Over at Evolution News, physicist Brian Miller has posted an article titled, A Dentist in the Sahara: Doug Axe on the Rarity of Proteins Is Decisively Confirmed (February 18, 2019). Dr. Miller claims that recent studies support Dr. Douglas Axe’s contention that “most natural proteins are too rare to evolve through an undirected search.” A few brief excerpts will suffice to convey the tenor of the article:
As a specific example, the Tokuriki and Tawfik study demonstrated the following effects of accumulating mutations:
- After only a few random mutations (1-2) under weak selection, around a third of subsequent changes to a protein completely disable it.
- After several more mutations accumulate (5-6), the protein is inactivated by slightly under two-thirds of subsequent changes.
- After random alteration of less than 10 percent of the protein’s initial sequence, it becomes permanently nonfunctional (fitness approaches zero)…
In the study, after 5-10 mutations, roughly 2 in 3 mutations inactivate a protein. Therefore, 1 in 3 amino acids at each position on average would correspond to a functional sequence. The rarity would then be less than 1/3 to the power of the sequence length. This estimate closely matches the result from Axe’s 2004 β-lactamase experiment that only 1 in 10^77 sequences corresponds to a functional fold/domainwithin the protein. The actual rarity is much more extreme, since almost no sequences are functional after 10 percent of a protein randomly changes…
The authors demonstrate that their results apply generally to globular proteins (e.g., enzymes and components of molecular machines). The reason is that the stability of a protein’s structure decreases on average with each added mutation. As a result, increasingly small percentages of sequences in the local region of sequence space are functional. The drop in stability can be slow at first, but after a certain threshold is reached, the structure rapidly destabilizes. The corresponding region of sequence space then becomes almost entirely devoid of functional sequences. Axe came to the same conclusions previously, but the authors neglected to give him due credit…
This definitive evidence refutes one of the most common criticisms of Axe’s protein research. Namely, critics often complain that he did not consider the possibility that the protein he studied might have performed some other function than the one for which he tested. In reality, since the functional loss is due to the loss of structural stability, all other functions dependent on a stable structure must also cease…
A common response to such probabilistic analyses is that vast numbers of different proteins might serve some particular function. Therefore, finding a specific protein might be quite unlikely, but finding any one of a multitude that perform a particular task could be a tractable problem. This objection fails as a result of studies examining the distribution of proteins in all of nature, for they determined that known proteins reside within only a few hundred thousand protein families…
…As I mentioned, after fewer than 10 mutations in the Tokuriki and Tawfik experiment, the rarity of functional sequences approximates to 1/3 to the power of the sequence length. The HisA article reported an even faster drop in fitness, indicating even greater rarity. And several other studies demonstrated a corresponding rarity that was similar. Using Tokuriki and Tawfik’s results, the probability of a trial finding a protein the size of that forming the flagellar filament (L=498) would equate to less than 1 in 10^200.
What do readers think? Is Dr. Miller’s argument valid, and if so, is it sound? I’d be interested in hearing from @swamidass, @Art, @Rumraket, and other contributors. Thoughts?
P.S. I should point out that the Tokuriki and Tawfik study cited by Dr. Miller is by no means a new one: it actually goes back to 2006!