Bird sex gene found
Researchers have cracked the long-time mystery of how sex is determined in birds: A dose-dependent effect of a single gene on one of the sex chromosomes does the trick, according to a study published this week in Nature.
Image: Wikimedia commons, linkurl:HerbertT;http://commons.wikimedia.org/wiki/File:Take_five.jpg "It's a major advance," said physiologist and geneticist linkurl:Art Arnold;http://www.physci.ucla.edu/html/arnold.htm of the University of California, Los Angeles, who was not invo
Researchers have cracked the long-time mystery of how sex is determined in birds: A dose-dependent effect of a single gene on one of the sex chromosomes does the trick, according to a study published this week in Nature
|Image: Wikimedia commons, linkurl:HerbertT;http://commons.wikimedia.org/wiki/File:Take_five.jpg |
"It's a major advance," said physiologist and geneticist linkurl:Art Arnold;http://www.physci.ucla.edu/html/arnold.htm of the University of California, Los Angeles, who was not involved in the work. "This is convincing evidence that this is how sex is determined in birds. And that's been long-sought evidence."
When sex is determined genetically, there are two possible mechanisms of sexual differentiation, Arnold explained. The sex chromosome unique to one sex may contain some sex-determining factor, as in the case of the male Y-chromosome in mammals. Alternatively, there could be a dose effect of a gene on the shared chromosome which causes embryos with two copies of the gene to develop differently from those with just one, he said. Or it could be some combination of the two, he added.
In birds, embryos with two Z-chromosomes differentiate into males, while embryos with one Z-chromosome and one W-chromosome become females. The Z-linked gene DMRT1
had been suspected of playing a role in sex determination in birds since it was first discovered about a decade ago, but nobody had actually demonstrated its effect in differentiation. Using RNA interference to knock down the expression of DMRT1
in freshly laid chicken eggs, developmental biologist Craig Smith of the linkurl:Murdoch Childrens Research Institute;http://www.mcri.edu.au/ and the University of Melbourne in Australia and his colleagues generated embryos containing ovary-like gonads from genetically male eggs, suggesting that DMRT1
is a critical factor in sexual differentiation.
The first sign of the sex reversal was a dramatic difference in the size of the developing chicks' two gonads. In female birds, the left gonad becomes a functional ovary while the right gonad regresses. "When we saw an asymmetry, that immediately alerted us to the fact that it might be a feminized male," Smith said. Looking closer at the histology of the gonads in the seemingly sex-reversed embryos, the researchers saw the "hallmarks of an ovary," he said, including a thickened outer cortex and an inner medulla fragmented with cavities, as opposed to the thick cords found throughout the testes.
Furthermore, the team also noticed expression of aromatase -- a robust marker of ovary development -- in the sex-reversed gonads. "Aromatase is only ever turned on in the developing ovary of the chicken," said Smith. "Never in the testis." Activation of aromatase throughout the gonads of feminized males suggests that they are well on their way to becoming ovaries, he said.
Although the strong evidence for DMRT1
's role in sex determination doesn't rule out the possibility that there are W-linked factors as well, this is "a clear case" of a dose- dependent effect of a Z-linked gene, Arnold said. It's a unique way of approaching sex determination, he noted. In most other animal groups with sex chromosomes, both males and females get the same dose of the sex-linked genes. In mammals, for example, one of the X-chromosomes in females is inactivated, resulting in a similar level of X-linked gene expression to that of males, which have just one X chromosome to begin with. But in birds, that's not the case. "Males are flying around with higher expression of most of their Z genes," Arnold said, making a dose-dependent mechanism for sex differentiation possible. "This is the first case where [a] double dose of [a sex-linked] gene [determines sex], as opposed to a sex-specific factor on the minor sex chromosome."
Two other genes also showed altered expression in the feminized male embryos. SOX9
-- a key conserved gene for testis formation in vertebrates -- was down-regulated, and FOXL2
-- a gene implicated in ovary development that isn't normally expressed in male gonads at all -- was turned on, suggesting a downstream role for both genes in the sex determination process. Smith and his colleagues are now looking for targets of DMRT1
in the embryonic chicken to work out the details of this pathway.
The team is also hoping to overexpress DMRT1
in genetically female eggs to see if this will result in masculinized gonads. The problem with this, however, is that global overexpression of this gene is lethal by day 4, before the gonads differentiate. "What we're trying to do now," Smith said, "is deliver DMRT1
in a tissue-specific way using a tissue-specific promoter" to target just the gonads.
In addition to bringing the field closer to a complete understanding of sexual differentiation, this research may eventually allow scientists to create all-female eggs that are required for some kinds of vaccine development, Smith said. "When we know about this process, [manipulating the sex ratios of poultry] becomes possible," Arnold agreed.
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[21st May 2002]