Excellent! Thank you for researching and writing up this article.
A few notes, from my discussion with Morpheus:
A single UPD has 1/23rd incorrect imprinting, so to speak. It’s plausible that a fairly benign UPD has some small effect that’s barely noticeable—but then if you have a zygote with many incorrect imprints, say 1⁄2 or 1⁄4 incorrect imprinting, that these effects would add up a lot and be quite detrimental, producing an epigenomic near-miss.
Indeed, we might sort of suspect this by default. On the model that says “Paternal/Maternal imprints make you grow More/Less”, having lots of missing imprints could make you grow way too much or way too little, whereas a few imprints might have only a small overall effect on growth.
It’s kinda curious that there’s these large effects from single regions being misimprinted. Is it the case that the large effects are always caused by the version of imprinting that makes there be zero or near zero expression? This would make some sense; you’re basically deleting a gene. But if not, what’s going on with the large deleterious effects? (It’s not crazy to think that ~2x overexpression would have deleterious effects; e.g. maybe that’s what’s happening with some/many trisomy disorders.)
It would be nice to understand weaker deleterious effects from less-bad UPDs. But since there are very few UPD cases, they might be hard to detect.
One approach could be analogous to the situation with the worst UPD disorders. There we can compare with genetic mutations that knockout (or upregulate) the gene in a way that corresponds to the UPD disorder. We could do the same by looking at people with genetic mutations in other regions believed to be sex-linked imprinting regions. There should be much larger cohorts of such cases compared to UPD cases. So we could maybe detect subtler health problems.
Excellent! Thank you for researching and writing up this article.
A few notes, from my discussion with Morpheus:
A single UPD has 1/23rd incorrect imprinting, so to speak. It’s plausible that a fairly benign UPD has some small effect that’s barely noticeable—but then if you have a zygote with many incorrect imprints, say 1⁄2 or 1⁄4 incorrect imprinting, that these effects would add up a lot and be quite detrimental, producing an epigenomic near-miss.
Indeed, we might sort of suspect this by default. On the model that says “Paternal/Maternal imprints make you grow More/Less”, having lots of missing imprints could make you grow way too much or way too little, whereas a few imprints might have only a small overall effect on growth.
It’s kinda curious that there’s these large effects from single regions being misimprinted. Is it the case that the large effects are always caused by the version of imprinting that makes there be zero or near zero expression? This would make some sense; you’re basically deleting a gene. But if not, what’s going on with the large deleterious effects? (It’s not crazy to think that ~2x overexpression would have deleterious effects; e.g. maybe that’s what’s happening with some/many trisomy disorders.)
It would be nice to understand weaker deleterious effects from less-bad UPDs. But since there are very few UPD cases, they might be hard to detect.
One approach could be analogous to the situation with the worst UPD disorders. There we can compare with genetic mutations that knockout (or upregulate) the gene in a way that corresponds to the UPD disorder. We could do the same by looking at people with genetic mutations in other regions believed to be sex-linked imprinting regions. There should be much larger cohorts of such cases compared to UPD cases. So we could maybe detect subtler health problems.