Research into sexual embryonic development and the forms of offspring progeneration has long been a source of study to determine yet another facet to early formation of the embryo. Mammals are a bit special when it comes to the topic of genetic development of the egg cell. All of our animal cousins among the reptiles, amphibians, and beyond have examples of singular parthenogenetic reproduction when necessary and even gynogenesis where the male sperm is only needed for egg cell activation, but no male chromosomal DNA is required and is discarded. Therefore, scientists have been trying for decades to see if they could induce similar forms of development in a mammalian species.

Mammals and Reproduction

For example, experiments in the 80’s involving transplantation of nuclear material found that there are particular genetic barriers to this process in mammals. These so-called “imprinting regions” are unique for males and females and it is only through the combination of these zones that embryonic development is allowed to proceed. The fact that these parental-specific regions differ from each other in males and females meant that direct combination of two male or two female chromosomal genomes would not be enough, as the imprinting regions would overlap and conflict.

Experiments into such single parent duplications of genomes resulted in either lethality to the oocyte or severe developmental deformations upon birth. The imprinting regions were thereafter shown to be distributed rather widely across multiple chromosomes, making dealing with them even more complicated. Continued investigation has since found over 100 specific genes responsible for these parental imprinting controls. And it has been confirmed that it is this asymmetry between male and female imprinting regions in mammals that has created the lack of other forms of reproduction, as all of the genes acting in this manner would have to be removed through random mutations and deletions in order for any alternative reproductive mechanism to evolve.

It was in 2004 that a group of scientists were successfully able to produce mice born from two mothers’ genomes, after having genetically engineered the removal of the H19 imprinting region. The process was not perfect, however, and removal of this single region did not appear to solve the overall issue. Also, because they were using immature oocytes that resulted in the genomes becoming heterogenous and dissimilar, it was hard to figure out what overlapping components were causing the genetic barrier. So there was much more work to do and, until now, mammals from two fathers hasn’t even achieved that much, due to one of the male imprinting regions being completely critical for development if dealing with only paternal genomes.

Removing Developmental Barriers

Researchers from the Chinese Academy of Sciences decided to try and tackle this issue from a new angle. Rather than using traditional female oocytes and introducing an additional female genome, or duplicating the existing one in the oocyte, they would employ haploid embryonic stem cells (haESCs). This specialized form of stem cells has already been made producible in mice, monkeys, humans, and several other species.They feature hypomethylation characteristics similar to the activation of gene regions in actively developing embryonic cells.

Taking genetically modified haESCs that have had three major imprinting regions removed and also made to be capable of parthenogenesis, they were injected into oocytes at the haploid metaphase II stage of division. The ESC genomes combined with the genome of the egg cell from a different mother and produced healthy offspring with no defects or notable negative outcomes. Thus, they had managed to make perfectly normal mice with the combined half chromosomes of two mothers.

Interestingly, a transcriptome analysis showed that the working version of the imprinting regions from the egg cell genome were expressed normally and worked as they would if the combined genome had been from a paternal source. The outcome was comparable to the original wild type genomes, except for one region that stayed demethylated due to lacking the parental regions needed to silence it. The fertility of the created litter was also tested to the next generation, with no issues or complications.

One Step Forward, Half A Step Back

The developmental barriers involving two paternal genomes proved trickier. The reproductive barriers therein were more numerous and required the deletion of six imprinting regions. While live pups managed to be produced from this method, making this the first time ever in mammals that offspring with two parental parents were born, they retained a number of severe detrimental features and traits that caused them to expire not long after birth. So, while the scientists confirmed that the reproductive barriers for males can be crossed as well, there are still further gene effects that need to be accounted for and controlled before a true healthy pup can be created in this fashion.

Further research into these imprinting regions, along with the methylation features of ESCs and mammalian reproduction in general are required in order to better perfect the technology behind this single-sex development system. At the same time, it also gives greater insight into how mammals formed in the first place and basic genetic aspects that guide and control how they have evolved in the millenia since.

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Photo CCs: Mouse litter from Wikimedia Commons

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