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Comment by Moshe_Silnorin | Hacker News Reader

If we replace degenerate alleles with the most-common version of that allele, isn't that pretty safe? It would have been tested on billions of people naturally.

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Not if the people with the degenerate version also have another mutation that interacts. If you only fix one, you run into a third kind of bug.

Exactly. For example, "fixing" MTHFR genes could lead to an increased risk of developing lymphoma: https://www.ncbi.nlm.nih.gov/m/pubmed/15551285/

>Not if the people with the degenerate version also have another mutation that interacts.

Is this common? An uncommon detrimental variant that is slightly-mitigated by another uncommon detrimental variant, such that the removal of one makes the other worse isn't the type of thing I would expect to come about through natural selection.

The degeneracy of a given allele is relative to the phenotype of the organism and also the organism's environment. Sickle-cell confers survival advantage in environments where malaria is endemic, but is considered a degenerate allele in environments without malaria.

Because we know genetic loci do not affect the phenotype in purely orthogonal ways (this is known as epistasis), there is a huge risk of having unforeseen second order consequences. In state space even on simple models like NK model for low K, epistasis can have profound effects on fitness metrics and survivability as organisms attempt to hill climb.

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