This guest post is by Joshua Plotkin on his group’s paper McCandlish et al. Epistasis not needed to explain low dN/dS arXived here.

Our lab has recently begun to post research pre-prints on arXiv. All members of the group enthusiastically support this trend, both within our own group and within the broader scientific community. The merits of sharing pre-prints have been described elsewhere. The benefits of pre-prints are so immediately apparent, I feel, that there is no need to add further verses to the praises that have already been sung.

Recently, however, my research group and I faced an unusual and difficult question: whether we should post a pre-print that does not describe primary research, but rather is a critique of a recent paper published by another group – a paper on the role of epistasis in molecular evolution from the group led by Fyodor Kondrashov. My group and I have never before written such a commentary; and so I faced this choice with some uncertainty. Here are some thoughts on our group’s decision to write the commentary and to post it to arXiv.

Kondrashov’s group is at the vanguard of contemporary research in molecular evolution. In this particular paper from his group, Breen et al. contend that epistasis is “pervasive throughout protein evolution”; a view that I mostly support and indeed have expressed, in a more limited scope, in several publications and commentaries (e.g. here, here, and here). However, in discussing the paper by Breen et al. over lunch, our research group came to the consensus that their argument is logically flawed. Breen et al. reached their conclusion because the dN/dS values observed in some genes are much lower than their expectation in the absence of epistasis. But when calculating the expected dN/dS ratio in the absence of epistasis, Breen et al. assumed that all amino acids observed in a protein alignment at any particular position have equal fitness. This assumption is unrealistic because, simply, some amino acids may be more fit than others. When we relaxed this unrealistic assumption, we found that the observed dN/dS values and the observed patterns of amino acid diversity at each site are perfectly consistent with a non-epistatic model of protein evolution, for all the nuclear and chloroplast genes in the Breen et al. dataset (but, interestingly, not for their mitochondrial genes).

In an ideal world, scientific disagreements would be resolved by straightforward transactions based solely on logic and data. But in reality, such disagreements inevitably involve intellectual biases, not to mention personalities, politics, reputations, et cetera. In fact, we (my research group and I) are colleagues and admirers of Kondrashov and his comrades (these two papers of his are among our favorites). Why risk our collegiality by publishing a critique on arXiv?

The answer is two-fold. First, we are passionate about understanding molecular evolution, both as individuals and within the context of a scientific community – and we believe this exchange will advance that understanding. Second, we have had extensive email correspondences with Fedya about the scientific issues at hand. These correspondences have been completely open and straightforward: we have shared our computer code so that Fedya can reproduce our analyses; and Fedya has agreed with our critique, in principle, although he has some reservations and may appreciate subtleties of his data that we do not. In any case, I feel that the scientific exchange has been honest, and it will hopefully avoid the snark that sometimes accompanies such disagreements, and focus instead on the scientific issues at stake.

I wish to thank Graham Coop for inviting me to contribute to Haldane’s Sieve. And thanks of course to my co-authors, including our own fearless leader, David McCandlish.

—Joshua B. Plotkin

N.B.: This blog post is meant as an exchange among scientific colleagues, and not as an advertisement to the media.