WHITEHEAD GENETICISTS REHABILITATE YCHROMOSOME FROM ORPHAN STATUS
By David N. LeffScience Editor
At the chromosomal level, maleness is an afterthought. It kicks inonly when the zygote contains a Y chromosome in its genome alongwith an X chromosome. The Y's maleness-determining geneexpresses the Y antigen, which moves in on the thus-far femaleground-plan of the incipient genitalia, to produce testes rather thanovaries.
Every normal human male contains one X and one Y chromosome inhis genome; every female, two Xs.
So far, all this is biology 101. But geneticists have long puzzled overthe fate of that Y chromosome, once it's discharged its sex-determining mission. For one thing, the stubby Y is less than one-third the length of the sex-linked X chromosome, which is lined withgenes of all kinds.
Some still-current genetics textbooks describe the lame-duck Ychromosome as "empty" of all functioning genes, except perhaps forone that encodes hairy ears.
According to received genetic dogma, mammalian X and Ychromosomes evolved in tandem from two autosomal (not sex-related) chromosomes about 120 million years ago. Any genes addedto the Y chromosome since then, the theory holds, have derivedentirely from its interactions with its accompanying X chromosome.
Molecular geneticist David Page was not persuaded by thisconventional wisdom, that the Y chromosome is akin to a disposablethrow-away. He is associate director of the Whitehead Institute'sCenter for Genome Research, in Boston.
Four years ago, Page and his colleagues created the firstcomprehensive physical map of the Y chromosome, which has sincefacilitated the search for its genes.
Then last year, he identified a gene on the Y that is present in healthy,fertile males, but absent in infertile ones with azoospermia _complete lack of sperm production. Page located that apparentfertility/infertility DNA sequence to a region of Y thought to harbor aseries of genes required to manufacture sperm cells. Page called thisgenomic neighborhood AZF _ Azoospermia Factor, and that firstdiscovered gene DAZ, for deleted in azoospermia. (See BioWorldToday, Aug. 2, 1995, p. 1.)
This year, in the November Nature Genetics, Page and his co-authorsreport that the DAZ gene exists on the Y chromosome in a smallcluster of three or more copies, all of which express their products inmale germ cells only.
Germ Line Gene On Autosomal Ancestor
Moreover, the group discovered a nearly identical homolog of DAZperched unexpectedly on human autosomal chromosome 3.
Their paper's title: "The DAZ gene cluster on the human Ychromosome arose from an autosomal gene that was transposed,repeatedly amplified and pruned."
"It turns out," Page told BioWorld Today, "that this autosomal geneis in an evolutionary sense the ancestor of the sex-linked genes on theY chromosome. It came first in evolutionary time, and by a complexseries of transpositions, modifications and amplifications, thatautosomal gene spun off a colony on the Y chromosome, which isnow the DAZ cluster."
From the standpoint of possible clinical applications to the diagnosisand treatment of male infertility, that double discovery has a down-side and an up-side:
"Two things are very immediate," Page said. "One is, that there beinga cluster of DAZ genes on the Y chromosome, it introduces certaintechnical complications in looking for more subtle mutations in thegene. Since those DAZ copies are 99.9 percent identical at the DNAsequence level, it is very difficult, using our conventional methods, tofocus on an individual copy, and ignore the others.
"On the more positive side," he continued, "the autosomal geneimmediately becomes a candidate for looking at defects in infertilemen."
The mutations in the DAZ gene that cause azoospermia are notinherited; they arise sporadically de novo. "We suspect," Pageobserved, "that they are due to the presence of Y-specific repeats oflocally monotonous DNA sequences. And we suspect that these areprone to mischief with each other."
He added: "We now face the questions: `Can mutations in thechromosome 3 autosomal DAZ gene be found in infertile men? Willthey prove to be another cause of male infertility?'"
Then there's another key question," he went on: "Once the Ychromosome finishes its job of male sex determination, what happensto the rest of it?' One answer: `There are quite a few genes that areshared between the X and the Y. Shared in the sense that there areidentical, or nearly identical, copies on both."
Why Y Is Like No Other
Page views Y as unique among the 44 autosomal plus two sex-linkedchromosomes in the human genome.
"The Y is actually a chromosome you can think about," he said. "Formost chromosomes, there is no coherent way to think about what theyare doing within the organism." He pictures Y as "sort of a book withthree chapters:"
* Chapter I: "Sex determination."
* Chapter II: "Other genes it might have recruited to enhance malefitness for reproduction."
* Chapter III: "Functions shared with the X chromosome, notablyTurner's syndrome."
One incidental discovery documented in the Nature Genetics paperconcerns the DYS1 gene on the Y chromosome.
"There was a time back in the early 80s, Page recounted, "whenpeople in the human genome project decided that names should begiven to so-called anonymous bits of human DNA, as they began tobe mapped on human chromosomes. So DYS1 was one of the veryfirst anonymous DNA probes, mapped to the human Y chromosome.
"D stands for DNA; Y for the Y chromosome; S _ a misnomer _ for"single copy;" 1, first in chronological order.
"Our Nature Genetics paper now reports," Page concluded, "thatDYS1 and DAZ are one and the same gene. So paradoxically, peoplehad been studying DAZ for at least 12 years, but didn't know it." n
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