Genome editing in zygotes or early embryos can lead to a condition called "mosaicism," where not all cells have the intended genomic edits. This poses a significant challenge for germline genome editing since screening embryos for mosaicism through Preimplantation Genetic Diagnosis (PGD) may not accurately reflect the overall genotype, and testing could destroy the embryo. The impact of mosaicism varies depending on the targeted gene; it is critical for genes essential for cellular functions but may be less problematic for those involved in producing secreted factors, as partial correction might still suffice. Furthermore, if the edited child has a mosaic germline, it may not resolve issues for future generations. Nevertheless, this complexity could facilitate the selection of disease-free embryos or the cultivation of edited stem cells, potentially leading to unaffected descendants. Overall, while mosaicism presents a major barrier to the clinical use of germline genome editing, advancements in the field may help overcome this challenge in the future.
summarise:
If genome editing were performed in a zygote (fertilized egg) or an early embryo, there
would be a significant chance that some of the cells in the resulting early embryo would not have
the desired (or even any) edits. This situation is called “mosaicism” and it presents a significant
challenge to the application of germline genome editing on zygotes or embryos. Screening of an
edited embryo by PGD to test for mosaicism would not ensure correct editing of the implanted
embryo because a single cell may not reflect the genotype of the other cells of the embryo, and
removal of multiple cells for testing would destroy the embryo.
The impact of mosaicism depends to some extent on the gene being targeted. Mosaicism is a
serious problem if the gene of interest encodes a required cellular function, but if the gene
encodes a secreted factor (e.g., growth hormone or erythropoietin), or leads to the secretion of a
required molecule (such as a blood clotting factor), then correcting the gene in only a subset of
cells may be sufficient. Furthermore, because the germline in the resulting child may also be
mosaic, editing only a subset of cells may not solve the problem for succeeding generations. But
it may offer a better chance of finding a disease-free embryo after PGD, or allow culture and
selection of edited spermatogonial stem cells (see section on potential alternative routes to
heritable edits, below), thereby enabling those children to have unaffected offspring. Overall, at
present, the issue of mosaicism would present a serious impediment to the clinical application of
human germline genome editing in zygotes or early embryos, although recent progress suggests
that this impediment may eventually become surmountable (Hashimoto et al., 2016).
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