Fertile mice created from two fathers, via epigenome editing

Mice born from two fathers have, for the first time, fathered viable, fertile offspring.

Researchers from Shanghai, China have created fertile mice known as 'androgenetic mice' using genetic material from the sperm of two male mice. Previous attempts have produced unviable or infertile offspring, due to a phenomenon called genetic imprinting, where parts of the genome carry epigenetic marks denoting whether the copy from the mother or the father should be expressed. To create either female-parent-only or male-parent-only offspring, these imprinted regions must be deleted or modified.

'Our findings, together with previous achievements of uniparental reproduction in mammals, support previous speculation that genomic imprinting is the fundamental barrier to the full-term development of uniparental mammalian embryos,' said the researchers from Shanghai Jiao Tong University led by Dr Yanchang Wei in their paper published in the journal PNAS.

The team used targeted CRISPR/Cas9 editing of DNA methylation sites in specific regions known as imprinting control regions (ICRs) in sperm cell DNA.

Japanese researchers previously found an alternate way to remove methylation in ICR, successfully creating mice from two egg cells in 2004 (see BioNews 255). However, it has proved more difficult to achieve using genetic material from two males (see BioNews 971).

The Shanghai team aimed at modifying the epigenome of the ICRs rather than trying to delete the genes themselves. The imprinted regions have DNA methylation patterns that can be reprogrammed using enzymes. They then replaced the genome of an egg cell with the modified sperm DNA, and used sperm from a different male to fertilise the egg. The generated blastocysts were then transferred into a female mouse to gestate.

Altering imprinting in humans has several potential applications. First, there are rare congenital conditions such as Angelman syndrome and Prader-Willi syndrome, both of which occur when a person inherits both copies of chromosome 15 (or a specific part of it) from one parent. Understanding how to alter imprinting may lead to new types of treatment for affected people.

Second, there is the possibility that in future, same-sex couples could have a child who is genetically related to both parents, rather than needing a genetic contribution from a donor. However, this is unlikely to happen soon, as the success rate in mice was very low, due to the difficulty in modifying seven ICRs at once. Out of the 259 blastocysts generated, the researchers obtained three viable offspring, but only two survived until adulthood.

'While this research on generating offspring from same-sex parents is promising, it is unthinkable to translate it to humans due to the large number of eggs required, the high number of surrogate women needed and the low success rate,' Dr Christophe Galichet from the Sainsbury Wellcome Centre in London, who was not involved in the research, told New Scientist.