Evo-Devo Revisited

I thought I had come to grips with evo-devo. Then along come Hopi Hoekstra and Jerry Coyne to call shenanigans on Sean Carroll's model of evo-devo. This is nothing new for Coyne, but I can't recall Hoekstra ever getting involved in the debate before now.

Before we get to Hoekstra and Coyne, let's allow Carroll to describe evo-devo in his own words. His most recent summary of the evolution of transcriptional regulatory regions can be found in this paper from a recent National Academies Sackler Colloquium. Here's how he and his colleagues explain the importance of cis regulatory regions (CREs) in morphological evolution:

[R]ecent studies have provided direct evidence of the role of CRE evolution in morphological evolution. More importantly, these detailed functional analyses have revealed some surprising and previously unanticipated features of how gene regulation evolves at the molecular level that, we suggest, reflect general principles. The goal of this article is to articulate these emerging principles, namely how regulatory evolution: (i) proceeds using available preexisting genetic components, (ii) introduces discrete changes in gene expression thus minimizing deleterious effects and fitness penalties, and (iii) allows the association between any transcription factor and any downstream gene and thereby provides immense potential for evolutionary novelty. These principles explain both how and why regulatory sequence evolution is a pervasive, although not the exclusive, mechanism underlying morphological diversification.

So, Carroll thinks that CREs are important for morphological adaptation/diversification/evolution, but he does allow for some protein sequence evolution. Hoekstra and Coyne, on the other hand, argue that Carroll's claims lack evidence. In their article, they say that we currently lack the evidence to decide whether CREs or proteins are responsible for morphological evolution, but the current state of affairs suggest that protein coding sequences are more important.

In making their argument, Hoekstra and Coyne redefine regulatory and structural mutations from how Carroll and colleagues use the terms. Hoekstra and Coyne argue that trying to differentiate between regulatory and structural protein coding genes can get tricky, so they treat all mutations in protein coding regions as structural and all non-protein coding mutations as regulatory. From here, their goal is to determine whether published results containing more evidence supporting regulatory or structural mutations as the main drivers of morphological evolution. Keep in mind that they are partitioning the data in a slightly different manner than Carroll and colleagues.

Before Hoekstra and Coyne evaluate the evidence for and against regulatory changes driving morphological evolution, they question why morphological evolution should be any different than the evolution of other phenotypes. Carroll's theory of evo-devo concerns only the evolution of form, not "behavior, biochemistry, metabolism, and physiology". Why not? Here's what Hoekstra and Coyne think:

The reason, then, why the evolution of anatomy is a "more open" question than that of physiology is not because there is some fundamental biological difference between the two classes of traits. It is only because we have less evidence about the nature of change affecting form, and therefore are less constrained by facts in speculating about its genetic basis.

Ouch! They also point out that the fossil record allows us to evaluate form, while other aspects of the phenotype are more difficult to examine in extinct organisms. But there is no real reason to say that regulatory changes are responsible for one aspect of phenotypic evolution, while showing no preference for regulatory changes for other aspects of phenotypic evolution.

Another aspect of Carroll et al's argument in favor of cis regulatory changes is that they are the only way to escape the pleiotropic effects of most mutations. Because structural mutations will affect all substrates upon which a protein acts, and cis regulatory changes only affect the expression of the gene in question, cis regulatory mutations should be more tolerable. Carroll and colleagues claim that gene duplication does not make up for the pleiotropic effects of structural mutations because gene duplications are too rare. They base this claim, however, on a misinterpretation of Lynch and Conery's result that there is approximately one duplication per gene per 100 million years. While this suggests that duplication is rare on a per gene basis, the estimate translates to over 100 duplications per genome per million years.

But all that is just idle hypothesis. What do the data reveal about the importance of cis regulatory changes in the evolution of form? First of all, there aren't any thorough studies of the genetic causes of the evolution of form. So we must turn to studies that address parts of the big question; one part is the role of cis and trans changes in the evolution of gene expression. And what studies do Hoekstra and Coyne turn to? Oh, just the same three papers I discussed last year in my post on the evolution of gene expression (1, 2, 3). I won't get into the details of Hoekstra and Coyne's argument because you can just read my post (in fact, this section of their article reads like they did just that).

What other data support the Hoekstra and Coyne's hypothesis that Carroll is being premature in concluding cis regulatory changes drive morphological evolution? Hoekstra and Coyne argue that studies of the morphological effects of mutations in single loci indicate no preference for regulatory versus structural mutations. Also, many studies of phenotypic evolution reveal the importance of protein coding sequence changes. And, finally, no Coyne paper would be complete without a treatment of speciation. He and Hoekstra point out that all known "speciation genes" are mutations in protein coding sequences, although it's hard to see how this is related to the evolution of form.

In the end, Hoekstra and Coyne are not saying that cis regulatory changes aren't important for the evolution of form, only that Carroll is being far too premature in arguing that they are the predominant mechanism. Additionally, a survey of the literature reveals that structural changes may be more important. This is the same argument that Coyne made in his critique of Carroll's book, expanded into a complete article. And, guess what, they have a valid a point. The research by Coyne Carroll and colleagues is shedding light on the morphological implications of regulatory evolution, but it's not appropriate to play up that research as if that's the only way organisms evolve in form.

Related: John Timmer comments. Also, see this article on natural selection and the evolution of gene expression and this article on the evolvability of gene expression.

Hoekstra HE and Coyne JA. 2007 The locus of evolution: evo devo and the genetics of adaptation. Evolution 61:995-1016 doi:10.1111/j.1558-5646.2007.00105.x

Prud'homme B, Gompel N, Carroll SB. 2007. Emerging principles of regulatory evolution. Proc Natl Acad Sci USA 104:8605-8612 doi:10.1073/pnas.0700488104