July 25, 2005 | David F. Coppedge

What Is Really Known About the Genetic Basis of Evolution?

Now that the genomes of a variety of plants and animals have been published, is there a clear picture of evolution emerging?  Sean Carroll (Howard Hughes Medical Institute) wrote a review in PLoS Biology,1 in which he explored the current thinking about the evolution of anatomy at the genetic level.  The thing to watch for in this article is evidence that evolutionary processes at the genetic level can produce complex, novel structures: innovations such as eyes, new organs, new body plans and the like.  Carroll’s article can be considered a kind of “State of the Evolutionary Theory Address” on this question.  Confident that evolutionists are on the right track, Carroll nonetheless admits that much is puzzling, and that a coherent theory is yet to be discovered.
    The picture is much more complicated now than the old neo-Darwinian idea that beneficial mutations in genes would be passed on to offspring, producing net changes over time.  Thirty-five years ago, Susumi Ohno suggested that, instead, gene duplication might be the primary source of beneficial variation.  Four years later, Allan King and Mary-Claire King suggested that changes in gene regulation might be more important than genetic mutations alone in driving the evolution of anatomy.  These ideas were both due to the observation that “the small degree of molecular divergence observed could not account for the anatomical or behavioral differences between chimps and humans.”
    Since those early days of comparative genomics, three molecular mechanisms have become candidates for the evolution of anatomy: (1) gene duplication and divergence, (2) regulatory element expansion, and (3) isoform evolution (new exon and splicing sites in genes that create the potential for alternative forms of a protein to be made).  One genetic phenomenon that complicates evolutionary change is pleiotropy: the multiple effects of single variations (see 03/31/2004 and 03/17/2003 entries).  This is the “law of unintended consequences,” so to speak; a mutation that might benefit one tissue could wreak havoc in another and therefore antagonize evolution by being selected against.  The three mechanisms listed above must, therefore, provide compartmentation against the damaging effects of antagonistic pleiotropy for the evolution of anatomy to proceed:

The three mechanisms gene duplication, regulatory sequence expansion and diversification, and alternative protein isoform expression accomplish essentially the same general result—they increase the sources of variation and minimize the pleiotropy associated with the evolution of coding sequences.  The global question of the genetic basis of the evolution of form then boils down to the relative contribution of gene duplication, regulatory sequence evolution, and the evolution of coding sequences, over evolutionary time.  I will first examine what is known about the role of regulatory sequences and then discuss the contributions of coding sequences and gene duplication to the evolution of anatomy.   (Emphasis added in all quotes.)

Having set the stage, Carroll examines the potential for each of these factors for explaining the evolution of anatomy:

  1. Regulatory Sequences:  Non-coding regions of DNA can affect the expression of coding regions (genes) during development, sometimes with dramatic effects.  Typical examples are extra or misplaced limbs in fruit flies or changes in pigmentation patterns.  Are changes to regulatory sequences fodder for evolution?  Carroll argues that while mutations in genes have pleiotropic effects, mutations in regulatory sequences do not, and as such, “enable a great diversity of patterns to arise from alterations in regulatory circuits through the evolution of novel combinations of sites for regulatory proteins.”  But can what is observed in pigmentation patterns account for the “more complex traits” like “body organization, appendage formation, and other, more slowly evolving characters”?  Carroll thinks so, but the only examples he provides,2 from a “handful of studies” on this subject, are pigmentation patterns in fruit flies and reductions in pelvic fin armor in stickleback fish (see 06/18/2004 entry).  Nevertheless, these examples are enough for him to draw attention to what he considers a key point:

    The crucial insight from the evolution of Pitx1, yellow, and Hoxc8 is that regulatory mutations provide a mechanism for change in one trait while preserving the role of pleiotropic genes in other processes.  This is perhaps the most important, most fundamental insight from evolutionary developmental biology.  While functional mutations in a coding region are usually poorly tolerated and eliminated by purifying selection, even complete loss-of-function mutations in regulatory elements are possible because the compartmentation created by the modularity of cis-regulatory elements limits the effects of mutations to individual body parts.

