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The Molecular Anatomy of an Ancient Adaptive Event

Protein engineering identifies the structural basis of a 3.5 billion-year-old adaptation

Antony Dean

Gradualism is a cornerstone of evolutionary theory. In the classic view, alterations to an organism or its parts accumulate slowly, imperceptibly changing form and function until gradually there emerges a being or an appendage or a cell or a protein that differs from the ancestral form. But gradualism is not the only game in town. For a while now, there have been some upstart ideas, ones that suggest that most changes to the genes that ultimately direct the formation of beings do not matter much. Furthermore, alterations that do matter—changes that adapt an organism or one of its parts to perform a new function—happen in fits and starts.

Figure 1. Two members of the ICDH family of enzymesClick to Enlarge Image

In 1968 Motoo Kimura of the National Institute of Genetics in Japan proposed something radical for the evolution of proteins, the macromolecules that provide much of a cell's structure and do almost all of its catalytic work. Proteins evolve when alterations to the genes encoding them result in a change in the sequence of their constituent amino acids. Kimura suggested that most amino acid replacements that accrue during the evolution of proteins are the result of pure blind chance. Evolution without adaptation! Though radical, his idea was grounded in two well-understood phenomena.

The first phenomenon is the familiar process of random mutation. Each generation produces a new crop of alleles (genetic variants), most of which are not adaptive and are simply eliminated by natural selection. Kimura supposed that adaptive mutations are so infrequent that they can be ignored, and that the remainder are selectively neutral—they are neither favored nor disfavored by natural selection. These neutral alleles enter the gene pool.

Figure 2. Random genetic driftClick to Enlarge Image

The second phenomenon, random genetic drift, is the tendency of gene pools to lose neutral alleles over many generations. Each generation is but a random sample of the previous generation's variants, and as such is subject to sampling error just as a Gallup poll would be. Over time, sampling errors accumulate: A lucky rare allele becomes common, or a common allele becomes rare, perhaps even lost from the gene pool (Figure 2).

Figure 3. Pitting neutral mutationClick to Enlarge Image

Kimura's radical idea pitted neutral mutation against random genetic drift. Mutation pumps new neutral alleles into the gene pool, while random genetic drift purges alleles from it. This churning flux of alleles causes neutral mutations to accumulate. Return to the gene pool in a million years and all the alleles have changed; in another million years they have all changed further still (Figure 3). Molecular evolution is a result of pure blind chance.

As a broad description of protein evolution this, the neutral theory of molecular evolution, has proved extraordinarily robust. After 30 years of intense research biologists have yet to provide a compelling picture of the molecular basis of a single ancient adaptive event. The difficulty arises from the very nature of the data collected. The linear sequences of amino acids in proteins, and of the nucleic acid bases in genes, are readily determined. By comparing the differences along these sequences it is possible to tease apart their historical relationships. Once determined, the neutral model can be subjected to various statistical tests. Unfortunately, the tests are so weak that rejection is possible only in extreme cases. Furthermore, minor modifications to the neutral theory frequently accommodate small deviations from naive expectation.

This is most frustrating, for even Kimura’s theory does not deny the importance of natural selection in evolution; its only claim is that adaptive mutations are rare, not nonexistent. Identifying rare adaptive amino acid replacements in an ocean of neutral change presents a formidable challenge.

Another place for biologists to start is with phenotypes. Phenotypes are the physical manifestations of genetic systems interacting with the environment. Although selection targets phenotypes (height, weight, eye color, catalytic efficiency, number of appendages etc.), only the genetic components are inherited by the next generation. It is perhaps for this reason that serious discussion of phenotypes rarely appears in studies of molecular evolution, which instead concentrate on the gene sequences. Yet phenotypes are crucial to understanding the process of natural selection because they show how organisms function in environments. If instead of merely analyzing gene sequences, evolutionists attempted to understand molecular phenotypes, the form and functions of proteins and enzymes in physiology and metabolism, they might gain deeper insights into the molecular basis of ancient adaptive events.

The challenge, then, is to return molecular phenotypes to molecular phylogenies, and in so doing to recover the molecular basis of truly ancient adaptive events. Here, I shall combine four approaches to do this. Each of the seemingly disparate fields of metabolism, phylogeny, x-ray crystallography and protein engineering makes its own very essential contribution to this story. None stands alone; indeed, their themes weave in and out, forming a tapestry rather than a simple linear string of arguments. An understanding of metabolism identifies the cause of selection, but the comparative methods of phylogenetics tease out the history. Establishing this history requires results from x-ray crystallography, results which also identify key amino acid replacements with important functional consequences. Techniques from protein engineering are then used to mutate these residues in an effort to show that they alone are responsible for the observed differences in phenotype.





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