Y do We Even Need Them

The Y of It All

The more I know about men, the more I like dogs.

- Gloria Allred feminist attorney 1995

by Malcolm Ritter, Associated Press

Scientists are close to deciphering the makeup of the Y chromosome, that essential core of maleness. By this winter, they hope to have worked out the DNA sequence of the Y chromosome - the identity of its DNA building blocks. The effort is part of the Human Genome Project which seeks to reveal the 3 billion chemical building blocks that make up all 23 pairs of human chromosomes.

The sequencing of the Y is being overseen by David Page of the Whitehead Institute in Cambridge, Massachusetts, and Robert Waterston and Rick Wilson of Washington University School of Medicine in St Louis. The work should help researchers learn about causes of male infertility because it will help identify genes on the Y that men need to make sperm. It also should give a big push to understanding the evolution and functions of the chromosome. One expert says that earlier failures to understand the Y have given it a bad rap as a genetic couch potato. "There's been almost a century of ignorance-based misunderstanding of the Y," Page says.

Chromosomes are the microscopic rods that hold genes. Chromosomes generally come in matched pairs, with one member of each pair from Mom and the other from Dad. But men have one mismatched pair, the X and the Y. The Y chromosome makes males. If you inherit it from Dad, you'll become a boy. If you get an X chromosome from Dad instead, you'll be a girl.

For decades, scientists regarded the Y as a wasteland, Page says. Yes, it carried some gene that determined sex in a fertilized egg, "but it was otherwise perceived to be the empty dance partner for the X chromosome in males." In fact, he says, the Y is unique for its degree of specialisation. Nearly all of its genes do one of two things: help make sperm or help cells do such essential housekeeping tasks as build proteins. One exception is the gene SRY, the master switch that turns on the boy-making machinery.

The ancestors of the human X and Y were a pair of identical chromosomes found 300 million years ago in reptiles, long before mammals arose. Genes didn't decode sex on their own in those creatures. They responded to temperature and other environmental cues. That still goes on in turtles and crocodiles.

But in a single animal, an odd thing happened: one of those sex genes became altered. As Page puts it, the mutated version became "a tyrannical male-determining gene that said, 'I will no longer respond to these environmental cues. If I am present, the male pathway will be followed.' "

The rogue gene made trouble for its chromosome because the other DNA in its immediate vicinity became altered. Normally, the pairs of identical chromosomes in people and other animals trade bits of corresponding DNA. That reshuffles the genetic deck and helps species get rid of harmful mutations. But as that zone of altered DNA widened around the rogue gene, the chromosome was able to do less trading with its unaltered partner. As a result, the once-identical chromosomes grew more unlike over time, eventually coming the X and Y chromosomes.

Every female inherited two X chromosomes, so those two could carry out the DNA exchange normally. But the Y chromosome never got a chance to pair up with another Y. Just like today, it kept being paired up with an X instead.

Because the Y couldn't do much trading with the X, the genes on the Y began to suffer minor mutations they couldn't get rid of, says William Rice, who studies the Y at the University of California, Santa Barbara. Eventually, the mutated genes simply stopped working. Once genes stop working, they tend to disappear. That's why the Y chromosome is only 1/3 the size of the X. And that's the threat to the Y's existence in the future. Even the master sex switch and the genes acquired for making sperm aren't guaranteed a free ride. If necessary, genes on other chromosomes might take over their jobs, leaving them free to slip into oblivion without taking the human race with them.

In fact, the Y chromosome has disappeared in hundreds of other species, Rice says.

Source: USA Today Tuesday 7 November 2000

Y Chromosome Reveals Hidden Sequence

by Roxanne Khamsi

The Y chromosome is often viewed as relatively empty of genetic information, but a recent analysis suggests it could have a more important function than many suspected. The chromosome plays a crucial role in determining male sex in humans. The DNA that makes up the chromosome is highly repetitive, making it very difficult to sequence. But in June 2003, researchers in the United States announced that they had done so, and had found 78 genes, including several involved in sperm production.

