Cas9-based tools enable the introduction of genetic lesions to investigate DNA repair outcomes and edit the genome at disease-relevant loci. DNA double-strand breaks (DSBs) induced by CRISPR/Cas9 result in frequent aneuploidy and large deletions, revealing a repair deficiency in early human embryos and limiting the clinical application of this technology. Here we evaluated the DNA repair outcomes of DNA nicks and mismatches introduced using base editors in human embryos at two targets, PCSK9 and HBG. Editing was efficient and, unlike Cas9-induced DSBs, did not result in either chromosomal abnormalities or large deletions. Small insertions or deletions after base editing were rare, and off-target activity was dependent on the guide RNA. Delivering the base editor as a protein at fertilization or at the pronuclear stage allowed normal development to the blastocyst stage and the derivation of edited stem cell lines. In stark contrast, introduction of the editor as RNA resulted in early embryo arrest. Our results demonstrated that, unlike DSBs, DNA nicks and mismatches are efficiently repaired in human embryos, allowing specific on-target changes without genotoxic consequences.
My overall thoughts: This type of study has been done in animals a lot (including primates) so it's not a surprise it works in humans too. Unlike He Jiankui's work, which was quite sloppy and rushed, this might actually be clinically useful.
It's always interesting to see East Africans doing so well. Even with technology like advances in shoes and diet/training, genetics is still a huge factor.
Also it must be an crazy feeling to be Kejelcha, the guy who came in 2nd place. It would have been a world record, except for Sawe!
This study covers about 10,000 years of recent human evolution in Europe and West Asia.
From the abstract:
>in the past ten millennia, we find that many hundreds of alleles have been affected by strong directional selection. We also document one-standard-deviation changes on the scale of modern variation in combinations of alleles that today predict complex traits. This includes decreases in predicted body fat and schizophrenia, and increases in measures of cognitive performance. These effects were measured in industrialized societies, and it remains unclear how these relate to phenotypes that were adaptive in the past. We estimate selection coefficients at 9.7 million variants, enabling study of how Darwinian forces couple to allelic effects and shape the genetic architecture of complex traits.
If they're going to all that effort to make allele-specific guides why not just cut out the centromere and eliminate the chromosome entirely? This seems like an overly complicated solution.
Interestingly, in "The Island" Dr. Merrick pitched investors on growing brainless clones, but actually kept the brains in, because it worked better (and gave him a labor supply).
I write https://denovo.substack.com/