23rd chromosome crippled... Male. Tough luck.

Do we need men?

The Y-chromosome - the ultimate symbol of machismo - is in a bad way. But, asks Bryan Sykes, apart from breeding, what real use is the male to the human race?

Bryan Sykes
Thursday August 28, 2003

Guardian

It is no secret that men are basically genetically modified women - the female being the fall-back developmental pathway for any foetus. The evolution of the two sexes could indeed be regarded as a long-running GM experiment.

Its legacy has been to endow men and women with different, and often conflicting, sets of genetic interests, and to ignite a powerful evolutionary struggle, which has accentuated the differences between the two sexes. In several respects, the experiment that gave us men is not going too well just now. Though it is a weary lament to lay most acts of violence and aggression, from the strictly local to the truly global, squarely at the feet of men, the association is strong, consistent and undeniable. Women very rarely commit violent crimes, become tyrants or start wars.

The experiment has created two irreconciliable genetic combatants. On the female side is mitochondrial DNA, which can only be passed down the maternal line. On the male side is the Y-chromosome, which is always passed from father to son. But while mitochondrial DNA is a model of slimmed-down efficiency, the Y-chromosome is a shambles, battered by mutation and going downhill fast, before it eventually disappears altogether. On this chromosome resides the single genetic switch (SRY) which, when flicked to "on", prevents human embryos from developing into baby girls and turns them into boys instead. Also spread out on this dying chromosome are the handful of other genes that men need to make fully operational sperm.

But why is this ultimate symbol of male machismo in such a mess? Originally the Y-chromosome was a perfectly respectable chromosome with a collection of genes doing all sorts of useful things - much like the X-chromosome today. But its fate was sealed when it took on the mantle of creating males. This probably happened in the early ancestors of mammals, perhaps 100m years ago when a mutation on the ancestor of the Y-chromosome suddenly, and quite by chance, enabled it to switch on the embryonic pathway to male development. Once this happened, the chromosome was doomed. It slowly lost contact with other chromosomes, thus missing out on the interaction that normally allows the shuffling of genes and so unable to properly heal the wounds inflicted by mutations. One by one, its thousands of useful genes were lost until now only 27 remain - and they are under constant threat.

Of all our chromosomes, it is the only one that is permanently locked into the germ cells of men, where the frenzy of cell division and error-prone DNA copying required to keep up the daily output of 150m sperm creates the ideal conditions for mutation. And it shows. Seven per cent of men are infertile or sub-fertile and in roughly a quarter of cases the problem is traceable to new Y-chromosome mutations, not present in their fathers, which disable one or other of the few remaining genes. This is an astonishigly high figure, and there is no reason to think things will improve in the future - quite the reverse in fact. One by one, Y-chromosomes will disappear, eliminated by the relentless onslaught of irreparable mutation, until only one is left. When that chromosome finally succumbs, men will become extinct.

But when? I estimate that, at the current rate, male fertility caused by Y-chromosome decay will decline to 1% of its present level within 5,000 generations - roughly 125,000 years. Not exactly the day after tomorrow - but equally, not an unimaginably long time ahead. Unless something changes in the way we breed, women will vanish too and Homo sapiens will disappear in the next 1-200,000 years. But is extinction inevitable?

Plenty of species a lot older than our own are still going, so how is it that they are not vulnerable to extinction by the same process of Y-chromosome decay? They will all eventually face the same challenge and I suspect that many species have already gone under for this very reason. Some, however, have found a way round their death sentence.

One strategy is to recruit genes on other chromosomes to take over the job of male development. It is a race against time. Can a species get all the genes it needs off the Y-chromosome, or recreate them elsewhere, before the chromosome finally vanishes? Always the last gene to go will be SRY, the male master switch itself. We know it is capable of smuggling itself onto another chromosome - the evidence lies in the rare cases of males who have no Y-chromosome.

Lots of species may have tried variations on this theme to avoid extinction, but it seemed that none succeeded until, in 1995, researchers found a mammal that had managed to escape this fate. When they looked at the chromosomes of a small burrowing rodent called the mole vole, Ellobius lutescens, which lives in the foothills of the Caucasus mountains, they discovered that the male voles didn't have a Y-chromosome. Neither, it transpired, did they have a master SRY gene either. This inconspicuous little rodent has managed to activate a gene relay one or two stages down the line from SRY. And only just in time. The mole vole Y-chromosome has now completely disappeared. The vole is now safe from Y-chromosome-driven extinction, the only mammal species known to have succeeded in getting itself out of danger.

But one thing distinguishes Homo sapiens - we are at least capable of being aware of our impending demise. So do we need men? They are still required for breeding, if nothing else. But for how much longer?

The wide application of Intra-Cellular Sperm Injection (ICSI), the fertilisation of eggs by injecting sperm, could delay the extinction but it would still not prevent the progressive deterioration of the Y-chromosome. Other remedies have yet to be proved effective, but if men are to be retained they are at least worth considering. For instance, could we deliberately engineer the solution so fortuitously arrived at by the mole vole? The human Y-chromosome could be left to decay, but men would be reprieved. We now know the 27 genes that are present and necessary on today's Y-chromosome to make a man in full working order. It would be easy to cut them out of the wreckage of the Y-chromosome and re-assemble them into a compact genetic package. From there, it would be relatively straightforward to insert the package into another chromosome, where it would probably work straight away.

The purpose of all this effort and ingenuity is to avoid the extinction of men, and with them our entire species. However, one radical solution to save the species is also the most genetically straightforward - to abandon men altogether. Though this sounds impossible, very little stands in its way from the genetic point of view. When sperm meets egg, it brings with it a set of nuclear chromosomes from the father, which, after fertilisation, mixes with a set of nuclear chromosomes from the mother. But there is nothing fundamental preventing the nuclear chromosomes coming not from a sperm but from another egg. We know from ICSI that sperm can be injected into eggs, and there is nothing to stop the nucleus from a second egg being injected instead.

But would it develop normally? At the moment the answer is no, but it is short-sighted to say that it is fundamentally impossible. Once the technical snags have been overcome - and I put the difficulties no higher than that - these embryos would grow into perfectly normal babies. The only difference from any other birth is that the sex is always predictable. The baby is always going to be a girl. The entire process has been accomplished without sperm, without Y-chromosomes and without men.

Importantly, the baby girls will not be clones. They are the same mixture of their parents' genes, shuffled just as thoroughly as any of today's children and they have two biological parents, not just one. Their only difference from any other child is that instead of a father and mother, these girls have two mothers. From a genetic point of view, they are completely normal, indistinguishable from any little girls around today and just as capable of having children with men (while they are still around).

Lesbian couples already enlist the help of a man to donate his set of chromosomes, packaged in a sperm, to fertilise the eggs of one of them. How much more attractive for these couples to have a baby to whom both, rather than just one, were parents. It is almost certain to happen and, unlike human cloning, I doubt there would be serious ethical objections. Men are now on notice.

· Adam's Curse by Bryan Sykes is published by Bantam Press at £18.99.

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