BS Model Gets "Lynched"

Protein Science has released their latest issue. It features Michael Lynch's answer to Behe & Snoke's (BS) 2004 paper, along with a response from BS themselves, and an editorial explaining what happened behind the scenes. Lynch's abstract is fairly clear:

A recent paper in this journal has challenged the idea that complex adaptive features of proteins can be explained by known molecular, genetic, and evolutionary mechanisms. It is shown here that the conclusions of this prior work are an artifact of unwarranted biological assumptions, inappropriate mathematical modeling, and faulty logic. Numerous simple pathways exist by which adaptive multiresidue functions can evolve on time scales of a million years (or much less) in populations of only moderate size. Thus, the classical evolutionary trajectory of descent with modification is adequate to explain the diversification of protein functions.

The main difference between the Lynch and BS models is over the issue of whether intermediate mutations on the way to a novel multi-residue feature of a protein are deleterious (BS) or neutral (Lynch). Here's what Lynch has to say about this problem:

[...] Behe and Snoke assume that all mutational changes contributing to the origin of a new multi-residue function must arise after the duplication process. They justify this assumption by stating that the majority of nonneutral point mutations to a gene yield a nonfunctional protein. To stretch this statement to imply that all amino acid changes lead to nonfunctionalization is a gross mischaracterization of one of the major conclusions from studies on protein biology—most protein-coding genes are tolerant of a broad spectrum of amino acid substitutions (Kimura 1983; Taverna and Goldstein 2002a,b). For example, in a large mutagenesis screen, Suckow et al. (1996) found that >44% of amino acid positions in the Lac repressor of Escherichia coli are tolerant of replacement substitutions. Axe et al. (1998) found that only 14% of amino acid sites in a bacterial ribonuclease are subject to inactivation by some replacement substitutions, with only one site being entirely nonsubstitutable. For human 3-methyladenine DNA glycosylase, ~66% of single amino acid substitutions retain function (Guo et al. 2004). Even for the highly conserved catalytic core regions of proteins, approximately one-third of amino acid sites can tolerate substitutions (Materon and Palzkill 2001; Guo et al. 2004). Many other studies (e.g., Kim et al. 1998; Akanuma et al. 2002), including all of those cited by Behe and Snoke, have obtained results of this nature. A deeper understanding of the fraction of amino-acid-altering mutations that have mild enough effects to permit persistence in a population comes from observations on within- and between-species variation in protein sequences (Li 1997; Keightley and Eyre-Walker 2000; Fay and Wu 2003), which generally indicate that 10% to 50% of replacement mutations are capable of being maintained within populations at moderate frequencies by selection-mutation balance and/or going to fixation. Because there is strong heterogeneity of substitution rates among amino acid sites (Yang 1996), these average constraint levels should not be generalized across all sites, many of which evolve at rates close to neutrality. Thus, most proteins in all organisms harbor tens to hundreds of amino acid sites available for evolutionary modification prior to gene duplication.

Here's BS' response:

• Experimental studies contradict Lynch’s assumption of complete neutrality as a rule; the majority of amino acid substitutions decrease protein function.
• Lynch’s and our models are not mutually exclusive. Some evolutionary pathways might involve both deleterious and neutral mutations.
• Lynch writes in the section "The Model" that we "imply that all amino acid changes lead to nonfunctionalization." We imply no such thing. Although we assumed that intermediate mutations required for a new feature decreased function, we wrote, "it can be calculated that on average a given position will tolerate about six amino acid residues and still maintain function." Our estimation of explicitly takes into account the tolerance of sites for substitution.
• In "The Model," Lynch writes, "As in Behe and Snoke (2004), this adaptation is assumed to be acquired at the expense of an essential function of the ancestral protein..." We made no such assumption. In our model, the final mutation might restore and enhance the original function.

Compare the argumentation. Lynch examines many lines of evidence (including a study by Axe, another advocate for intelligent design) and concludes, reasonably, that a large fraction of aminoacid substitutions are neutral. This means that BS' original model is fatally flawed. And how do BS respond? They merely assert that they are right, and quibble about definitions. A wonderful demonstration of faith-based science in action.

Lynch's paper includes many other valid criticisms of the BS model. Interestingly, some of the points raised by Musgrave, Reuland & Cartwright in their early review have not yet appeared in print -- I think they should still do it.