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On Science: Why do men still exist?

This article first appeared in the St. Louis Beacon, Jan. 20, 2010 - Our view of the differences between the sexes has recently undergone radical revision. How do males and females differ? Seen through a biologist's eyes, the most basic difference between males and females is that all females have two copies of the "so-called" X chromosome. The X chromosome is about the same size as other 22 human chromosomes, which also occur in pairs, and like them is packed with about 1,000 genes.

The reason there are two copies of the X and other chromosome is to allow for the repair of the inevitable damage that occurs over time to individual genes because of wear-and-tear, chemical damage and mistakes in copying. Because this sort of damage is passed on to offspring, it tends to accumulate over time. For this reason, genes must be edited every so often to repair the accumulated mutations (biologists call damage to genes mutation).

How can a cell detect and edit out a mutation involving only one or a few nucleotides in one strand of DNA? How does it know which of the two DNA strand is the "correct" version and which the altered one? This neat trick is achieved by every cell having two nearly identical copies of each chromosome. By comparing the two versions with each other, a cell can identify the "typos" and fix them.

Here is how it works: Every DNA molecules is composed of two strands. When a cell detects a DNA duplex with a difference between its two DNA strands, that duplex is "repaired" by the rather Draconian expedient of chopping out the entire region, on both strands of the DNA molecule. No effort is made by the cell to determine which strand is correct -- both are discarded. The gap that this creates is filled by copying off the sequence present at that region on the other chromosome. All this editing happens when the two versions of the chromosome are paired closely together in the early stages of gamete (egg and sperm) formation, the process we biologists call meiosis.

It's very important, this repairing of mistakes. Most biologists think the need for this repair is the reason sex evolved. Asexual organisms, which don't do meiosis and so cannot pair-up their chromosomes to edit them, accumulate mutational damage in a process of irreversible genetic decay biologists call Muller's Ratchet, a progressive loss of genes that can lead to eventual extinction.

Men in Danger?

So what are we to make of males? Males, by contrast to females, have only one copy of this X chromosome, not two. The other chromosome of the pair in males is called the Y chromosome and is much smaller than the X. Biologists thought until very recently that the Y chromosome had only a few active genes. Because there is no other Y to serve as a pairing partner in meiosis, most of its genes had been thought to have decayed, the victims of Muller's Ratchet, leaving the Y chromosome a genetic wasteland with only a very few active genes surviving on it.

One of the few genes documented to be on the Y chromosome (it's inherited, seen in families that carry it in all males and no females) causes very hairy ears.

Another gene known to reside on the Y chromosome is a key sex determination gene. For the first 40 days after conception, all human embryos develop in much the same way. Then, a sex-determining gene on the male's Y chromosome called SRY (for "Sex-determining Region of the Y chromosome") comes into play. The product of the SRY gene converts the gonad cells of the early human embryo into testes, which in turn triggers development of male sexual organs. If expression of SRY is blocked, the embryo's gonad cells go on to become ovaries and female sexual organs develop. In other words, all human embryos will develop into females unless they are masculinized by the product of the SRY gene.

This view of males as females with an extra gene has a profound implication -- that there is very little genetic difference between the sexes, just a gene or so. All the "Men Are From Mars, Women Are From Venus" differences, although real enough, are in this view the result of hormonal differences. Said succinctly, males are what testosterone makes them. Due to such hormone differences, as many as 15 percent of mammalian genes are more active in one sex than the other.

More to Y Than Thought

We now know this view to have been way too simple. In June of 2003, a team of researchers led by David Page of the Whitehead Institute in Cambridge, Mass., working with scientists at the Washington University School of Medicine, reported the full gene sequence of the human Y chromosome, and it was nothing like biologists had expected. The human Y chromosome contains not one or two active genes, but 78!

Some like SRY are concerned with male development, most of the others with sperm production and fertility. A few, like "hairy ear," have no obvious role in sex. One of this later group makes a component of ribosomes (complex tiny engines in the cell which assemble proteins), meaning that every ribosome in a man's body is slightly different from those in a woman's.

Taking all these genes into account, geneticists conclude that men and women differ by 1 to 2 percent of their genomes -- which is the same as the difference between a man and a male chimpanzee (or a woman and a female chimpanzee). So we are going to have to re-examine the basis of the differences between the sexes. A lot more of it may be built into the genes than we had supposed.

The sequence of the Y chromosome gives us the answer to another question that has plagued biologists: Why are the X and Y chromosomes so different? The Y chromosome is much smaller than the X, and can only pair up with the X at the tips. Thus there can be no close pairing between X and Y during meiosis, the sort of pairing that allows the proofreading and editing discussed above.

