Richard Gayle
Sex, the Single Chromosome and the Blind man November 5, 1999
One of the truly exciting things about research is the joy that comes from finding something new and unexpected - that makes the natural world that much more interesting. Recently there were 3 papers published in Nature and Science that deal with the X chromosome. These papers all use nucleotide sequences from this chromosome to tell us a little about where we came from and how.
The 46 chromosomes of a human being are broken into 2 groups: 22 pairs of autosomes that contain the vast majority of functioning genes, and 2 sex chromosomes, the X and Y. We all know that these last 2 determine sex but they are also unique in several other fashions. All other pairs of chromosomes are able to line up with their partner and recombine, exchanging portions of themselves and greatly enhancing the spread of useful alleles in a population. The flow of genes from one autosome to its partner increases the variability of the genome. The more variable a population is, the greater chance they have to survive anything nature can throw at them.
Recombination also serves to prevent genes from becoming inactive. In a normal cell, there will be 2 copies of any gene, so if one becomes inactive, due to mutation or gene rearrangement, the other allele will keep the cell from lacking the gene product totally. But this inactive gene would then always be associated with many other genes, some of which would be very useful. In meiosis, these good genes would always be associated with the bad gene, unless they could recombine and join a good allele. Thus recombination helps save good genes from the presence of bad ones. No recombination, there is no selective advantage for good genes to reside on the chromosome.
The X and Y chromosomes, although they can line up with each other, can only recombine at the tips. The genes located in the other regions of the X and Y chromosome do not recombine. They do not move from the X to the Y, or vice versa. They are completely separated from one another and are free to mutate independently as time passes, with no gene flow between them. No gene flow means that there will selective pressure to move good genes to other chromosomes that do recombine. This is what happened but it means that there is even less pressure for recombination between the sex chromosomes. Meaning the degradation of the chromosome will coninue until there are no regions that recombine any longer.
Even though these regions can no longer exchange genes, they still contain homologous DNA sequences, so called "fossils". Mutations will separately accumulate in these genes on each sex chromosome. It is almost like comparing homologous regions on the same chromosome between humans and chimpanzees (more about that later). By looking at the rate of mutation accumulation, you can get an idea of when the genes separated from one another, never to exchange again. Because at some time in the past, greater regions of the two sex chromosomes did recombine, not just the tips.
There are at least 19 X-Y gene pairs, at least that we can see. In a recent Science paper (see below), Lahn and Page identified the location of each of these pairs on the X and the Y chromosome. Nucleotide changes in the gene sequences that do not result in altering the protein sequence (synonymous substitutions) were examined. These changes should be relatively neutral and not be selected for or selected against.
Now the unexpected. There are 4 clusters of genes, each cluster determined by the number of synonymous substitutions present. Check out the paper for a good picture. The upshot is that there appears to have been 4 separate events, most likely chromosome inversions, that occurred during the evolution of the X and Y chromosomes. And these events appear to be timed fairly closely to previously reports of major divergences in mammalian sex chromosomes. For example, the divergence of simians from prosimians was roughly 50 million years ago. This is also the same time frame for the most recent event. In fact, the very first event is timed pretty closely to the last common ancestor between mammals and birds. Since birds use an entirely different system to determine sex, this matches quite well. Pretty neat and not something that would have predicted before sequences from the sex chromosomes were examined.
But it may be that an important event in the evolution of major groups of animals was the inversion of specific sites on the sex chromosomes. Only groups that had similar inversions would produce viable offspring. Thus the two groups would no longer be able to exchange genes, the gene flow would be zero and they would now adapt to the environment in different ways, yielding different groups. Nice hypothesis.
A second paper in Science takes a step back and looks at the genetic variation between humans and chimpanzees. This paper examines a region over 10,000 base pairs long on the X xhromosome, known as Xq13.3. The DNA from 30 chimps representing three different subspecies was sequenced, as well as 5 bonobos (a separate but similar species of chimp). These sequences were then compared to the same region from 70 humans.
The data indicate that the chimps have almost 4 times the sequence variability as humans. Using appropriate tools, estimates of the most recent common ancestor (MRCA) for the different chimp sequences are about 2,000,000 years. All of the human variability found in this region could have been derived from a population starting about 700,000 years ago. That is, millions of years are needed to explain the huge amount of chimpanzee variability, while all the human differences can be explained in a few hundred thousand years. Although there are some differences in the timing compared with other data, this appears correspond to a postulated bottleneck in the human population. Something happened to greatly reduce the number of different sequences present in the human population and we have only had a few hundred thousand years to add some more back. The chimpanzees did not have such a reduction and have continued to add to the sequence variations at Xq13.3. What caused this reduction is an open question but has the makings of a great science fiction story.
The final short paper was published in Nature. Primates have 3 genes encoding proteins responsible for color vision (opsins) that allow us to see in full color. The one that reacts to short wavelength light (S) is on an autosome, but the middle wavelength (M) and long wavelength (L) opsins are on the X chromosome, some of the only genes active on the X chromosome. Loss of function in either the L or M opsin results color blindness (i.e. the person is unable to see the reds properly).
The use of 3 opsins for color vision, called trichromatic, has been seen previously only in primates. It turns out that prosimians, such as lemurs and bush babies, have only 2 genes, one autosomal and one X-linked. They can only see in 2 colors. This report describes a polymorphism in the X-linked gene that creates either an M or an L allele of the opsin. This means that a female, with two X chromosomes, could carry one of each type and potentially could be trichromatic. The 2 alleles can be quite common in certain species, indicating that there is a selective advantage to being heterozygotic, at least for the females.
Too bad for males. But, if at some point, recombination but both an M and L allele on the same chromosome, all memebers of the species could see in color. It is likely that a similar event happened to humans.
So, even though the X chromosome is mainly thought of as determining sex, it has a long history dealing with vision. And aren't we glad that our ancestors somehow managed to put both M and L forms on one chromosome? Otherwise only women would have the ability to see in full color. All the men would suffer from red-green color blindness. Think of all the arguments that would have occurred between husband and wife regarding which color to paint a wall.Talk about trying to describe the color blue to a blind man...
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