The secret life of sperm is unlocked

Infertile couples may be spared years of fruitless treatment with the discovery that the human egg can read the father's genetic key and screen out failures

Thousands of infertile couples could be spared the pain, anguish and expense of fruitless IVF treatments, thanks to the discovery of a lock-and-key mechanism between sperm and egg cells.

The research could explain why so many couples with no apparent reproductive problems are unable to conceive. Although more than 40,000 in vitro fertilisation cycles are prescribed in Britain each year, only 10,000 births result.

In addition to the £5,000 cost of each cycle, the couples face huge amounts of stress and can suffer severe depression and in some cases divorce. "Our work has quite a lot of relevance for humans and society and one of the main ones is infertility," said Dr Martin Brinkworth, a member of the team at the universities of Bradford and Leeds that discovered the lock-and-key mechanism.

Some 15 per cent of couples have trouble conceiving, about half of them because the man has a problem. But in only one third of cases is the cause obvious, such as a low sperm count, malformation or poor swimming ability. This leaves 2 per cent of the male population, about 330,000 adult men in the UK (not all of whom will be trying to have children), who are infertile for no discernable reason.

Dr David Miller at the University of Leeds thinks the secret could be that the genetic keys in their sperm don't quite fit their partners' locks. "Our research offers a plausible explanation for why some sperm malfunction," he said.

His colleague Dr David Iles added: "There is a definite pattern to the way DNA is packaged in sperm cells. It is the same in unrelated fertile men, but it is different in the sperm of infertile men."

If a test could be developed to identify these men, up to a quarter of women who have intrusive fertility checks would be spared the procedures. It could also sharply decrease the 75 per cent failure rate of IVF by filtering out male candidates who have no chance of success. Private patients and the NHS could save as much as £50m a year if all cases of male infertility were identified in advance.

The Leeds-Bradford research, and parallel work by a US team at the University of Utah, fundamentally changes our understanding of the importance sperm has in the developing embryo.

Although the egg and sperm each supply half the DNA for the new baby, the egg provides all the cellular support systems, including enzymes and proteins. Until now, it was thought that sperm simply delivered the father's tightly packed DNA to the egg, leaving control and regulation of the process to the mother's DNA.

But the two teams of scientists, have found that some genes are left exposed in sperm, in an "open conformation", allowing them to play an important role in the development of the embryo. "It contradicts the dogma that the egg does everything," said Dr Brinkworth, a senior lecturer at the University of Bradford.

The British team has also identified how these "open" areas are formed and evidence that they can be read by the egg, suggesting that they act as a signature or key, revealing the species the sperm comes from and signalling whether the DNA is in good shape.

Although no clinical test is available now, the researchers are hopeful that one can be developed after they've identified all the DNA bases in the open areas, some of which might be usable as markers.

The molecule at the heart of the lock-and-key mechanism is a protein called CTCF, say the scientists in a paper published in the journal Genome Research. "CTCF sets the stage during sperm development," said Dr Iles. "And open bases can be recognised by CTCF in the egg."

If stretched out end to end, the DNA from a single human cell would be about 1.8m long. But in the cell nucleus, it is wrapped around molecules called histones, which link up to form an efficient three-dimensional scaffold, 40,000 times shorter than the unfolded DNA. Histones also play a role in turning genes on so that their coded instructions can be copied and sent to other parts of the cell.

But sperm don't have elaborate cells, just a tightly packed nucleus and a tail for swimming to the egg. So when they form, the histones are stripped off and replaced with another molecule called protamine, which shapes the DNA into an even tighter bundle, where the genes cannot be read.

The British researchers have found, however, that CTCF protects some histones in sperm from being replaced, leaving about 4 per cent of the genome in an open conformation, so that its instructions can be copied. Since the pattern of exposed areas is not random, they believe it must have a purpose, and the simplest explanation is that it is a key that influences the developing embryo even before the father's genetic contribution has been unpacked.

The discovery has implications for research in fields other than human reproduction. Although the bulk of their work involved 50 million human sperm cells from several donors, the Bradford-Leeds team also found similar structures in mouse sperm.

The lock-and-key mechanism could help to explain how closely related species maintain their separate identities, even when individual members have sex. "DNA from different organisms can be extremely similar," said Dr Iles. "Why do they not produce offspring, or if they do, why is it sterile, like mules and donkeys?"

The team speculates that this may have been the fate of prehistoric couplings between humans and their close cousins, Neanderthals, with incompatible keys and locks ensuring that any offspring would be unable to breed.

This would explain why the human genome has no trace of Neanderthal DNA despite the two similar species living close together for millennia.

The misery of unexplained infertility

Susan Seenan is deputy chief executive of the Infertility Network UK

About a third of the couples we speak to suffer from unexplained infertility, which can often be harder to deal with. I think men find it particularly difficult if they find out they're infertile. In general men find it very hard to talk about infertility and there's a stigma attached; some still see it as a slight on their manhood if they can't have a child.

At least with a low sperm count or blocked fallopian tubes a couple can try to find a solution and they know what they're dealing with. But when it's unexplained it's stressful.

It can be difficult for other people to understand what's wrong with you; the longer time that goes by without conceiving, the more stressed you get. When it's unexplained there's always a hope that it might happen naturally, so the emotional impact of the disappointment every month when you haven't conceived is really tough. At least if you know what's wrong you know where you stand.

If you have a proven cause of infertility then you can be eligible for NHS treatment, but those whose infertility is unexplained have to wait for three years. That can be a long time when you're older and time is not on your side.

www.infertilitynetworkuk.com

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