Molecular coevolution is an ongoing process by which a change in the sequence or function of a nucleic acid or protein molecule alters the selective effect of substitutions in another molecule or at other sites in the same molecule. Examples are given that illustrate that coevolution can be the consequence of a variety of forces, including positive selection to maintain compatibility (e.g. gamete recognition proteins) in the interacting molecules or due to relaxation of selective constraints at some sites due to substitutions at other sites with which they interact (e.g. the growth hormone and its receptors). Methods to detect molecular coevolution are constantly developing, and examples of these are provided that generally indicate that explicit consideration of evolutionary relationships and of background neutral rates of substitution improves inferences.

Key Concepts:

• The negative or positive selective pressures acting at a site in a molecule are conditional depending on the content of the molecular sites with which it interacts.
  
• The acceptance of mutations into a population that can have important consequences for binding or function can be driven by positive selection for function or by neutral acceptance of formally deleterious mutations rendered permissible by changes at other interacting sites.
  
• Coevolution is frequently accompanied by an increase in the rate of amino acid replacement.
  
• Detection of coevolution is improved by accounting for the underlying patterns of relationship among the species and for the underlying rate of neutral mutation.
  
• Coevolution of interacting molecules may reinforce reproductive isolation between species via gamete recognition or effects on molecular function.