A gene for feathered fellas
A double dose of DNA turns developing chicks into cockerels.
The expression of just one gene in chickens controls whether boys will be boys, according to a paper in this week's Nature1. The finding should resolve a long-standing debate about what determines the sex of birds.
In many organisms, sex is decided by genes on one of two sex chromosomes. In humans and most other mammals, a gene on the Y chromosome confers maleness, whereas in fruitflies and many other insects, the amount of an X-linked gene governs sex.
In birds, however, the picture is less clear. The distribution of the sex chromosomes is reversed — males have two Z chromosomes, and females have one Z and one W — and it has been hotly contested whether the sex of avian embryos is decided by a female-specific gene on the W chromosome, or whether it's the number of Z chromosomes that matters.
Two leading candidates have been proposed to settle the mystery. On the one side, the W-linked gene HINTW has been touted as a potential female-only factor; on the other, the Z-linked gene DMRT1, which is involved in sexual differentiation in many organisms, provides a potential dose-sensitive sex determinant. New data now strongly tips the balance towards the latter gene as the master sex regulator.
Let's talk about chicken sex
A team led by Craig Smith of the Murdoch Childrens Research Institute in Melbourne, Australia, reduced the expression of DMRT1 in young chick embryos using RNA interference (RNAi). They found that male chicks — those with two Zs — with abnormally low levels of the gene developed partially feminized gonads instead of proper testes. Earlier this year, Smith's group showed that overexpressing HINTW in male embryos did not alter the course of male development2. Together, these studies throw weight behind the theory that the Z-linked double dose mitigates avian gender.
"Everybody has been expecting that this gene would be the sex-determining gene," says Jenny Graves, a molecular geneticist at the Australian National University in Canberra. But it has been hard to nail down because genetic manipulations are difficult to perform in birds. "Good old RNAi wins again," she says.
"These experiments are giving us the ultimate proof," says Michael Schmid, a geneticist at the University of Würzburg, Germany. "This system of sex determination is valid for all 500 other birds."
Graves notes, however, that DMRT1 might work in concert with a gene on the W chromosome that enhances the dose signal coming from the master regulator. "A two-to-one ratio is a bit dicey," she says. "With something as important as sex you'd want to be a bit more robust than that."
DMRT1 has already been implicated in sexual development in insects, nematodes, and even humans — deletions in the gene on human chromosome 9 can turn boys into girls, for example3. But in humans, other placental mammals and marsupials, a gene called SRY now dominates the sex determination pathway. DMRT1's central role in sex determination in birds — one of our closest non-mammalian relatives — suggests that SRY may have usurped DMRT1 at some point in our own ancestry, Smith says.
Hans Ellegren, an evolutionary biologist at Uppsala University in Sweden, says that the new findings are consistent with the dose hypothesis, but they don't definitively show that it is the number of gene copies — rather than the expression levels of those genes — that is the key factor.
"The experiments cannot formally exclude the dominant-W hypothesis," he adds, explaining that there could be a W-linked gene in females that suppresses DMRT1 to prevent male development.
Ideally, says Smith, he would also like to increase the expression of DMRT1 to show that it led to masculinization of genetically female chicks. But when he tried using a virus to boost expression levels, all the embryos died after four days — before their gonads started to develop. He is now attempting to overexpress DMRT1 only in the gonads, as well as breeding his feminized ZZ birds to maturity. He expects that they will grow into apparently female birds. "The question is, would they be fertile at the adult stage?"
- Smith, C. A. et al. Nature advance online publication doi:10.1038/nature08298 (2009).
- Smith, C. A., Roeszler, K. N. & Sinclair, A. H. Int. J. Dev. Biol. 53, 59-67 (2009).
- Raymond, C. S. et al. Genes Dev. 14, 2587–2595 (2000).