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It’s been known for some time that bacteria evade antibiotics by mutating the target of the antibiotic, often at a cost to themselves. Mutating the target can lead to a loss or reduction in some function for the bacterium, but because that cost is more than offset by the bacterium’s survival in the face of the antibiotic, the mutation is beneficial for the bacterium. Thus even though a mutation causes a loss of some function, that loss can also be beneficial, as long as it leads to a greater growth rate or more reproductive success. In the case of the bacterium, the mutation is beneficial only as long as the antibiotic is around.
This phenomenon is well known to geneticists. They put it to use in the screens and selections they use to identify mutations that affect some trait. Challenge bacteria with a bacteriophage infection, for example. (I’ll bet you didn’t know that bacteria have their own little viruses, called bacteriophages, that make them sick and kill them.) Any members of the bacterial population that have the right inactivated cell surface protein will be immune to the phage — the phage can no longer bind to its target protein. The surviving mutant bacteria have a loss-of-function mutation, in that their cell surface protein is incapacitated, but it can also be described as a beneficial mutation, which it also is, in the context of a phage infection.
Not Lost on Behe
This observation and pattern was not lost on Michael Behe, a professor of biochemistry at Lehigh University and author of Darwin’s Black Box, The Edge of Evolution, and the forthcoming Darwin Devolves. In 2010 he published a paper in The Quarterly Review of Biology, “Experimental Evolution, Loss-of-Function Mutations, and the First Rule of Adaptive Evolution.” In the paper, he summarized years of work by geneticists on numerous bacteria and viruses, and laid out this principle, the First Rule of Adaptive Evolution:
Break or blunt any functional coded element whose loss would yield a net fitness gain.
He detailed study after study, analyzing the mutations that were beneficial and then classifying them as loss of function, gain of function, or modification of function. Most proved to be loss of function. The reason is simple. It is much easier to damage or destroy an existing function than it is to build a new one. In the above example, the cell surface protein is a bridge for the phage to infect the bacterium. The available choices are to disable or eliminate the bridge, to modify it so it is no longer a bridge, or to make something new that diverts the phage from the bridge or destroys the phage. Building is very hard, even impossible in the face of an immediate threat. Modifying is also hard because there are limited ways of modifying the protein so that the phage does not bind but the protein is preserved. However, there are many ways to disable or eliminate the cell surface protein.
Behe was pointing out an inconvenient truth. Much of evolution occurs by loss of function — as long as breaking or blunting that coded functional element (losing its function) actually helps the organism survive or reproduce better. But this is a one-way road. Many kinds of mutation such as deletions, insertions, and rearrangements can be essentially irreversible, unless the missing encoded functional element can be restored from elsewhere by something like horizontal gene transfer.
Lang and Desai
In the years since that paper was published, many cases of beneficial loss-of-function mutations have come to light. With the acceleration of genome sequencing more and more evidence has been accumulating. In 2014, a review article appeared in a special volume of Genomics devoted to experimental evolution. It outlined what could be learned from the many genomic studies to date. Gregory Lang and Michael Desai described many “adaptive mutations,” meaning mutations that helped the organism or cell grow faster or reproduce more. One could also call these beneficial mutations, and they did. They noted this:
Most long-term evolution experiments thus far have been performed in bacteria or haploid yeast populations, where, in most environments, there exist a number of loss-of-function mutations that provide a selective advantage. Given the large target size for these types of mutations, loss-of-function mutations often predominate the spectra of mutations recovered from long-term evolution experiments. Some of these loss events are neutral, attributable to mutation accumulation in the absence of selection for function, such as the reduction of catabolic breadth in E. coli, , . However, many loss-of-function mutations have been confirmed to provide a selective advantage. For instance sterility in yeast provides a selective advantage by eliminating unnecessary gene expression . The availability of beneficial loss-of-function mutations and the large target size for these events ensure that these mutations will come to dominate experimental evolution over short time scales. Over long time scales or in specialized conditions, mutational spectra may shift towards gain of function mutations. In diploid populations, we may also see a shift in the mutational spectrum away from loss-of-function mutations, towards dominant or overdominant mutations , . However, there is currently only limited data describing the mutations that occur during experimental evolution in diploids, leaving the exact nature of this shift unclear. [Emphasis added.]
