Gil grabs some ammunition and shoots down Doug Axe's 2004 extrapolation by a factor of more than 10^44

No the disconnect still is that you don’t understand that his method is based on similarity searches, because he literally explicitly does similarity-based searches when he’s looking for homologous sequences in other species to the one he’s interested in.

There isn’t any way around this.

But I’m not, for reasons already explained.

Your subjective views on the degree to which the sequences are “similar” is not a relevant factor here Bill.

What matters to the question of whether the method is based on similarity or not, is how Gpuccio finds and includes a sequence to use so as to extrapolate the amount of tolerated variation for some sequence to implement a function. He does that by doing similarity-based searches. That is what happens when you use a BLAST search tool.

Even were he to use names of proteins from different species(in other words lets say he tries to avoid using blast), say he wants to find ATP synthase subunit beta in some unicellular eukaryote, he could just be searching for that (“ATP synthase subunit beta”) on uniprot for example, and then choose to sort results by taxonomy. He’d find lots of candidate gene sequences that haven’t actually been experimentally characterized to be ATP synthase subunit beta, but merely inferred to be that merely on the basis of some sort of similarity measure. That’s how these genes are often times automatically annotated in these databases.

Only a very small subset of them have been experimentally characterized to function in some specific way expected from their similarity.

Now since these BLAST-based searches used to collect homologous sequence for use in the extrapolation of FI, are in fact based on sequence similarity, and since this in turn means that to calculate FI you are implicitly accepting that the similar sequences you use in your calculation are in fact homologous, then it will be hypocritical to suddenly arbitrarily reject similarity-based inferences of relatedness when those very same similarity-based searches can be used to show deeper ancestral relationships to proteins with different functions, or with simpler structures and shorter, more likely sequences.

You can’t have your cake and eat it too.

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