Definitions Matter: Negative Selection and Postive Selection

 
In recent issues of the Proceedings of the National Academy of Sciences (USA) we have an interesting example of misuse of a key term in evolution.

The paper in question is by Sun et al. (2008a) of the University of California, San Francisco. The title of the paper is important: "Experimental evidence for negative selection in the evolution of a Yersinia pestis pseudogene." Here's how they describe this negative selection in the abstract,

Yersinia pestis, the agent of bubonic plague, evolved from the enteric pathogen Yersinia pseudotuberculosis within the past 20,000 years. Because ancestor and descendant both exist, it is possible to infer steps in molecular evolution by direct experimental approaches. The Y. pestis life cycle includes establishment of a biofilm within its vector, the flea. Although Y. pseudotuberculosis makes biofilms in other environments, it fails to do so in the insect. We show that rcsA, a negative regulator of biofilms that is functional in Y. pseudotuberculosis, is a pseudogene in Y. pestis. Replacement of the pseudogene with the functional Y. pseudotuberculosis rcsA allele strongly represses biofilm formation and essentially abolishes flea biofilms. The conversion of rcsA to a pseudogene during Y. pestis evolution, therefore, was a case of negative selection rather than neutral genetic drift.

Hmmm ... something about this form of "negative selection" seems puzzling. Does anyone see what it is?

The article was published online on June 3, 2008 and appeared in the June 10, 2008 issue of PNAS. It was communicated by National Academy member Stanley Falkow of Stanford University.

In this week's issue (Oct. 21, 2008) we see a letter from Jianzhi Zhang of the Department of Ecology and Evolutionary Biology, University of Michigan (Zhang, 2008).

There are two types of natural selection in biological evolution: Positive (Darwinian) selection promotes the spread of beneficial alleles, and negative (or purifying) selection hinders the spread of deleterious alleles (1). Pseudogenization is normally detrimental and prevented by negative selection. However, changes in genetic background or environment may render a formerly useful gene worthless, leading to the relaxation of the negative selection. Consequently, mutations disrupting the gene are fixed by genetic drift, and the gene becomes a pseudogene. This is the common type of pseudogenization by neutral evolution. Sometimes, however, a previously useful gene may become harmful to an organism. In this case, mutations destroying the gene would be beneficial and would be fixed by positive selection. Thus, pseudogenization can be adaptive (2). Recently, Sun et al. (3) reported an excellent example of adaptive pseudogenization, convincingly demonstrating that gene loss can also serve as an “engine” of evolution (4). Nevertheless, instead of calling it “positive selection,” they mistakenly used “negative selection.” The case involves Yersinia pestis, the agent of bubonic plague that is frequently transmitted by fleas. The authors found that the rcsA gene of Y. pestis became a pseudogene in the last 20,000 years (3). Replacing the rcsA pseudogene with its functional version represses the formation of biofilms in fleas (3), which would reduce the transmission rate of the bacteria. That is, the pseudogenization of rcsA allowed the formation of Y. pestis biofilms, which enhances the transmission of the bacteria, and hence was likely driven by positive selection.

That looks like a pretty devastating criticism to me. I'm convinced that the title of the paper was inaccurate. They were publishing an example of positive selection and not negative selection as claimed.

The authors replied in the same issue (Sun et al., 2008b).

In our article (1) we used “negative selection” to succinctly convey that a previously functional allele became deleterious and therefore was removed by natural selection. However, Zhang (2) is correct that our usage was contrary to the usual meaning. Olson's term, “adaptive gene loss” (3), would have been more appropriate. We are gratified that Zhang agrees with our conclusion that the pseudogenization of rcsA was adaptive.

Translation: "We really screwed up."

How did this happen? Normally, before a paper is published the work is presented at meetings and in lab group meetings. Was there nobody who recognized that the authors were using the wrong term? Clearly the authors themselves (all three) never questioned what they were putting into the title. Clearly the person who communicated the article didn't either, and neither did any of the reviewers.

What's happening to science these days? Now, don't get me wrong. These sorts of things happened in the "olden days" as well but I'm convinced that the problem is much more serious today. There is too much stuff being published that should never have made it past the lab group, let alone past reviewers.

Here's a question for everyone who has read this far. What should be done with the original paper? The title is wrong. How do we alert people to the fact that the authors have agreed that they made an error?

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Sun, Y-C., Hinnebusch, J.B. and Darby, C. (2008a) Experimental evidence for negative selection in the evolution of a Yersinia pestis pseudogene. Proc. Natl. Acad. Sci. (USA) 105:8097-8101. [DOI: 10.1073/pnas.0803525105]

Sun, Y-C., Hinnebusch, J.B. and Darby, C. (2008b) Reply to Zhang: Adaptive gene loss in Yersinia pestis rcsA pseudogenization. Proc. Natl. Acad. Sci. (USA) 105:E70; published ahead of print October 15, 2008. [doi:10.1073/pnas.0807434105]

Zhang, J. (2008) Positive selection, not negative selection, in the pseudogenization of rcsA in Yersinia pestis. Proc. Natl. Acad. Sci. (USA) 105:E69; published ahead of print October 15, 2008 [doi:10.1073/pnas.0806419105]