Lang and Desai clearly acknowledge that loss-of-function mutations dominate experimental evolution in bacteria. They hold out hope that in diploid populations, gain-of-function mutations may become more common, which would be useful for evolutionary progress. However, as they acknowledge, the exact nature of the shift, if it occurs, is unclear.
Note: Cancer is not a good model for asking this question in eukaryotes, because the gain-of-function mutations in cancer do not produce structures or traits that lead to anything beneficial for the organism.
Not Just Bacteria
In fact, we have evidence that it’s not just bacteria that can benefit from the reduction or elimination of a gene if the resulting loss of function increases fitness. It can even happen just because a gene product is no longer needed. In the cases listed below, eukaryotic organisms reduce or eliminate gene expression when they are not needed, or when an adaptive advantage is gained:
- Blind cave-dwelling animals have lost elements necessary for eye development.
- Yeast lose the ability to reproduce sexually when grown for many generations using exclusively asexual reproduction.
- Ant species without wings have lost them through gene inactivation.
- Polar bears differ from brown bears because of loss-of-function mutations in several key genes.
- Cetacean evolution appears to have occurred, at least in part, by a loss-of-function mutations in key genes.
Take note. Evolution by loss of function means loss by point mutation, insertion, deletion, or rearrangement of DNA, and it may be in an irreversible way. It means blowing up bridges rather than building them, to use Behe’s cogent metaphor. Those yeast can no longer reproduce sexually. Whales are not going back on land. Polar bears might recover lost function by interbreeding, and if they are lucky. Perhaps those yeast could recover the sexual reproduction they lost by horizontal gene transfer. Maybe. It depends on the organization of those genes.
That brings me to a very recent study published in Cell, “Tempo and Mode of Genome Evolution in the Budding Yeast Subphylum.” I will quote their summary in full.
Budding yeasts (subphylum Saccharomycotina) are found in every biome and are as genetically diverse as plants or animals. To understand budding yeast evolution, we analyzed the genomes of 332 yeast species, including 220 newly sequenced ones, which represent nearly one-third of all known budding yeast diversity. Here, we establish a robust genus-level phylogeny comprising 12 major clades, infer the timescale of diversification from the Devonian period to the present, quantify horizontal gene transfer (HGT), and reconstruct the evolution of 45 metabolic traits and the metabolic toolkit of the budding yeast common ancestor (BYCA). We infer that BYCA was metabolically complex and chronicle the tempo and mode of genomic and phenotypic evolution across the subphylum, which is characterized by very low HGT levels and widespread losses of traits and the genes that control them. More generally, our results argue that reductive evolution is a major mode of evolutionary diversification.
In plain English, these authors sequenced the genomes of 332 yeast species, and established a tree of relatedness based on those genomic sequences. They then inferred what metabolic traits the metabolically complex ancestor of all those species must have had. They report, based on their phylogeny, that the subsequent diversification of the different yeast genera occurred by “widespread losses” of metabolic traits and the genes that encode them. There was little horizontal gene transfer. They say that “reductive evolution is a major mode of evolutionary diversification.” Note: budding yeast are eukaryotes that reproduce both sexually and asexually. So evolution by loss of function is not just a bacterial or viral thing.
Two things leap out at me. First, the ancestor was complex, the descendants reduced. Second, the loss of genetic information, at least as far as each genus of yeast is concerned, is irreversible. This is not the standard evolutionary story.
But maybe it ought to be. Here’s a 2013 paper, in Bioessays, by Yuri Wolf and Eugene Koonin, called “Genome reduction as the dominant mode of evolution.” They list a number of prokaryotic and eukaryotic groups that share these features: a complex ancestor and evolution by reductive evolution.
Behe is vindicated, but he is not standing still. He has continued to work on his ideas: the limits of evolution, and loss of function as the main mode of evolution. This leads directly to the topic of his new book to be released next February, which is called, of all things, Darwin Devolves. Imagine that.