The mouse was born (and survived) from an unfertilized egg

She gave birth to a child herself… or almost. A baby mouse born from an oocyte not fertilized by male gametes managed to survive to adulthood and reproduce. This phenomenon, called parthenogenesis, a uniparental mode of reproduction common in some plants or reptiles, is usually not possible in mammals. But researchers at the University of Shanghai in China managed to dispense with the male gamete to create this mouse through genetic modification. The results are published in the journal PNAS.

Sexual reproduction in animals typically involves male and female gametes, each containing genetic material unique to the other. The embryo then receives two copies of each gene. To avoid conflict between two versions of the same gene, some of them are deactivated on the paternal or maternal side: only one of the two genes will be expressed. This genetic process is called parental imprinting.

Use of CRISPR-Cas9 for genome manipulation

The problem with trying to develop an embryo from an unfertilized egg is that it will have two sets of DNA from its mother, and therefore two sets of genes with the same fingerprint pattern. This means that the same fingerprint is present twice: certain genes then come into conflict or are not activated together. To get around this problem, the Shanghai team started by creating mouse oocytes with twice as many chromosomes as usual. They then modified the genome with CRISPR-Cas9, a tool capable of interfering at the gene level. Behind “edit“In these genetic areas, the researchers used the mechanism of DNA methylation, a process that acts as a template at the cellular level and determines whether a gene is expressed or not.

Thereby”pair of genetic scissors“They were able to interfere with seven regions that could control imprinting, and thus make the target regions, even if they come from maternal DNA, look like paternal genetic material.”The idea here is to transform the epigenome of one of the nuclei to look more like a male imprint and the second nucleus to look more like a maternal imprint. Imprinting occurs only in the germline, in growing sperm and eggs.“, emphasizes Professor Azim Surani, a biologist at the University of Cambridge in Science and the future. Then all the genes necessary for the development of the embryo can be expressed.

227 unfertilized eggs per 3 puppies born

To achieve the birth of a viable mouse, the team modified 227 unfertilized eggs. Then they received 192 embryos, of which only 14 continued their development to term. Only three puppies were born, one of which survived to adulthood. The three puppies that were able to be born weighed less than the classic puppies and contained genetic abnormalities. “Parthenogenetic embryos created from a single oocyte, as in this case, may contain recessive mutant genes that do not affect the development of normal fertilized eggs. But when creating such parthenogenetic embryos from a single egg, such homozygous mutations will affect viability and development. There may also be erroneous editing of the epigenome by CRISPR-Cas9 tools.“Either the gene editing didn’t work the way the scientists wanted, or the areas of imprinting they touched still have features that are still unknown.”Advances continue in epigenome editing, which involves altering epigenetic marks, such as removing a DNA methylation mark to induce expression of a silent gene. The method works quite effectively, but not in 100% of cases..”

In 2020, Professor Tony Perry discovered 71 new imprinted genes in mouse embryos, real barriers to parthenogenesis. In 2019, researchers succeeded in developing mouse embryos without oocytes or male gametes, using only stem cells transformed into embryos. In 2004, another team used two mouse eggs at different developmental stages and targeted specific areas of imprinting, which also led to the development and then birth of the mouse. However, this is not considered true parthenogenesis in the sense that the embryo originated from two cells joined together, not just from one.

This new method was not designed to develop new ways of reproduction. On the other hand, more knowledge about the parental imprint and the genes involved in this process allows us to better understand certain diseases such as Beckwith-Wiedemann syndrome (characterized by excessive growth, a predisposition to tumors, and congenital malformations) or Prader-Willi syndrome (characterized by lack of muscle tone, difficulty eating and early obesity). It will also provide a better understanding of some of the very early developmental mechanisms of the embryo, as well as how the two parental genomes are regulated. Contacted Science and the futurethe research team did not respond to our inquiries.

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