Mutations and Complex Adaptations

Michael Lynch is one of those rare scientists who not only think outside the box but successfully stimulate others to do so. I read all of his papers and I'm always very impressed, even though I don't always agree with everything he says.

I recently attended the 18th Annual Meeting of the Society for Molecular Biology and Evolution in Lyons, France, where I met Michael Lynch for the first time. He gave a talk on Evolution of Mutation Rates, a topic many of us treat with a large degree of skepticism—until we're confronted by Michael Lynch. He makes a convincing case for variable rates of mutation in different species and he challenged us (me) to defend the idea that there was a linkage between DNA replication rates and mutation rates. That's a linkage I've always assumed would constrain mutation rates to a narrow range. Now I'm not so sure.

I've been putting off posts about the many exciting things I heard in Lyon because I'm busy with the 5th edition of my textbook but SteveF provoked me into saying something about Michael Lynch by posting a comment on my blog [Larry, you might find this shiny new paper by Michael Lynch in PNAS interesting]. Damn you, SteveF, and thanks.

We had been discussing how the IDiots view mutation and I mentioned that Michael Behe was mostly, but not entirely, correct when he said that if two mutations are required for a complex adaptation then it is very unlikely to happen [Bated Breath].

In a paper just published in PNAS, Michael Lynch explains why it's "not entirely correct" (Lynch, 2010).
The development of theory in this area is rendered difficult by the multidimensional nature of the problem. One strategy has been to ignore all deleterious mutations and to assume that selection is strong enough and mutation weak enough relative to the power of random genetic drift and recombination that evolution always proceeds by the sequential fixation of single mutations (e.g., refs. 6–11). Such an approach provides a useful entree into the evolutionary dynamics of rare adaptive mutations with large effects. Under these conditions, the expectations are clear—with larger numbers of mutational targets and a reduced power of random genetic drift, the rate of adaptation will increase with population size, although more slowly than expected under the assumption of sequential fixation (12, 13). The motivation for these models, which are specifically focused on total organismal fitness, derives from case studies of adaptations with apparently simple genetic bases, e.g., some aspects of insecticide resistance (14), skin pigmentation (15), and skeletal morphology in vertebrates (16).

Nevertheless, a broad subset of adaptations cannot be accommodated by the sequential model, most notably those in which multiple mutations must be acquired to confer a benefit. Such traits, here referred to as complex adaptations, include the origin of new protein functions involving multiresidue interactions, the emergence of multimeric enzymes, the assembly of molecular machines, the colonization and refinement of introns, and the establishment of interactions between transcription factors and their binding sites, etc. The routes by which such evolutionary novelties can be procured include sojourns through one or more deleterious intermediate states. Because such intermediate haplotypes are expected to be kept at low frequencies by selection, evolutionary progress would be impeded in large populations were sequential fixation the only path to adaptation. However, in all but very small populations, complex adaptations appear to be achieved by the fortuitous appearance of combinations of mutations within single individuals before fixation of any intermediate steps at the population level (e.g., refs. 17–26).
Read the paper. You'll find an interesting discussion of recombination—a discussion that does not assume most of the standard myths about recombination. Lynch points out that when it comes to fixing two independent mutation the effect of recombination is just as likely to break up linkage as enhance it. Recombination cannot make much of a contribution to the fixation of two mutations that are required for a complex adaptation unless the mutations are closely linked (e.g. same gene).

However, there are some circumstances where large population sizes can overcome the problem of fixing multiple mutations even if there's a negative correlation between mutation rate and population size. This is the "scaling" parameter mentioned in the title of Lynch's paper.

This is not unlike what Behe's says in The Edge of Evolution where he points out that in malaria parasites (e.g. Plasmodium falciparum) the probability of a double mutation is significant because there are trillions of organisms. In large mammals, however, the probability is much lower because the population size in much smaller.
Changing multiple amino acids of a protein at the same time requires a population size of an enormous number of organisms. In the case of the malaria parasite, these numbers are available. In the case of larger creatures, they aren't.
Behe concludes that this is the "edge" of evolution. Since these kinds of mutations are required for complex adaptations, it follows that evolution can't account for complex adaptations. You'll have to read Behe's book to find out who can design such complex adaptations.

So far, this is pretty much standard orthodoxy. Given that multiple, independent, mutations might be required simultaneously it's very unlikely that evolution will ever see them in some species. It's one of the reasons why Behe's book is so unexciting. There are other ways to account for the adaptive value of multiple mutations, including the fact that many of the individual mutations may be slightly deletersious but, nevertheless, fixed by random genetic drift.

What Lynch's paper shows is that the standard orthodoxy might be wrong! His models suggest that fixation of multiple mutations in small population may be well within the range of probability required for evolution of complex adaptations.
In summary, the preceding results suggest that some general scaling properties may exist for the rapidity with which various types of adaptations can be assimilated in different populationgenetic contexts. In particular, prokaryotes appear to be much more efficient than eukaryotes at promoting simple to moderately complex molecular adaptations, and substantially so for those involving joint changes at different genetic loci. In contrast, adaptations requiring three or more novel mutations may arise more frequently in small populations, regardless of the level of recombination between selected sites. In the absence of comprehensive information on the molecular basis of adaptation in multiple lineages (i.e., the typical number of sites involved and their degree of epistatic interactions), these general predictions are currently difficult to test. Nevertheless, the ideas presented herein are likely to bear significantly on a number of ongoing controversies regarding the nature of adaptation, including the barriers imposed by adaptive valleys in a fitness landscape (22, 40), the role of compensatory mutation in evolution (41), and the relative rates of incorporation of adaptive and nonadaptive mutations in various lineages (42–44).(my emphasis-LAM)

Lynch, M. (2010) Scaling expectations for the time to establishment of complex adaptations. Proc. Natl. Acad. Sci. (USA) publishe online, Sept. 7, 2010 [doi: 10.1073/pnas.1010836107]
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