The Mouse with Two Dads Welcomes Its First Offspring

For the first time, male mice with two fathers have successfully produced offspring. This significant advancement paves the way for the possibility of two men having a genetically related child, although there are still numerous obstacles to overcome before this could be realized in people.

Yang Chang Wei in Shanghai, China, achieved this by merging two sperm cells with eggs stripped of their nucleus. The research team also reprogrammed seven areas of sperm DNA through a process called epigenome editing to facilitate embryo development.

Out of 259 embryos transferred to female mice, only two male offspring survived and grew, highlighting the low success rates. After mating with a female, both offspring were found to be descendants of the father, exhibiting normal size, weight, and appearance.

Generating a mouse with two fathers has proven far more challenging than producing one with two mothers. The initial report of a viable mouse with two mothers, named Kaguya, surfaced in 2004.

While Kaguya was genetically modified, Wei and his team successfully created similar paternalless mice in 2022 utilizing only epigenome editing without altering DNA sequences. This method was also instrumental in developing motherless mice.

The birth of mammals with two fathers or mothers is notably significant due to the concept of imprinting, which occurs as most animals possess two sets of chromosomes.

During the formation of eggs and sperm, chemical markers are applied to these chromosomes, activating certain genes while deactivating others. These alterations are termed “epigenetic” because they do not modify the actual DNA sequence, yet they can influence gene expression during cell division.

Crucially, the epigenetic programming of mothers differs from that of fathers; genes marked “active” in sperm may be marked “inactive” in eggs, and vice versa.

This discrepancy means that if an egg contains two sets of paternal chromosomes or maternal chromosomes, it will struggle to develop correctly. A gene that should be turned on in one chromosome could become overactive if only one copy of both is present or if both copies are included.

In Kaguya’s scenario, researchers managed this issue by removing some genes, normalizing overall gene activity. However, creating a mouse with two fathers necessitates additional alterations.

Earlier this year, a different team from China managed to produce mice with two fathers after implementing 20 genetic modifications to standardize gene activity, but these mice exhibited neither full health nor fertility.

Although modifying gene activity through genetic alterations aids in researching imprinting in laboratory animals, it remains unpalatable for human application, especially considering the unknown implications of genetic modifications.

For their epigenetic approach, Wei and his team employed modified versions of the CRISPR protein, typically utilized for gene editing. These modified proteins, like standard CRISPR versions, are designed to locate specific sites in the genome. When these sites are identified, the modified proteins can add or remove epigenetic labels without altering the DNA itself.

This research marks a significant breakthrough. Helen O’Neill, University College London, stated, “We confirm that genome imprinting is the primary barrier to mammalian reproduction overnight and demonstrate that it can be surpassed.”

Since this technique does not involve direct genetic modification, it may, in theory, allow same-sex couples to have genetically related children. However, a considerably higher success rate is necessary before such a method can be deemed acceptable for human use. “While this study on producing offspring from same-sex parents is encouraging, it is unlikely to translate to humans due to the vast number of eggs required, the large pool of surrogate women necessary, and the low success rate,” explained Christoph Galichet from the Sainsbury Welcome Centre in the UK.

The low success rate can be attributed to various factors. Firstly, merging the two sperm cells resulted in some embryos containing two Y chromosomes, leading to underdevelopment. Additionally, for effective epigenome editing, all seven targeted sites in the embryo must be successfully modified, and there might have been off-target effects in some instances.

It’s plausible that animal success rates and health could be enhanced by modifying more than seven sites; however, these modifications likely wouldn’t be applicable to human use, considering the differing sites that require changes in humans compared to mice.

If a human baby were to be conceived using this method, the mitochondria within the cell—containing a small amount of DNA—would originate from the egg donor, essentially making it three contributing genetic sources.

In 2023, a Japanese team reported the birth of a mouse puppy with two fathers through a distinct method involving the conversion of mouse stem cells into eggs. However, it remains uncertain whether the puppies thrived into adulthood, and no successful attempts have yet been made to transform human stem cells into eggs.