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Zarkower is available at (612) 625-9450.
Contacts:
David Zarkower, Medical School Biochemistry Department, (612) 625-9450
Deane Morrison, News Service, (612) 624-2346, [email protected]
It's a Guy Thing: Ancient Gene for Maleness Found in Humans, Fruit Flies and Nematodes, U of Minnesota Study Finds
Biologists have long thought that sex-determining genes went their separate ways as the animal kingdom evolved. Plenty of genes are known to regulate the sex of offspring in various animals, but human genes looked nothing like sex-determining genes in fruit flies or nematode worms. Until now. A study led by University of Minnesota molecular biologist David Zarkower has found that a nematode maleness gene is very similar to maleness genes in fruit flies and maybe humans. These are the first examples of sex-determining genes whose structure has been conserved through eons of evolution, in this case the approximately 500 million years since ancestors of the three animal species split from each other. The work will be published in the Feb. 12 issue of Nature.
The human gene in question is called DMT1 and is found on chromosome 9. Its counterpart in nematodes, discovered years ago by Zarkower's collaborator Jonathan Hodgkin, is called mab-3 (male abnormal), and its counterpart in fruit flies is called doublesex. Zarkower said these genes all seem to get turned on by a cascade of gene activity that occurs during the animal's development.
What the genes do varies from species to species, but is related to sex determination in each case.
"In male nematodes, mab-3 is necessary for the growth of sense organs in the tail that are used to find mating partners," said Zarkower. "The mab-3 gene is also necessary to keep the males from producing yolk. In male fruit flies, the doublesex gene is required to keep males from producing yolk, as well as for sex-specific bristles and genitalia." As for DMT1, it hasn't been proven to be a sex-determining gene, but it's found at a location that, when defective, causes male-to-female sex reversal, he said.
Zarkower said his research has a lighter side in that it indicates how far science has come since the days of Aristotle.
"Aristotle proposed a model of sex determination more than 2,000 years ago, suggesting that the more heated the passion of intercourse, the more likely the conception of male heirs," Zarkower said. "He suggested that elderly men might try for male heirs in the summer. It was not until early in this century that human sex chromosomes were discovered and Aristotle could be proven wrong."
The mab-3, DMT1 and doublesex genes exist as several stretches of DNA, only one of which shows similarity between the three animals. That stretch encodes a protein that attaches to DNA elsewhere, controlling other genes. If mab-3 is inactivated in nematodes, it can be replaced by the male fruit fly's doublesex gene, allowing the worm to grow normal male sense organs. Not too surprising, said Zarkower, since the fruit fly gene also controls the development of bristly male sense organs. The human DMT1 gene cannot substitute for the nematode gene, however. But then, why should it, since human males have no structures that qualify as "sex bristles"?
What DMT1 does is the subject of Zarkower's current investigations. Humans with one X and one Y chromosome are supposed to be male, but an XY embryo that's missing one of the normal two copies of DMT1 (one is on each chromosome 9) will grow up female. And sterile. But that doesn't prove the sex reversal is due to loss of a functional DMT1 gene; it could be due to a gene located very close to DMT1. Therefore, Zarkower is testing a large group of XY females, searching for a tiny mutation in the DMT1 gene itself.
"Finding such a mutation would really nail DMT1 as a sex-determining gene," he said.
Zarkower can supply slides of nematodes and of human chromosomes that have been labelled with red dye at the location of the DMT1 gene, near the tip of the chromosome.
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