Minneapolis,
MN (2/12/98)- The genes that determine maleness appear to be conserved
in everything from worms and flies to humans, report University of Minnesota
scientists.
Molecular biologist David Zarkower conducted research indicating that
a gene associated with maleness in nematodes is very similar to maleness
genes in fruit flies and possibly humans. His work uncovered the first
examples of sex-determining genes whose structure has been conserved for
the 500 million years of evolution that have occurred since ancestors of
the three animal species split from each other.
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. The new discovery
changes this outlook.
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 determined that these
genes are all activated 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.
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.
Scientists have speculated about the mechanics of sex determination
since the Golden Age of Athens.
"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 research appears in the February 12, 1998 issue of Nature.
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