Compensatory Evolution in Disease‐Associated Genes


Genetic diseases are caused by amino acid replacements at functionally important positions of protein sequences. These positions are conserved at the interspecific level, indicating that their replacement would be expected to be deleterious between homologous sequences. However, several examples of human disease‐associated mutations have been found in the genomes of non‐human species. Following the model of compensatory evolution, the acceptability of human deleterious mutations in other species is strictly dependent on the presence of a compensatory partner variant that is able to compensate for the negative effect of the mutation. The co‐occurrence of a compensated mutation and its compensatory partner has now been documented for a large number of proteins involved in human genetic disease, thereby increasing theoretical and experimental support for the model of compensatory evolution at the same time as providing us with an improved understanding of the molecular and selective forces underlying the mechanism of amino acid interaction.

Key Concepts

  • A high number of human disease‐associated mutations are found in non‐human species.
  • Many human disease‐associated mutations are compensated in non‐human species by epistatic interactions with a compensatory variant.
  • The deleterious impact of a variant depends on the genetic background where it occurs.
  • The basis of molecular compensation results from the structural interaction between amino acid variants.

Keywords: human disease; deleterious mutation; compensatory evolution; epistasis; amino acid interaction; genetic background; comparative genetics

Figure 1. The compensatory evolution model. (a) Identification of a pair of mutation (red) and the corresponding compensatory site (blue) in the analysis of multiple sequence alignment. (b) Provided as a real example (Kondrashov et al., ) a human disease‐associated allele (red) within the beta globin protein is compensated in the horse protein by a spatially interacting partner (blue).


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Weinreich DM, Watson RA and Chao L (2005) Perspective: Sign epistasis and genetic constraint on evolutionary trajectories. Evolution 59 (6): 1165–1174.

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Azevedo, Luisa(Feb 2015) Compensatory Evolution in Disease‐Associated Genes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022402]