Can two male mice raise healthy offspring? Chinese researchers break the barriers— know how

Scientists in China have successfully bred mice with two male parents that can survive to adulthood in a groundbreaking study published on January 28, 2025, in Cell Stem Cell. This achievement comes after a similar effort by Japanese researchers in 2023 who used a different approach to produce two-dad mice. But the Chinese team's work provides a unique window into the intricate world of "imprinting genes," genes whose activity depends on which parent they are inherited from.

The Chinese team approach starts with extracting DNA from an immature egg cell (oocyte) taken from a female mouse. Then sperm from a male mouse is inserted into the egg, and it starts creating embryonic stem cells that are specifically unique to the embryo. These stem cells, with sperm from the other male mouse, are put into another egg, which culminates into a fertilized egg. These embryos carry the DNA of two male mice in them.
Important to this approach was the change of 20 specific genetic markers that control imprinting gene expression. Imprinting genes in mammals are special because two copies of every gene are passed on to offspring from each parent, but one copy has to be silenced.
Normally, one of the two copies is functioning, and the other is silenced. Problems with this process lead to a wide range of developmental disorders, one of which is Angelman syndrome, caused by an imprinting problem in humans.

In breeding two-dad mice, efforts to avoid imprinting disorders were an initial problem since no maternal counterpart was available to balance the overactivated paternal copy. Most of these problems would account for the failure of previous attempts to produce a child with viable offspring from two male parents.
They found that even minute changes in genes failed to produce healthy offspring during earlier research. This study was an exception where 20 specific genetic tweaks resulted in the two-dad mice reaching maturity, which had been proven to be the strong barriers against their successful breeding.

The scientists made multiple attempts to solve the problem of imprinting. In an earlier attempt with only seven genetic changes, the resulting fetuses survived pregnancy but died after birth due to severe developmental abnormalities, such as umbilical hernias and enlarged organs. By introducing additional genetic modifications, the scientists were able to overcome many of these issues. With 18 genetic tweaks, the mice could survive to adulthood, although they faced difficulties in suckling after birth. The mice with 19 modifications had placental growth problems during pregnancy but were better after birth. The final modification, the 20th, corrected the placental problem and allowed the mice to survive.
Interestingly, the team found that imprinting challenges were harder to overcome in bipaternal mice than in bimaternal mice. Other researchers had successfully bred two-mother mice with fewer genetic modifications, indicating the complexity of imprinting in males.

Even though the new mice survived to adulthood, they were still not like other mice. They showed some deficits that included shorter lifespans and infertility. They were unlike other studies such as the Japanese study where fertile two-dad mice were produced. The Chinese mice remained infertile. The team still hopes to modify imprinting genes further to alleviate remaining health issues.
The research group, led by Zhi-kun Li of the Chinese Academy of Sciences, also plans to extend their study to other species. The hope is that by doing so, they will get a better insight into imprinting disorders in humans, which can lead to the development of gene-editing therapy.
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