Of the 46 human chromosomes, 44 are members of identical pairs. But two -- the X and the Y -- stand apart because they have no perfect match. Nevertheless, evolution has charged these two genetic loners with the critical task of sex determination: embryos with two X chromosomes develop into females, while embryos with an X and a Y chromosome develop into males.
The rationale behind this arrangement has long perplexed scientists like Professor of Biology David Page, a member of the Whitehead Institute and an expert on the Y chromosome, who wonder how these unique chromosomes first came about. Now research by Professor Page indicates that sex chromosomes descended from an ordinary pair of autosomes (chromosomes that are not sex chromosomes) that evolved into the modern X and Y chromosomes over hundreds of millions of years.
In a study published in the October 29 issue of Science, Professor Page and Dr. Bruce Lahn, then a postdoctoral fellow at Whitehead, reported that they have reconstructed the stages of sex chromosome evolution and the time course over which these chromosomes were built. This research provides a glimpse back in time and a means to understand how sex chromosomes -- one of nature's greatest experiments -- first emerged.
Millions of years ago, sex was probably determined not by sex chromosomes but by some environmental factor such as the temperature of the water at which the egg incubated. (Sex determination still occurs this way in some animals like crocodiles and sea turtles.) Over the years, a pair of autosomes differentiated into two distinct chromosomes, the X and the Y. Today the X is still home to thousands of genes, but the Y has only a few dozen. Of those, 19 are shared between the X and Y.
These 19 genes are essentially living fossils in that they are able to provide scientists with information about the history of sex chromosomes, said Professor Page, who is also an investigator at the Howard Hughes Medical Institute. "Sex chromosomes are the only chromosomes with a long intellectual history, but those 19 genes can tell us a great deal about their evolutionary history as well," he said. "In this study, he and Dr. Lahn took advantage of these voices from the past to learn more about the events that produced the modern sex chromosomes.
First they compared the locations of all 19 pairs of genes on the human X and Y chromosomes. They found that all of these genes are concentrated on the tip of the short arm of the X, whereas they are scattered across the length of the Y. In general, the order of the genes is not consistent between the two chromosomes.
They then measured for each of the gene pairs' synonymous nucleotide divergence -- silent changes in the nucleotide sequence. Due to the redundancy of the genetic code, such changes do not affect the encoded amino acid or the resulting protein. Because they are therefore selectively neutral, synonymous substitutions serve as a molecular clock, providing a measure of the evolutionary time that has elapsed since the gene pairs began to differentiate.
To their amazement, the scientists found that the genes were clustered into four groups, each group with a different level of sequence similarity. "The most striking observation was that on the X chromosome, the four groups of genes are physically arranged as four consecutive blocks, essentially like the layers of rock are arranged in geological strata," explained Professor Page. In contrast, the groups appear to be scrambled on the Y chromosome.
During evolution, X-Y differentiation was probably initiated one stratum at a time, with stratum 1 having been the first to embark on the differentiation pathway and stratum 4 having been the most recent, said Dr. Lahn, who is now on the faculty at the University of Chicago. Differentiation could have occurred only after X-Y recombination was suppressed in each stratum.
"Most likely this suppression was the result of a series of chromosomal inversions on the Y chromosome, which would also explain why the genes appear to be in order on the X but scrambled on the Y," Dr. Lahn said.
The next step was to determine exactly when differentiation actually occurred for each stratum. By comparing the genes in each stratum with homologs in other mammals, Professor Page and Dr. Lahn were able to determine the minimum and maximum ages for all of the strata.
Furthermore, they were able to place the differentiation events on an evolutionary continuum with respect to the evolution of other animals. For example, they learned that the first stratum differentiated 240 to 320 million years ago, shortly after the ancestors of mammals parted company with the ancestors of birds. The second stratum differentiated 130 to 170 million years ago, shortly after our ancestors parted company with the ancestors of the duck bill platypus.
The third stratum differentiated 80 to 130 million years ago, shortly after our ancestors parted company with the ancestors of kangaroos. Finally, the fourth and most recent stratum differentiated 30 to 50 million years ago, shortly after our ancestors parted company with the ancestors of lemurs.
The Science paper builds on a study published last year by the Page lab that proposed a pathway for X-Y gene evolution whereby a gene shared between the X and the Y evolves into an X-linked gene with no homolog on the Y. Most of the genes on the X today are products of this pathway, their former Y counterparts having long since decayed. The 19 remaining X-Y genes are still en route on the evolutionary pathway, said Professor Page.
"Before that paper, most scientists -- myself included -- thought of the few X-Y genes as genetic oddities, with no fundamental place in the understanding of either chromosome," he said. "The central idea of the paper was that those genes were intermediates on an evolutionary pathway through which all genes on the sex chromosomes have traveled and to which those persisting X-Y genes bear witness."
This study was supported by the National Institutes of Health.
A version of this article appeared in MIT Tech Talk on November 3, 1999.