Referee 1's review (Daniel Perez):

A couple of comments in the discussion:

lines 225-227 : "The method offers a means by which to measure epistatic evolution among isolates across groups of localities, helping identify functional geographic units at a variety of spatial scales." I do not understand what the sentence means. Basically the authors should make an effort to help the reader understand how these analysis would in the future be available to any health authority of animal health authority make decisions regarding movement of animals and people to stop the spread of any given disease.

lines 288-289: Yet another model proposes these antigenic shifts arise from changes in host population immunity" Do you mean antigenic drift?

**********
N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.