There are several genetic diseases which originate not from mutations in the nuclear genome but mutations in the mitochondrial genome. In humans, the threshold for disease occurrence is if 60% of the mitochondria has mutated mitochondrial DNA (mtDNA) (a mixed mitochondrial origin is called heteroplasmy). There is currently no cure, and no good way to prevent these genetic diseases.
Since the source of the mitochondria is solely from the oocyte, a lot of effort is invested in trying to get rid of mutated mitochondria by in-vitro fertilization (IVF) procedures – thus preventing the disease in the offspring. Two methods have been tried so far – pronuclear transfer (PNT) and spindle-chromosome transfer (ST). The idea is to extract the nuclear genetic material of the oocyte or zygote and transfer it to an enucleated oocyte or zygote with healthy mitochondria. However, in both cases, there is still carry-over of some mutated mitochondria to levels that can be as high as 44%.
In this new paper published in Cell, a group of researchers from China suggest a different approach. During the oocyte, and later zygote development, a unique germ cell that is extruded. These are called polar body 1 (PB1), a diploid germ cell, which is extruded from the oocyte before ovulation and PB2, a haploid germ cell, which is extruded from the zygote after fertilization. The authors reasoned that the nuclear genetic material in PB1 and PB2 is identical to the spindle chromosome and female pronuclear, respectively. But, PB1 and PB2 are very small cells and therefore may contain very few mitochondria.
Indeed, staining with MitoTracker (a dye specific for mitochondria) shows only a small amount of mitochondria in PB1 and PB2. So, after several tested to see if the PB1 and PB2 has characteristics similar to the corresponding oocyte/zygote nuclei (using immunofluorescence against specific nuclear and epigenetic markers) they compared the four different methods (PNT, ST and PB1 or PB2 transfer) to prevent mitochondrial transfer in IVF.
Their results are pretty amazing.
All methods have similar success rates of the IVF procedure and give similar number of offspring, with normal development. However, PNT still maintains high levels of heteroplasmy (20-60% in 2nd generation (F2) mice). ST maintains moderate-low heteroplasmy (5-20% in F2). PB2T has even lower heteroplasmy rates (<5% in F2). But PB1T has no heteroplasmy (at least, below the detection level).
This work, done in mice, is a real breakthrough , because if this also works in humans then we can have genetic screens for heteroplasmy and women with high levels of heteroplasmy (or already suffering from an inherited mitochondrial disease) could use PB1T-IVF to give birth to healthy children.
Wang, T., Sha, H., Ji, D., Zhang, H., Chen, D., Cao, Y., & Zhu, J. (2014). Polar Body Genome Transfer for Preventing the Transmission of Inherited Mitochondrial Diseases Cell, 157 (7), 1591-1604 DOI: 10.1016/j.cell.2014.04.042