Now, however, scientists at the University of Heidelberg in Germany have given it another go and found a region of the chromosome that originally went undetected. When they initially compared the physical map of the chromosome with the cloned sequence, the sequence didn't seem to be long enough, explains team member Gudrun Rappold. "So we took the effort to sort out what was going on." The new section spans just over half a million base pairs of DNA. "I was very surprised," says Rappold. "That's about 2% of the chromosome that was not detected before." Her team reports the result in Genome Research.

The region contains 8 sequences that appear to be new genes. "We have to check if they are functional," cautions Rappold. But after comparing these sequences with others, she speculates that they may be involved in determining men's height, and may also provide clues about cancers of male sex organs.

Source: nature.com 19 January 2005

X Chromosome Key to Differences in Men and Women

by Malcolm Ritter

Women get more work out of hundreds of genes on the X chromosome than men do, and that could help explain biological differences between the sexes, a new study says. The results imply that women make higher doses of certain proteins than men do, which could play out in gender differences in both normal life and disease, researchers said. So far, however, none of the genes identified in the study has been linked to any such observable differences, said senior study author Huntington Willard of Duke University.

He and Laura Carrel of Pennsylvania State University describe their analysis of the X chromosome genes in the journal Nature. A second paper in the same issue presents a comprehensive analysis of the chromosome's DNA, in which an international team of scientists found 1,098 genes.

Chromosomes are the threadlike packages of genes and other DNA found in cells of the body. People have 24 kinds, numbered 1 through 22 plus the X chromosome and its runty partner, the Y. Women carry two copies of the X chromosome, one inherited from each parent, while men have one X plus one Y chromosome. Long before birth, females permanently turn off one copy of their X chromosome in each cell, so that like males they operate with just one copy functioning. But scientists have long known that inactivation isn't perfect. Some genes on the inactivated copy continue to function, sending out chemical orders for the cell to manufacture specific proteins.

The work by Willard and Carrel suggests the inactivated chromosome contains 200 to 300 such genes, in two categories. First, they found that 15% of the inactivated chromosome's genes continue to function to some degree. More surprising, Willard said, was what researchers discovered about another 10% of the genes. For each, the activity level varied widely from one woman to the next, from zero in some women to varying levels in others.

That contrasts with the relatively consistent activity levels one sees in X chromosomes from men, or in other chromosomes in either sex, Willard said. In fact, when the study compared the inactivated X chromosomes of 40 women, each of them showed a different pattern of gene activity.

Dr Jeannie T Lee, who studies X chromosome inactivation at Harvard Medical School, said the study provides a better estimate than scientists had before of how many genes escape inactivation. And she agreed that the variability between women was a surprise. The work raises the possibility that varying activity of genes on the X chromosome can account for not only some differences between the sexes, but also between women, she said.

Source: livescience.com 16 March 2006

Birth of a Miracle

by Claire Ainsworth

Soon you may not need eggs or sperm to have children of your own

Men and women who can't produce sperm or eggs could one day have "natural" children of their own thanks to a form of cloning.

Gianpiero Palermo of Cornell University in New York has created artificial human eggs that contains just one set of a would-be mother's chromosomes. Such eggs could be fertilised with the partner's sperm, just like a normal egg. And in Australia, Orly Lacham-Kaplan of Monash University in Melbourne has shown that you can fertilise eggs, not with sperm, but with cells taken from elsewhere in the body. But there are still considerable obstacles to overcome before either technique could be used to create human babies.

The trouble is that we inherit not just genes, but chemical marks, or imprints, that turn some genes off. Chromosomes taken from body cells have different patterns of imprinting to egg and sperm cells, and that could cause developmental abnormalities. This may be why some clones have problems. Because of the risks, adds Palermo, careful testing in animals and further understanding of how imprinting works are needed before the new methods are applied to humans. "It's something we are evaluating," he says. "We're just going one step at a time."

