Researchers from Shanghai Jiao Tong University successfully bred mice with two genetic fathers capable of having offspring of their own. The embryos were created by fusing two sperm cells, effectively removing the maternal DNA contribution. This method marks the first time viable mice have been produced from two sperm cells.
The team, led by Yanchang Wei, identified seven DNA regions essential for correct genetic imprinting and normal embryo development. They used epigenome engineering to reprogram the sperm DNA, allowing an embryo to develop. By epigenetically modifying those regions with the CRISPR-Cas cutting and pasting technique, they allowed embryos to grow with only fathers.
This research circumvents the fundamental barrier to unisexual reproduction in mammals posed by genomic imprinting, a process where certain maternal or paternal genes are shut down during development. "Imprinting is probably the main barrier that hinders the development of embryos with two parents of the same sex," explained Wei and his colleagues, according to Scinexx.
The researchers combined two sperm cells into an egg cell with its nuclear material removed. A total of 259 fertilized egg cells were placed in the wombs of eighteen female mice. Only two male mice survived to adulthood. These mice were normal in size and appearance, grew to adulthood, and fathered their own offspring, demonstrating fertility. This is the first time mice with two fathers have been created and have successfully fathered offspring.
Previously, attempts to create mice with two fathers have been less successful due to genomic imprinting. In 2018, researchers succeeded in editing the imprinting pattern so that viable mice with two mothers were produced, supporting speculation that genomic imprinting is the fundamental barrier to the full-term development of uniparental mammalian embryos. However, the offspring of two fathers died before or immediately after birth.
The research enhances understanding of reproduction and imprinting in mammals through adjustment of the epigenetic imprinting pattern. Epigenetics is the study of changes that affect gene expression without altering the DNA sequence. Epigenetic modifications can affect how the body "reads" a DNA sequence, turning genes "on" and "off." The researchers modified CRISPR proteins to add or remove epigenetic markers called methyl groups instead of editing genes. When added at the right place on the DNA molecule, methyl groups can prevent proteins from binding to and "reading" the DNA. Once the epigenetic editing was complete, the embryos were transplanted into a female mouse.
Experts are cautious about the possibility of translating the research to humans. "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," said Christophe Galichet at the Sainsbury Wellcome Centre in the UK, according to IFLScience.
Bart Gadella, a researcher at the University of Utrecht's Veterinary Medicine department, provided insight into the study. "In earlier studies, it has already been possible to breed embryos and even adult mice from two haploid stem cells—stem cells with only one set of DNA," stated Gadella, according to NRC. He added, "The new aspect of the Chinese study is that DNA was used from sperm cells of two different male mice." "Making such androgenic mice is very inefficient," remarked Gadella. Sixteen females became pregnant, and three living male offspring were born from them, one of whom died quickly.
The scientific value of the achievement lies primarily in gathering knowledge, not in producing animals—or humans—with only fathers. "By gaining more insights into what happens in the epigenome, and being able to restore that with such 'epigenome editing', we may eventually develop treatments against certain forms of infertility," Gadella stated.
This achievement breaks the existing barrier in mammals against uniparental reproduction, as animals with only fathers do not exist in nature. The research was published on Monday in the scientific journal PNAS.
Some avian and reptile species can reproduce via parthenogenesis, a phenomenon where the egg cell is not fertilized but still develops into an embryo with two sets of chromosomes. However, this does not occur naturally in mammals due to genomic imprinting mechanisms that regulate gene expression from maternal and paternal chromosomes.
The creation of these mice could, in theory, have implications for humans, though this is still a long way off from becoming reality. "But be careful: actually, we are dealing with three-parent embryos here," cautioned Gadella. He added, "The mitochondria and the egg cell without a nucleus would still be from a mother. And there would also need to be a surrogate mother."
Written with the help of a news-analysis system.