We can now see that there is a very good reason evolution has acted to prevent the close pairing of X and Y -- those 78 Y chromosome genes. Because close pairing allows the exchange of large segments as well as small ones, any association of X and Y would lead to gene swapping, and the "male-determining" genes of the Y chromosome would sneak into the X, making everybody male.

The Palindrome Solution

One mystery remains. If the Y chromosome cannot pair with the X chromosome, how does it make do without copy-editing to prevent the accumulation of mutations? Why hasn't Muller's ratchet long ago driven males to extinction? The answer to this question is right there for us to see in the Y chromosome sequence, and an elegant answer it is.

Most of the 78 active genes on the Y chromosome lie within eight vast palindromes, regions of the DNA sequence that repeat the same sequence twice, running in opposite directions, like the sentence "Madam, I'm Adam," or Napoleon's quip "Able was I, ere I saw Elba."

A palindrome has a very neat property: It can bend back on itself, forming a hairpin in which the two strands are aligned with nearly identical DNA sequences. This is the same sort of situation -- alignment of nearly identical stretches of chromosomes -- that permits the copy-edit of the X chromosome during meiosis. Thus in the Y chromosome, mutations can be "corrected" by conversion to the undamaged sequence preserved on the other arm of the palindrome. Damage does not accumulate, Muller's ratchet is avoided, and males persist.

A cute story. Last week, it got even cuter. David Page, the researcher who worked for 13 years to decode the human Y chromosome in 2003, reported last week the results of his eight year effort with the same Washington University team to decode the chimpanzee Y chromosome.

Lesson from Chimps

They had not expected many differences. Chimps (Pan trogodytes) and humans share a common ancestor who lived only 6 million years ago, a short stretch in evolutionary time. There has not been much time for the two species to diverge, and when the rest of the chimp genome was sequenced a few years ago, it indeed proved to be little different from the human genome - the two genomes differ in less than 1 percent of their DNA.

Not so the Y. The human and chimp Y chromosomes differ in 30 percent of their DNA!

The more closely you look, the more different are the two Y chromosomes. For example, the chimp Y has less than half as many protein-encoding genes as the human Y. Now where the heck did they go? The Y chromosome originally had the same set of genes as the X chromosome, but most of the X-related genes have been chewed up by mutation over the last 200 million years. Is that what happened to the missing 41 chimp genes? Has the mutation-cleaning palindrome system worked less well in chimps, allowing more damage to accumulate?

Certainly the mutation-cleaning system provided by the Y chromosome palindromes is not foolproof. More than 30 percent of the chimp and human Y chromosomes do not align, while only 2 percent of the remainder of the genomes fail to align. And blocks of genes appear to have moved from place to place far more frequently than in other chromosomes. Have a significant number of differences accumulated within genes nested within palindromes? Yep. Clearly lots of mutational difference has crept into the Y over 6 million years. It certainly seems to me reasonable to conclude, comparing chimp to human, that Muller's ratchet is in fact alive and well on the Y chromosome.

So, in a very real way, we are right back where we were eight years ago. The conclusion we drew from Page's original decoding of the human Y chromosome, that palindromes within the Y prevent the accumulation of mutations, was a pretty idea that doesn't hold water. So why aren't males extinct? What IS keeping these chromosomes going?

Good question. Page surmises that the guilty party is the usual suspect, natural selection. Most of the genes on the Y encode proteins whose functions have to do with sperm production. Female chimps, when receptive, often mate with many males, one after the other, so that the male with the most virile sperm has the highest likelihood of success. This suggests to Page that natural selection may have acted strongly on sperm-production genes of chimp Y chromosomes, causing these genes to evolve rapidly, accumulating mutational changes that improve their function while eliminating any changes that reduce it.

Like Page's earlier palindrome-cleaning idea, this suggestion has real merit, and may well be true. And, like his palindrome-cleaning hypothesis, it may not be. That's what I love about science: Its ideas are in a constant state of flux, any hypothesis subject to future revision when we know more. David Page is a very lucky man, to have found such a wonderful conceptual playground.

George B. Johnson's "On Science" column looks at scientific issues and explains them in an accessible manner. 

Johnson, Ph.D., professor emeritus of Biology at Washington University, has taught biology and genetics to undergraduates for more than 30 years. Also professor of genetics at Washington University’s School of Medicine, Johnson is a student of population genetics and evolution, renowned for his pioneering studies of genetic variability. He has authored more than 50 scientific publications and seven texts.

As the founding director of The Living World, the education center at the St Louis Zoo, from 1987 to 1990, he was responsible for developing innovative high-tech exhibits and new educational programs.

Copyright George Johnson