If the technique can be made safe, it would help the growing number of people who can conceive only with the help of donated eggs or sperm-and are therefore not genetically related to their children. Some women lose their eggs because of chemotherapy or ovarian surgery. But many women are also finding themselves in this situation because they've put off childbirth until it's too late. And although existing fertility treatments can help men with low sperm counts, they don't work for men who make abnormal sperm, or no sperm at all.

One solution would be cloning: transplanting genetic material from, say, a skin cell of the would-be mother or father into an egg from which the DNA has been removed. But because the baby would be identical to its parent, this technique is highly controversial and likely to be banned in many countries. So Palermo and his colleagues are trying to use cloning techniques to create eggs that behave more as nature intended. Like normal cells in our body, a mature human egg usually has two sets of chromosomes - one inherited from the woman's mother, the other from her father. When the egg is fertilised, it retains one set in a so-called pronucleus, and spits out the rest in a little package called the polar body. The fertilising sperm, which contains just one set of chromosomes, then restores the full complement.

Palermo's team has mimicked this process by transplanting a nucleus from a body cell into a mature human egg that has had its genetic material removed. By prodding the reconstituted egg with a pulse of electricity, they can make the nucleus divide in half, forming two pronuclei. The team removes one pronucleus and then fertilises the egg by injecting a sperm. So far, however, the resulting embryos have stopped developing after only one or two rounds of cell division, they told a conference on human reproduction in Switzerland this week. "This is preliminary work," cautions Palermo, "but at least in theory, it might be a way to provide eggs for sterile women." However, a child created this way would inherit the DNA-containing structures called mitochondria from the donor egg, and would thus effectively have three parents.

Meanwhile, a related technique being being developed by Lacham-Kaplan and her colleagues might help infertile men. The team has succeeded in "fertilising" a normal mouse egg using a cell taken from the body of a male. This is surprising, because the body cell has two sets of chromosomes. But the team found that when the egg is exposed to certain chemicals, it spits out two polar bodies. One, as normal, contains the egg's spare chromosomes. But the other contains half the chromosomes of the transplanted nucleus, leaving the fertilised egg with the usual two sets.

Even more surprising, such eggs go on to develop relatively normally in the lab, up to the pre-implantation stage. Lacham-Kaplan is now trying to transfer these embryos into surrogate mice.

Source: New Scientist magazine 07 July 2001

Genetic Conflict and Catharsis

Those readers in the habit of browsing through obscure journals of genetic and evolutionary theory will recently have noticed an increasingly frenzied dispute over something called Haldane's rule. A journal called Evolution published a series of three buttals, rebuttals and derebuttals in November. Genetics followed suit shortly afterwards. The argument is as technical as it is heated, but behind the baffling complexities lies a profound question about the nature of evolution. An old discovery is being seized on as evidence for a new theory.

J B S Haldane, a polymathic British biologist, had many ideas and made many discoveries. Until now the one that he stumbled on in 1922 was among the least momentous, even though it came to be called Haldane's rule. It concerns hybrids. When two species are crossed, the offspring are often sterile (mules are an example). In many cases, though, the sterility is confined to one sex, while hybrids of the other sex are happily able to breed with one of the parent species. Occasionally, the hybrid offspring are all of the same sex. Haldane's insight was to note that the sterile or absent sex is the male in mammals, the female in birds, the male in flies, the female in butterflies, and to understand that seemingly random pattern.

All of the species involved have sex chromosomes, called X and Y. A bird with two Xs is a male; a bird with an X and a Y (or just one X) is a female. It is the same in butterflies, the other way round in mammals and flies. Haldane's rule is that the sex with an X and a Y (the "heterogametic sex") is the one which is rendered sterile in hybrids. Like many rules, Haldane's was empirically true and theoretically dull, in that no one had any idea what it had to do with the wider world. For decades, biologists' infrequent efforts to explain it were neither convincing nor interesting. Last year two teams of researchers independently dusted it off and provided new explanations that are certainly interesting and may well prove convincing.

Steve Frank of the University of California at Irvine, and Laurence Hurst and Andrew Pomiankowski at Oxford suggested that the reason the heterogametic sex is sterile in hybrids might have something to do with selfish genes. They have become increasingly intrigued by a rare genetic phenomenon called meiotic drive, in which a gene in effect kills its rival in order to get into the next generation.

