Adult male mice that have two fathers and continued to have their own offspring
Yanchang Wei
For the first time, the mice of two fathers continued to have their own offspring – marking an important step towards the permit to allow two men to have children to whom they are both genetically linked. However, there is still a long way to go before it can be tempted among people.
Yanchang Wei at the University of Shanghai Jiao Tong in China achieved the feat by bringing together two sperm in an egg whose nucleus had been removed. The team then used a method called epigenome edition to reprogram seven sites in sperm DNA, which was necessary to allow the embryo to develop.
Of the 259 of these embryos which were transferred to female mice, only two descendants – the two men – survived and grew up in adulthood, which makes the success rate very low. The two then generated offspring – which seemed normal in terms of size, weight and appearance – after mating with women.
The creation of mice with two fathers has proven to be much more difficult than creating mice with two mothers. The birth of the first fertile mouse with two mothers, Kaguya, was reported in 2004.
Kaguya had to be genetically modified, but in 2022, Wei and his colleagues were able to create similar father mice using only the epigenome edition, which does not change the DNA sequence. This same method was used to make mice without mother.
The reason why it is such an important feat to create mammals with two fathers or two mothers is due to a phenomenon called imprint, which is linked to the fact that most animals have two chromosomes, one inherited from the mother and one of the father.
During the formation of eggs and sperm, chemical labels are added to these chromosomes which program certain genes to be active and others to be inactive. These changes are called “epigenetics” because they do not change the underlying DNA sequence, but labels can always be transmitted when cells divide, which means that their effects can last a lifetime.
Above all, epigenetic programming in mothers is different from that of fathers, with certain genes which are labeled as “on” in the sperm labeled as “off” in the eggs, and vice versa.
This means that if an egg has two sets of maternal chromosomes, or two sets of panerteaux, it cannot develop normally. A gene that must be active in a pair chromosome can be deactivated in both, or both copies of a gene can be active when only one should be, causing a “overdose” of this gene.
In the case of Kaguya, the researchers went around this by removing part of a gene to make global genetic activity more normal. But the creation of mice with two fathers requires many other changes.
Earlier this year, a separate team in China obtained some mice with two fathers to grow up in adulthood after making 20 genetic modifications to normalize their gene activity, but these mice were not entirely healthy or fertile.
Although the correction of gene activity via genetic modification is useful for studying printing in laboratory animals, it would be unacceptable in people, especially because the effects of genetic changes are not fully understood.
For their epigenetic approach, Wei and his team used modified forms of CRISPR proteins which are generally used for genes. Like standard CRISPR proteins, they can be made to search for specific sites on genomes. But when these sequences are found, modified proteins add or eliminate epigenetic labels rather than modifying DNA.
The study is a step as a major front, explains Helen O’Neill at the University College in London. “This confirms that the genomic imprint is the main barrier for uniparental reproduction in mammals and shows that it can be overcome.”
Because this does not imply genetic modification, the epigenome editing approach could, in principle, be used to allow same -sex couples to have their own genetic children. However, the success rate should be much higher before the technique can be considered for use in people. “Although this research on the generation of the offspring of parents of the same sex is promising, it is unthinkable to translate it into humans due to the large number of eggs required, the high number of substitution women needed and the low success rate,” explains Christophe Galichet to Sainsbury Wellcome Center in the United Kingdom.
There are several reasons why the success rate was so low. To start, the combination of two sperm means that a quarter of the embryos had two chromosomes and would not have developed far. In addition, the epigenome edition only worked on the seven sites in a small proportion of embryos, and it could have had the target effects in certain cases.
The success rate and animal health could probably be improved by modifying more than seven sites, but this would probably not be translated to use it in people because the sites that must be modified are probably different from those of the mouse.
If human babies with two fathers were created in this way, they would technically be babies to three parents because the mitochondria of their cells, which contain a tiny amount of DNA, would come from the egg donor.
In 2023, a team in Japan announced the birth of mouse puppies with two fathers using a third technique that involves transforming stem cells from eggs. However, it is not clear if puppies have survived adulthood, and so far, no one has managed to transform human stem cells into eggs.
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