Saturday, May 21, 2016

No Y genes? No problem, bro.

The Y-chromosome is one of the smallest chromosomes in the human genome and contains genes involved in male development and production of sperm. Previous research has shown that just two genes on the Y chromosome are necessary to make male mice who can sort of produce sperm. By “sort of” I mean that the mice make things called “round spermatids”, which genetically are the same as sperm, but are underdeveloped, so they can’t naturally fertilize an egg. A lab in Hawaii took these round spermatids and injected them into oocytes to demonstrate that the resulting zygotes are viable and develop into normal mice. In other words, the experimental mice have only one X chromosome and the two Y genes, and they develop into males who can reproduce with a little help from scientists.  That is pretty amazing that only two genes can make a male.

The necessary Y genes
So what are these two genes? One of them is called Sry, which encodes for a transcription factor that regulates expression of other genes important for the development of the male reproductive system (see the figure below). The other necessary gene is Eif2s3y, which is involved in protein synthesis and somehow necessary for the production of sperm. There is a similar gene on the X-chromosome, which may serve the same function. Normal XY males express both Eif2s3y and Eif2s3x, the version on the X-chromosome.

In a paper that came out earlier this year in Science, Yamauchi et al. asked whether they could replace the function of Sry and Eif2s3y with other genes that are found on other chromosomes. Instead of a male mouse with Eif2s3y, what if you made a mouse that was overexpressing Eif2s3x?  Could the X version compensate for the Y version? And instead of Sry, could you overexpress one of its target genes to replace its function?

Through the power of mouse genetics, the researchers created a mouse line with one X-chromosome and no Y-chromosome, which overexpressed Eif2s3x and Sox9, one of the Sry targets. In other words, these mice do not have any genes that are normally found on the Y-chromosome.

A male mouse with no Y
The mice with no Y-chromosomes and no Y genes, but overexpression of Sox9, developed into males, with male reproductive systems (though smaller and less developed). When Eif2s3x was overexpressed along with Sox9, the males were able to produce the round spermatids (precursors for sperm). The researchers did their artificial fertilization with these round spermatids and were able to produce healthy offspring. 


So just to repeat: the mice without a single gene from the Y-chromosome developed into males and produced sperm that are good enough for successful in vitro fertilization. Just by overexpressing two genes found on other chromosomes. That’s amazing!

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