Sex can be complex. The results can be predictable and reassuring orunexpected and puzzling. And that is just at the level of thechromosome. Textbooks tell us that two X chromosomes make afemale and an X and a Y make a male. But close the book and go intothe lab and it becomes more complex. It is, after all, sex.

There are individuals with XY chromosomes who develop ovariantissue, a distinctly female trait. And there are individuals with XXchromosomes who develop testicular tissue, a distinctly male trait.These individuals are rare but they prove there is more to sexdetermination than simply drawing different combination of Xs andYs when the chromosomal hand is dealt at the time of conception.

These gender-confusing finds long ago made geneticists think theremust be other sex-determination genes on autosomes chromosomesother than the traditional X and Y "sex" chromosomes. Now, EvaEicher, a developmental geneticist at the Jackson Laboratory, in BarHarbor, Maine, and her colleagues report that two and very possiblythree genes on mice autosomes appear to affect gonadal sexdetermination. Their report, "Sex-determining genes on mouseautosomes identified by linkage analysis of C57BL/6J-YPOS sexreversal" appears in this month's issue of Nature Genetics.

"It started out as an accidental discovery," Eicher said. It was 1982when Eicher and her colleague Linda Washburn noticed that therewere a lot more females than chance would predict in two strains ofmice they were studying. Closer examination revealed that thefemales were not XX females but XY females.

And the "males" turned out to have both ovarian and testicular tissue;they were hermaphrodites. Investigation showed that the Ychromosome was not the cause of the sex reversal, however. Noindication of a mutation showed up when it was placed in otherstrains mice. XY individuals in these mice were all normal males.The sex reversal, which included the development of ovarian tissue inXY individuals, only happened when the Y chromosome was placedin a strain of mice known as Black 6. Furthermore, when Ychromosomes obtained from wild European mice were placed inBlack 6 mice, XY females and hermaphrodites dominated the litters.

In these mice, it is appears that every XY individual forms someovarian tissue and some go all the way to form only ovarian tissue.

"The project has been a difficult one. But we finally made abreakthrough," Eicher told BioWorld Today.

At this point, the researchers looked at the gene known as Sry locatedon the Y chromosome. Identified in 1990 by British researchers, Sry(for Sex determining Region, Y chromosome) is responsible fordirecting the fetal gonad to develop into testis. "We have got two Srygenes that appear to be identical. One causes sex reversals, one doesnot. That has led now to our feeling, and we kind of felt it all along,that it was a regulatory problem," Eicher said.

The problem may be in getting Sry turned on in time. "If you put thetestis gene [Sry] on the Y chromosome in an individual that is goingto be male," Eicher explained, "then you want to make sure it comeson before the ovarian determining genes come on. In a female, youmake the thing work right by just not having the testis determininggene there."

Eicher said it is possible that the Black 6 genes responsible forturning Sry on at the right time can not do their jobs, perhaps becauseof a feature in the Sry gene. Or it may be that a regulatory substanceis not produced in sufficient amounts. Alternatively "it could be thatthe ovarian determining genes are coming on when they shouldn't becoming on," Eicher added.

Eicher's colleague, Barbara Lee, found that another gene involved inthe sex reversal appeared to be on mouse chromosome 4. Workingwith David Page, of the Whitehead Institute, in Cambridge, Mass.,Eicher's group searched for still more such genes. Genetic mappingexperiments revealed another sex-influencing gene on chromosome2. They also found a suggestion that a third gene might be located onchromosome 5. The researchers called these genes tda genes, forTestis Determining Autosomal genes,"

"This is the first instance of tracking down autosomal sex-determining genes in the mouse using linkage analysis," said ColinBishop, professor of obstetrics-gynecology and molecular and humangenetics at the Baylor College of Medicine. Candidate genes havebeen identified in humans but they have not been identified byscanning the genome the way this work was, according to Bishop.

"The problem in humans is you don't have big families [whichexhibit sex reversal]," Bishop said. He described the mouse strainEicher and her colleagues studies as "a very powerful model."

Furthermore, Bishop noted, because mice and humans are mammalswho share a distant evolutionary history, locating a gene on a mousechromosome can point the way to where its analogue might reside ona human chromosome, To find out exactly how tda genes influencethe development of sex organs, it will, of course, be necessary toclone them, something Eicher's group intends to do.

The geneticists have a way to go. As with human diseases, you mayknow a gene is on a particular chromosome in a particular region, butyou have to zero in on it before you can copy it.

"From studying such systems," Eicher said, "we learn a lot about hownormal things happen." n

-- Dean A. Haycock Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.