* Lots can go wrong during meiosis; many gametes have severe genetic abnormalities (e.g. aneuploidy). Due to these abnormalities, upwards of 20% of conceptions result in spontaneous abortion (often before the mother even knows she’s pregnant).
* Normal stem cell lines already have a proclivity to undergo cancer-like selection when being cultured, acquiring growth-enhancing mutations.
* Haploid cell lines are genetically unstable and have a proclivity to revert back to a diploid state (or quickly acquire chromosomal abnormalities in the process of trying to revert to a diploid state).
* Haploid cell lines that manage to remain haploid can select for cancerous mutations much more quickly than their diploid counterparts.
This doesn’t even touch on issues with polygenic scores, or that optimizing for a genome with the most alleles contributing to a PGS for a given trait has no guarantee of actually maximizing that trait, since many alleles are epistatic—their effects are dependent on the presence or absence of a specific set of other alleles, which is not captured by the simple linear mixed models used to compute a PGS. Analogously, throwing together all the most commonly used spices across all 3 Michelin star restaurants would result in a horrible dish, even though each spice on its own would contribute highly to a “polyspice dish score.”
Even if we had some magic way of solving all the aforementioned problems, we still have no way of knowing that optimizing for a certain set of alleles that definitively results in some desirable traits would not also inadvertently result in some other horrible traits, which we would have no way of knowing from population statistics because they’ve been selected out of the population.
I really like the food analogy here. This is a perfect explanation for why embryo selection using this method would absolutely fail. Polygenic scores are touted as this magic bullet for understanding the contribution of genetics to a phenotype but are utterly imperfect models for what actually occurs due to pleiotropy and epigenetics (among other things). In my opinion the best way for embryo selection is to just have a lot of offspring. Let natural selection do it's job. It gave us us after all.
> Polygenic scores are touted as this magic bullet for understanding the contribution of genetics to a phenotype but are utterly imperfect models for what actually occurs due to pleiotropy and epigenetics
Agreed! To be a bit more charitable to polygenic scores, they can be mediocre descriptive models—given a real individual’s genotype, they can sometimes decently predict their phenotype (if you consider explaining ~10% of phenotypic variance “decent”).
They are unequivocally horrible generative models—you will not obtain a synthetic genotype that would result in a desired phenotype by sampling from a PGS model, i.e. by randomly maximizing the number of high-scoring PGS alleles in a synthetic genome, as proposed by the article.
I like the contrast between descriptive vs generative here. Really puts this into context. If you want to understand the contribution of any particular allele PGS is reasonable. But using PGS to generate a phenotype violates so many assumptions.
Author here (sorry for the late response, I didn't see this got posted to HN).
These are all valid concerns (especially about spontaneous diploidization), but I think they can be overcome with sufficiently rigorous quality control (probably whole genome sequencing, not just genotyping).
The issues with epistasis (i.e. will polygenic scores continue to be valid at extreme values) are also worth noting. I think that improved models (besides the linear ones in current use) are likely to solve this though.
* Lots can go wrong during meiosis; many gametes have severe genetic abnormalities (e.g. aneuploidy). Due to these abnormalities, upwards of 20% of conceptions result in spontaneous abortion (often before the mother even knows she’s pregnant).
* Normal stem cell lines already have a proclivity to undergo cancer-like selection when being cultured, acquiring growth-enhancing mutations.
* Haploid cell lines are genetically unstable and have a proclivity to revert back to a diploid state (or quickly acquire chromosomal abnormalities in the process of trying to revert to a diploid state).
* Haploid cell lines that manage to remain haploid can select for cancerous mutations much more quickly than their diploid counterparts.
This doesn’t even touch on issues with polygenic scores, or that optimizing for a genome with the most alleles contributing to a PGS for a given trait has no guarantee of actually maximizing that trait, since many alleles are epistatic—their effects are dependent on the presence or absence of a specific set of other alleles, which is not captured by the simple linear mixed models used to compute a PGS. Analogously, throwing together all the most commonly used spices across all 3 Michelin star restaurants would result in a horrible dish, even though each spice on its own would contribute highly to a “polyspice dish score.”
Even if we had some magic way of solving all the aforementioned problems, we still have no way of knowing that optimizing for a certain set of alleles that definitively results in some desirable traits would not also inadvertently result in some other horrible traits, which we would have no way of knowing from population statistics because they’ve been selected out of the population.