By Dean Haycock

Special To BioWorld Today

Flies, worms and humans may share more when it comes to sex than previously thought.

Sex has always generated questions. One that has interested biologists (in their professional capacities) is: Do animals share any common mechanisms for regulating sexual development?

For years studies of animals belonging to different phyla — the 15 major classifications within the animal kingdom — indicated no significant commonalties in the mechanisms that influenced sex differentiation. For lack of other evidence, scientists assumed the genetic controls were not related in different phyla.

But that was before a new study, "Evidence for evolutionary conservation of sex-determining genes," appeared in the Feb 12, 1998, issue of Nature. The new findings suggest the lowly worm and fruit fly may share some common regulatory mechanisms that control the sexual development of their young. The commonalty may even extend to humans.

The link from fly to worm to human begins with the well-studied fruit fly, Drosophila melanogaster. Its doublesex gene (dsx) was known to be a sex regulatory gene.

As described in the Nature paper, David Zarkower, an assistant professor in the department of biochemistry and a researcher at the Institute of Human Genetics at the University of Minnesota Medical School, and his co-authors isolated a male regulatory gene in the nematode roundworm, Caenorhabditis elegans. They found the worm gene, mab-3, is related to the fly sex regulatory gene, dsx. These genes are two of the many that take part in a cascade of gene activity that occurs during development.

The genes have several features in common, all of which point to their role as regulators of sexual differentiation. Both encode proteins with amino acid sequences that bind to DNA, a finding consistent with a protein that regulates gene expression. Both control the differentiation of sex-specific cells that develop into nerve cells in peripheral sense organs. And both prevent the expression of other genes that produce yolk proteins. (Males, of course, have no need to produce yolk since they don't produce eggs).

Fly Gene Worked In Worms

"Our finding that mab-3 and dsx are similar to each other would not ordinarily be particularly surprising because that is the basis of using model organisms to study development; you can expect you will find similarities. It is only surprising because it has been studied so well in several systems and no one has found similarities. People were forced to conclude that it must be different. The real surprise is that it conforms to the convention," Zarkower told BioWorld Today.

Zarkower and his colleagues have shown the protein produced by the dsx gene in male fruit flies can work in the roundworm. When the researchers insert the dsx gene into worms, which lack a functional mab-3 gene, they found the fly gene could direct male-specific differentiation of developing worm cells. Both dsx and mab-3 are similar types of "maleness" genes that regulate the development of bristly male sense organs.

These similarities among genes from animals of different phyla are enough to challenge the prevailing assumption that the mechanisms that determine sex differentiation are unique in animals as far apart as flies and worms.

To the authors, the similarities suggest different phyla may share a common evolutionary origin of some of the genes that regulate sexual development.

This suggestion is made even more interesting by the authors' observation that a human gene, specific to the testis, encodes a protein with a DNA-binding domain similar to that in the fly and worm genes.

Furthermore, the human gene, DMT1, is located on chromosome 9 in a region which has been implicated in a condition called XY-sex-reversal. One X and one Y chromosome normally produce a male, but if part of chromosome 9 is deleted, individuals will be infertile and feminized to varying degrees. This suggests that DMT1 may have a role in determining "maleness."

If the human gene indeed turns out to be homologous to the fly and worm gene, it could mean that a common evolutionary origin of certain sexual regulation processes extends to mammals. That makes it much more likely that an ancestor common to all three species passed on a similar sex-determining gene approximately 500 million years ago.

Similarities In Genes Could Be Coincidence

Zarkower and his co-authors were careful to acknowledge another possible explanation of their discovery. The three genes could all be the result of convergent evolution, that is, the result of nature solving the same problem independently three times in the same way.

"My personal bias is that it is divergent, not convergent, evolution. There are only a few genes known to exist that look like this. For two of them to be used to control the same part of the pathway and to be interchangeable seems like a huge coincidence to me. But you cannot exclude the possibility that this is the only gene that can perform this function," Zarkower said.

The case for DMT1 being a sex-determining gene is not yet as strong as it is for the worm and fly genes.

"We have nice circumstantial evidence that DMT1 is a sex-determining gene, but we don't have any proof," Zarkower said.

One way to prove DMT1 has a role in sex determination would be to find a mutation that is linked to the XY-sex reversal condition. This is seen in individuals who lack a portion of chromosome 9 that includes DMT1.

While acknowledging an unidentified gene located near DMT1 also could be responsible for the condition, Zarkower and his colleagues are now screening XY females with the hope of finding a mutated DMT1 gene.

Zarkower is optimistic about what identification of DMT1 as a human sex-regulating gene would allow scientists to do. Unlike a previously identified human sex regulating gene, SRY, the mab-3 and dsx genes — and maybe the DMT1 gene — seem to bind to very specific sequences of DNA.

This feature may make these genes much better candidates than SRY as keys for finding other genes in the pathway, according to Zarkower. *

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