Genes and the chromosomes they inhabit come in pairs, and only one chromosome from each pair is picked in the process that produces eggs and sperm - meiosis. So a gene (call it Cain) that kills its brother chromosome gets to monopolise the next generation and thrives at the expense of Abel genes. Such meiotic drive is good for Cain genes, but not necessarily good for the whole organism, since the only thing Cain clearly excels at is killing Abel.

You might expect every gene to try to be a Cain - but even for molecules, murder is not always easy. Cain genes will die unless they find protection against the tools they use to do away their brethren. This most of them have done; for every Cain there will be a separate gene (call it the Mark), which protects the chromosome it shares with Cain from Cain's murderous devices. This would work well except for one thing: just before eggs and sperms are made in meiosis, every pair of chromosomes exchanges some of their genes. This has an effect rather like prison warders constantly moving prisoners around to break up gangs. It means that the Mark is often taken from Cain's chromosome and plonked down on Abel's chromosome. Cain commits suicide, Abel is saved.

Crossing over has long been thought to be an integral part of the gene shuffling that people call sex, but meiotic drive suggests a more specific explanation for it. David Haig at Oxford thinks the shuffling has evolved to frustrate meiotic drive, to enforce social harmony among the genes by making it hard for cheats, especially murderous ones, to prosper. Dr Hurst and Dr Pomiankowski think that, while true, this may not be the whole story, that all may not have contrived to arrange itself for the best in the best of all genetic worlds. They suggest there may be constant active policing at work in the system - a mechanism that aborts the whole crossing-over procedure if it detects genes trying to do each other down. It would be like a prison governor saying "you'll all stay in your cells until somebody owns up."

Either way, Haldane's rule would follow. The only pair of chromosomes that does not engage in crossing over is the pair consisting of the X and the Y. So Cain genes on X chromosomes could safely kill Y chromosomes to ensure that they got into the next generation. They would not risk suicide because there is no crossing over to remove the Mark. Therefore meiotic drive genes would accumulate on the x chromosome and work against the Y. In a normal individual such a process would be kept in check by suppressor genes on the Y while killer genes on the Y would be kept in check by suppressors on the X, resulting in an armed stand-off. But in a hybrid the suppressors come from a different species and do not recognise the gene they are to suppress. Either that, or the generalised shutdown suggested by Dr Hurst and Dr Pomiankowski is triggered by the incompatibility of the X and Y.

Dr Hurst has recently found what he thinks is a "smoking gene": a dormant meiotic-drive gene with just the right properties to be responsible for Haldane's rule. Called "stellate" it is a gene in fruit flies that serves no useful purpose and, when not suppressed, renders the fly sterile. It lies on the X chromosome and is suppressed by a gene on the Y chromosome, just as expected.

The conjecture has not gone uncriticised, which is what all the fervour in the journals is about. A group led by Jerry Coyne at the University of Chicago has challenged the assumptions, facts and logic of the meiotic-drive arguments. They believe in a subtler and less revolutionary explanation of Haldane's rule - that recessive, beneficial genes tend to accumulate on the X - for which there is equally little evidence. Andrew Read and Sean Nee at Oxford challenge the very rule itself, saying the evidence is inflated by counting closely related species as separate examples of the rule. Manuscripts are flying thick and fast. So far the meiotic drivers appear to have the better of the argument.

If they win, they will have provided the first good test of a view that is gathering adherents in biology: that the goings-on at the level of the gene are best viewed as a compromise between a free-for-all of selfish genes and a joint effort in which harmonious co-operation reigns. Egbert Leigh, of the Smithsonian Tropical Research Institute, calls the elegant compromise - without which all the interesting bits of biology, such as people, would be impossible - the "parliament of the genes". He nicely captures the idea that genes govern themselves in the same sort of ways as every other group of half-co-operating, half-competing individuals, from a wolf pack to a medieval village to the United Nations.

Source: The Economist 21 March 1992