    He seems to be emphasizing that mutations to non-coding regions have the advantage of permitting “tinkering” without damaging the machinery as a whole.  “Does this mean that coding sequences cannot contribute to morphological evolution?“ he asks, then answers, “Not at all” –

  2. Coding Sequences:  Carroll discusses examples of Hox genes in fruit flies that have apparently diversified by duplication and selection into new forms.  Some apparently retain Hox function and some do not; these have taken on other functions, such as new dorsoventral patterning in some lineages of fruit flies.  “These arthropod Hox proteins demonstrate that some of the most conserved proteins can, under certain circumstances, evolve new and different activities.”  Yet, at best, these seem to be examples of genes that have modified existing anatomical parts rather than generated new ones de novo.  Further, they cannot represent the whole evolutionary bag of creative tricks, because “these events are, in the long span of the history of these lineages, rare relative to the extensive diversification of body forms.”  One case in point is that a change in the Ubx protein “has been well preserved throughout the course of more than 300 million years of insect evolution.”  Clearly there must be mechanisms for more rapid evolution.  Again, Carroll is confident: “Are there more common and rapid means of evolving morphological diversity via coding mutations?  Definitely,” he boasts.  OK, like what?  Like mutations in the MC1R gene, that “are associated with scale, fur, or plumage color variation and divergence in a wide range of species,” indicating that “the MC1R gene has evolved under natural and sexual selection.”  But again, this seems to assume that evolution rather than demonstrate it.  Another example about repeat sequences on a gene that differ between dog breeds, while interesting, might not help the evolutionary explanation: “this variation may have accompanying deleterious, pleiotropic effects that, while manageable under domestication, would limit its contribution to evolution under natural selection.”
  3. Gene Duplication:  While gene duplication is certainly in the explanatory toolkit for the evolution of anatomy, there is a limitation: “Empirical evidence suggests, however, that while gene duplication has contributed to the evolution of form, the frequency of duplication events is not at all sufficient to account for the continuous diversification of lineages.”  The rate is estimated to be one duplication per gene per 100 million years, far too slow to produce changes at the rate expected by evolutionary theory, yielding “the 300,000 known species of beetles, or 10,000 species of birds” in far less time.  Furthermore, there is such dramatic stasis observed even in genes where past duplication is inferred: “the number and diversity of Hox genes in highly diversified phyla, such as the arthropods and tetrapods, appears to have remained fairly stable for very long periods (perhaps approximately 500 million years).”  Why, also, are some gene families found far back, among the most primitive multicellular organisms?  “Such deep ancestral complexity,” Carroll says, with apparent repudiation of long-assumed evolutionary mechanisms, “is much greater than would be expected under the hypothesis that diversity evolves primarily through the evolution of new genes.”  Why also did the human genome fail to fulfill expectations that it would contain more genes than lower forms of life?  And why do many of our genes have syntenic orthologs in the mouse?  For these reasons, Carroll rejects the idea that gene duplication is the essential part of the story of anatomical evolution.  The story must lie more in the way regulatory mechanisms evolve.
  4. All Three in the Mix:  Now that changes in genes and the regulatory sequences that affect them are players, is Carroll prepared to stick his neck out and announce which mechanism is the leader in the evolution of form?  To do so seems to require working up one’s courage:

    The more subjective issue is whether, from the small sample of case studies mentioned here and in the literature, one can make (and defend) statements about the relative contribution of regulatory and coding sequence evolution to the evolution of anatomy.  We are, after all, in much better position now to do so than King and Wilson were 30 years ago.
        While the agnostic, “wait and see” position would appear safer, that would not at all be in keeping with the bold spirit of the pioneers who first wrestled with the question.  Moreover, I argue that a trend is evident, and that that trend should, of course, inform ongoing and future work.  Based upon (i) empirical studies of the evolution of traits and of gene regulation in development, (ii) the rate of gene duplication and the specific histories of important developmental gene families, (iii) the fact that regulatory proteins are the most slowly evolving of all classes of proteins, and (iv) theoretical considerations concerning the pleiotropy of mutations, I argue that there is adequate basis to conclude that the evolution of anatomy occurs primarily through changes in regulatory sequences.

    Carroll hastens to say this should come as no surprise to most theorists, but he chides the people working in comparative genomics and population genetics who seem to downplay the importance of the regulatory factor.

To bring the discussion home, Carroll returns to the differences between chimps and people.  Can changes in gene regulation explain the profound anatomical differences between us, including “brain size, craniofacial morphology, cortical speech and language areas, hand and digit form, dentition, and body skeletal morphology” that must have occurred within the last six million years?  He thinks so, but there are only a few studies that map a gene to a change in a trait.  One, the FOXP2 gene, appears to be related to speech, and has been implicated in the evolution of human language (see 05/26/2004 entry); another relates a muscle gene to chewing.  Carroll thinks these studies miss the point: “My concern here is not whether these specific associations did or did not play a role in human evolution; rather, my concern is the exclusive focus, by choice or by necessity, on the evolution of coding sequences in these and more genome-wide population genetic surveys of chimp-human differences,” he says.  We need to get off our gene-centric chauvinism and focus on the regulatory elements if we are to make progress.  In fact, the FOXP2 study can lead to “dramatically different conclusions one might draw, depending upon the methodologies and assumptions applied.”  He elaborates on the case, showing that it is simplistic to assume a point mutation in one gene is going to lead to a major anatomical change; what about pleiotropy?  (FOXP2, after all, is expressed not only in the brain, but in the lungs, heart and gut.)  What about how this gene is regulated?  We must get past the simplistic explanatory phase, he says, because the puzzle is deeper than expected:

