methyl groups. Usually
this methylation inactivates the gene, but in some cases it can make it more
active.
In 1991, biologists David Haig and Chris Graham of Oxford University proposed
that imprinting evolved in a tug-of-war between the sexes to help both parents
get what they want. 鈥淭he paternal genes are more selfish and make bigger
offspring,鈥� says Wolf Reik of the Babraham Institute in Cambridge, 鈥渂ut you can
kill the mother if you grow too big.鈥�
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A classic example of an imprinted gene that fits this scenario is
igf2, which codes for a growth factor in mice. It is activated by
methylation in the sperm. The egg鈥檚 copy, however, is unmethylated and
inactive.
Now Reik and Joern Walter of the Max Planck Institute for Molecular Genetics
in Berlin have discovered that in a fertilised mouse egg, some of the methyl
groups on the father鈥檚 copy of igf2 are stripped away. They measured
the degree of methylation of the gene in sperm and fertilised eggs using a
chemical that changes unmethylated cytosine bases to thymines. Any cytosines
that showed up when the gene sequence was read must therefore have been
methylated.
As expected, the maternal copy of igf2 was only slightly methylated,
whereas the father鈥檚 had methyl groups on most of the cytosines. But as little
as 9 hours after the father鈥檚 copy entered the egg, nearly every methyl group
had been removed, the researchers will report in an upcoming issue of
Current Biology. The results suggest that the egg is resisting the father鈥檚
attempt to make his offspring bigger by making igf2 more active.
鈥淭his must be an active demethylation,鈥� says Reik. The idea that the
demethylation enzyme targets paternal DNA is supported by work done on a second
gene that starts out heavily methylated in both sperm and egg. The enzyme
removed methyl groups only from the paternal copy of the gene.
鈥淭his is a new enzymatic process that hasn鈥檛 been seen before,鈥� says Alan
Wolffe, a biochemist at the US National Institutes of Health near Washington DC.
The question now is to work out how the egg controls this new weapon, he says.
For example, why aren鈥檛 all imprints stripped from the paternal genome? It may
be part of a system that strikes a balance between maternal and paternal
imprints so that neither dominates, he says.
Understanding demethylation will also be critical for cloning research,
Wolffe says. As cells specialise, their methylation patterns change. Cloning can
only work when the recipient egg somehow resets the donor DNA to an embryonic
state. One of the main causes of failure in cloning is overgrowth of the embryo,
as if paternal imprints were winning out.