A genome engineering system that exploits CRISPR-Cas9 technology has been used to bias the sex ratio of mouse offspring entirely toward females. Although the system should also work with other mammals, it is unlikely to bring about a feminist utopia. Rather, it is meant to bias sex production of livestock—cattle, swine, and chicken.

Other techniques, such as the sorting of sperm, have been used to bias sex selection, but they haven’t included any convenient genetic approaches, such as CRISPR-Cas9. Using this genome engineering technology, researchers based at Tel Aviv University (TAU) have found a way to produce maternal and paternal mouse lines that will, upon being crossed, bring together CRISPR-Cas9 system components to ensure that all male embryos are eliminated. That is, in male embryos—but not female embryos—all the system components needed to target vital genes are present.

The TAU scientists, led by Udi Qimron, PhD, professor, department of clinical microbiology and immunology, noted that their system could be reconfigured to bias sex populations toward males, which are usually preferred in the beef industry. The current configuration, however, should suit the dairy and layer-poultry industries, which usually prefer female calves and chicks.

“To date, there has been no accessible genetic way to regulate the sex ratio, which is naturally left around 50:50,” said Qimron. “We approached this problem in an innovative way, using genetic engineering.”

The new approach was detailed in an article (“A genetic system for biasing the sex ratio in mice”) that appeared July 1 in EMBO Reports. The article noted that both genetic and nongenetic approaches have been used to biasing the sex ratio of populations of different organisms, including plants, insects, crustacean, and fish. For mammals, however, genetic techniques hadn’t been demonstrated—until now.

The researchers crossed two types of genetically engineered mice. The maternal mouse encoded a Cas9 protein, a CRISPR-protein that is inactive unless programmed by guide RNAs. The paternal mouse encoded these guide-RNAs on the Y-sex chromosome, a sex chromosome present only in males. After fertilization, the guide-RNAs from the paternal sperm and the Cas9 protein from the maternal egg were combined in the male mouse embryos, but not in the female embryos (because the females lack the Y chromosome). The combination of guide-RNAs with Cas9 results in a complex that eliminates the male embryos.

The crossing of the engineered cell lines brings together the elements needed to target vital genes in male embryos. “We show that these genes are specifically targeted in males and that this breeding consequently self‐destructs solely males,” the authors indicated. “Our results pave the way for a genetic system that allows biased sex production of livestock.”

As currently configured, the system does not target vital genes in females because the Y chromosome is not transferred to them. Consequently, the embryonic development of females is not affected.

“When two transgenic types of mice encoding Cas9 or Y-chromosome-encoded guide-RNAs are crossed, lethality of males occurs because Cas9 is guided from the Y chromosome to target essential genes,”  Qimron explained. “This does not happen in females because the Y chromosome is not transferred to them. This cross thus halts embryonic development of males without affecting the development of females.”

Qimron asserted that his team’s research presents a first-of-its-kind approach to determining mammalian sex through genetic means. “We believe,” he added, “that the producers of cattle, swine, and chicken may benefit greatly from the technology.”

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