Having the birds and bees talk can be a little awkward for some parents, but at least the rules were straight forward. Well one of those basic rules—that you need a sperm and an egg to make an embryo—just isn’t true anymore. A seminal discovery in mammalian genetics was that fertilization in mice required maternal and paternal genomes, and that these genomes must have genetic asymmetries. These asymmetries were later discovered to be imprinted genes, genes that are epigenetically silence in a parent-of-origin specific manner. One theory to explain imprinted genes is genetic conflict theory which proposes that paternally inherited imprinted genes extract nutrients from the mother to maximize fetal growth while maternally inherited genes counteract the effect of paternal genes to optimize fetal growth and maternal health. These differences underly the uniparental reproduction barriers in mammals. Several researchers have perturbed this system to better understand it.
A new study from the lab of Qi Zhou at the Chinese Academy of Sciences sought to identify and overcome the barriers to same-sex reproduction in mice. Previously, this group generated bi-maternal mice by injecting haploid embryonic stem cells (hESCs) with deletions of the H19 and Dlk-Dio3 imprinted regions into oocytes. They used hESCs as they can be genetically manipulated and maintained in their haploid state in culture before being used to generate embryos. Using this culture method, they were able to use CRISPR-Cas9 to test the effect of removing several imprinted regions.
Here’s what they found:
- Reduced representation bisulfite sequencing (RRBS) revealed that haploid ESCs show global hypomethylation as well as demethylation dynamics similar to natural gametes
- Using CRISPR-Cas9, they deleted three imprinted regions (H19, IG, and Rasgrf1) from hESCs and generated normally growing bimaternal mice that are able to reproduce
- Since fusion of two male pronuecli is known to result in failed embryo growth much earlier than female-female fusions, they deleted more imprinted regions this time around
- The authors first deleted 6 imprinted regions known to be important in embryonic lethality but the embryos could not develop beyond E8.5
- The Gnas imprinted region is hypomethyled in these KO mice
- Deletion of Gnas exon 1 plus the other 6 regions results in pups that survive to just after birth
The seemingly obvious takeaway from this work is the notion that same-sex parentage may be possible in humans. However, commentary co-released with this paper in nature points out that this is unlikely; hundreds of embryos needed to be implanted to get the small number of full-term pups that were achieved. Also, human and mouse imprinting and development have key differences, and these approaches may not work in humans. The more important take-away from this study is a dramatic illustration of the barriers to same-sex reproduction in mammals. It shows just how important imprinting is to sexual reproduction and may give researchers some important targets for future work. So, when it comes to explaining the birds and the bees, if you want to keep it simple maybe leave out the mice.
Check out the full story in Nature, October 2018