Any statements or claims, then, about the genetic changes that “make us human” must be weighed critically in light of the power and limitations of the methodology employed, and the scope of the hypotheses being tested.  While it is understandable that some biologists have reached for the “low-hanging fruit” of coding sequence changes, the task of unraveling the regulatory puzzle is yet to come.

In conclusion, Carroll makes the case that considering what we now know, “regulatory sequence evolution should be the primary hypothesis considered.”  That’s going to be difficult, because “it is impossible to distinguish meaningless from functional changes by mere inspection” – i.e., what was formerly considered “junk DNA” (see 07/15/2005 entry), with its repetitions and apparent pseudogenes, is going to be more difficult to interpret than the coding regions.  But the task is clear: “In order to approach the origins of human traits, much greater emphasis has to be placed on comparative studies of gene expression, regulation, and development in apes and other primates.”  Thirty years after King and Wilson predicted the importance of gene regulation, his concluding sentence indicates the work has not yet begun: “This is precisely the requirement forecast by King and Wilson 30 years ago, only now we have the means to meet it.”


1Sean Carroll, “Evolution at Two Levels: On Genes and Form,” Public Library of Science: Biology, 3:7, July 2005.  This article is based on the Allan Wilson Memorial Lectures, UC Berkeley, Oct. 2004.
2Carroll also mentions how differences in Hox gene expression are “associated with large-scale differences in axial patterning in vertebrates, arthropods, and annelids,” but this assumes evolution rather than demonstrating it.

If you thought Charlie had figured this all out 146 years ago, wake up and smell the bitter coffee.  Here we have The Theory of Evolution, that rock-solid foundation for all of law, ethics, philosophy, art, science, education and even religion, so secure that no student in public school should ever be allowed to hear anything else, and now they tell us that everything you thought you knew about it was wrong, and the biologists have to start over.  This can make one mad enough to spit the bitter coffee back into the face of the Darwin Party waiter who handed it to us and said there was nothing else to drink.
    The conceptual nakedness of evolutionary theory at the genetic level, where all the action is supposed to take place, cannot be clothed by small stitches of Hox cloth.  This is shameful.  Despite his bravado, did Sean Carroll provide any evidence strong to convince a skeptic that random changes in regulatory genes could produce an Einstein from Bonzo, or a from a flatworm for that matter, in any conceivable universe?  Assuredly not: the most solid items in his discussion were arguments against the evolution of anatomy: (1) pleiotropy, a phenomenon that resists change, (2) ultraconserved elements (see 05/27/2005 entry), which show no evolution for 500 million imaginary years, and (3) his utter silence on how a change to a regulatory element could ever produce a wing, eye, brain or any other complex system.  How can a regulatory element regulate something that is not already there, for crying out loud?  For all the case he makes for regulatory mutations in development providing the most important, fundamental insight into evolutionary mechanisms (evo-devo), other evolutionists disagree (see 06/29/2005 review of Carroll’s book by Jerry Coyne).  These opposite Darwinian perspectives essentially falsify each other on theoretical grounds; then there is the data, which falsifies them both.  If the complex regulatory mechanisms were already present at the beginning, what does that tell you?
    Carroll’s specific examples – stickleback fish fins and fruit fly pigment spots – are sad and poultry excuses for real evolutionary change, and I mean poultry, not paltry, because they are mere chicken feed.  Not only that, he pulled the roost out from under those who earlier had clucked the spring egg song over the FOXP2 mutation explaining Shakespeare (see 05/26/2004 entry).  Whether you call it gene duplication, gene regulatory mutation or gene coding mutation, it’s all chance in Old McDarwin’s chicken coop.
    This entry was longer than most because of its significance.  Here we listened to a faithful lord in the Darwin Party, giving the Allan Wilson Memorial Lecture at Berkeley, which he would not be in position to do if he didn’t know the score, and all he could say is that everyone has been on the wrong track for 30 years, and we should have turned when Wilson and King said so back there and checked out that other dead end.  Talk about being lost in a cave of their own making, and watching shadows on the wall.  Come to the light.

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Categories: Genetics

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