cysteinechapel
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- cysteinechapel parentTo push back a little, isn't there causality inherently in these sequence-to-function models, in the sense that causality must proceed in the direction of genetics -> predicted molecular function? And the genetic contribution to phenotype must pass through molecular function.
- There are existing frameworks for integrating functional and statistical fine mapping methods (e.g. polyfun + susie/finemap). They use annotation overlaps like epigenetic or conservation tracks but can be extended to variant effect predictions from models like this. They essentially modify the prior probability of a variant being causal from uniform to one that depends on the functional annotation.
- Such an advantage that is rare and across such long time scales would be so small on average that it would be effectively neutral. Natural selection can only really act on fitness advantages greater than on the order of the inverse of effective population size, which for large multicellular organisms such as animals, is low. Most of this is really just noisy transcription/binding/etc.
For example, we don't keep transposons in general because they're useful, which are almost half of our genomes, and are a major source of disruptive variation. They persist because we're just not very good at preventing them from spreading, we have some suppressive mechanisms but they don't work all the time, and there's a bit of an arms race between transposons and host. Nonetheless, they can occasionally provide variation that is beneficial.
- Plenty of simple models in biology that don't model the underlying details provide profoundly generalizable insights across scales. The percolation threshold model explains phase transition behavior from the savanna-forest transition to the complement immune system to epidemics to morphogenesis to social networks.
- Scales can also decouple from each other. Complex trait genetic variation at the whole genome level acts predominantly in an additive fashion even though individual genes and variants have clearly non-linear epistatic interactions.