Fig 2. Distinguishing between additive and epistatic episodic selection.

Each pair of sites can be characterized by excess or deficit of rapid substitutions in the same lineage (horizontal axis), vs. clustering or repulsion of substitutions in different lineages (vertical axis). On the scheme, substitutions at one of the two considered sites are shown in black, and substitutions at the other are shown in gray. An excess of rapid consecutive substitutions accompanied by clustering of nonconsecutive substitutions (quadrant I) implies concurrent episodic selection and can be observed without any epistatic interactions between sites. Analogously, a deficit of rapid consecutive substitutions accompanied by repulsion of nonconsecutive substitutions (quadrant III) implies episodes of selection that are distinct between the two sites and does not necessarily require epistasis. By contrast, an excess of rapid consecutive substitutions together with repulsion of nonconsecutive substitutions (quadrant IV) cannot be explained by episodic selection alone and is indicative of positive epistasis. Similarly, a deficit of rapid consecutive substitutions along with clustering of nonconsecutive ones indicates negative epistasis.