Compensatory Evolution in Disease‐Associated Genes

Abstract

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).
close

References

Azevedo L, Suriano G, van Asch B, et al. (2006) Epistatic interactions: how strong in disease and evolution? Trends in Genetics 22 (11): 581–585.

Azevedo L, Carneiro J, van Asch B, et al. (2009) Epistatic interactions modulate the evolution of mammalian mitochondrial respiratory complex components. BMC Genomics 10 (1): 266.

Baresic A, Hopcroft LE, Rogers HH, et al. (2010) Compensated pathogenic deviations: analysis of structural effects. Journal of Molecular Biology 396 (1): 19–30.

Benit P, Rey F, Melle D, et al. (1994) Five novel missense mutations of the phenylalanine hydroxylase gene in phenylketonuria. Human Mutation 4 (3): 229–231.

Breen MS, Kemena C, Vlasov PK, et al. (2012) Epistasis as the primary factor in molecular evolution. Nature 490 (7421): 535–538.

Davis BH, Poon AFY and Whitlock MC (2009) Compensatory mutations are repeatable and clustered within proteins. Proceedings of the Royal Society B: Biological Sciences 276 (1663): 1823–1827.

Ferrer‐Costa C, Orozco M and de la Cruz X (2007) Characterization of compensated mutations in terms of structural and physico‐chemical properties. Journal of Molecular Biology 365 (1): 249–256.

Gao L and Zhang J (2003) Why are some human disease‐associated mutations fixed in mice? Trends in Genetics 19 (12): 678–681.

Gibbs RA, Rogers J, Katze MG, et al. (2007) Evolutionary and biomedical insights from the rhesus macaque genome. Science 316 (5822): 222–234.

Gilbert‐Dussardier B, Segues B, Rozet JM, et al. (1996) Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia. Human Mutation 8 (1): 74–76.

Ivankov DN, Finkelstein AV and Kondrashov FA (2014) A structural perspective of compensatory evolution. Current Opinion in Structural Biology 26: 104–112.

Kondrashov AS, Sunyaev S and Kondrashov FA (2002) Dobzhansky‐Muller incompatibilities in protein evolution. Proceedings of the National Academy of Sciences of the United States of America 99 (23): 14878–14883.

Kulathinal RJ, Bettencourt BR and Hartl DL (2004) Compensated deleterious mutations in insect genomes. Science 306 (5701): 1553–1554.

Miller M and Kumar S (2001) Understanding human disease mutations through the use of interspecific genetic variation. Human Molecular Genetics 10 (21): 2319–2328.

Numata S, Harada E, Maeno Y, et al. (2008) Paternal transmission and slow elimination of mutant alleles associated with late‐onset ornithine transcarbamylase deficiency in male patients. Journal of Human Genetics 53 (1): 10–17.

Polymeropoulos MH, Lavedan C, Leroy E, et al. (1997) Mutation in the alpha‐synuclein gene identified in families with Parkinson's disease. Science 276 (5321): 2045–2047.

Stenson PD, Mort M, Ball EV, et al. (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Human Genetics 133 (1): 1–9.

Subramanian S and Kumar S (2006) Evolutionary anatomies of positions and types of disease‐associated and neutral amino acid mutations in the human genome. BMC Genomics 7 (1): 306.

Suriano G, Azevedo L, Novais M, et al. (2007) In vitro demonstration of intra‐locus compensation using the ornithine transcarbamylase protein as model. Human Molecular Genetics 16 (18): 2209–2214.

The Chimpanzee Sequencing and Analysis Consortium (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437 (7055): 69–87.

Thomas PD and Kejariwal A (2004) Coding single‐nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. Proceedings of the National Academy of Sciences of the United States of America 101 (43): 15398–15403.

Tuchman M, Plante RJ, McCann MT, et al. (1994) Seven new mutations in the human ornithine transcarbamylase gene. Human Mutation 4 (1): 57–60.

Waterston RH, Lindblad‐Toh K, Birney E, et al. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420 (6915): 520–562.

Xu J and Zhang J (2014) Why human disease‐associated residues appear as the wild‐type in other species: genome‐scale structural evidence for the compensation hypothesis. Molecular Biology and Evolution 31 (7): 1787–1792.

Zhang G, Pei Z, Krawczak M, et al. (2010) Triangulation of the human, chimpanzee, and Neanderthal genome sequences identifies potentially compensated mutations. Human Mutation 31 (12): 1286–1293.

Further Reading

DePristo MA, Weinreich DM and Hartl DL (2005) Missense meanderings in sequence space: a biophysical view of protein evolution. Nature Reviews Genetics 6 (9): 678–687.

Kern AD and Kondrashov FA (2004) Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs. Nature Genetics 36 (11): 1207–1212.

Lehner B (2011) Molecular mechanisms of epistasis within and between genes. Trends in Genetics 27 (8): 323–331.

Poon A and Chao L (2005) The rate of compensatory mutation in the DNA bacteriophage phiX174. Genetics 170 (3): 989–999.

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

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Azevedo, Luisa(Feb 2015) Compensatory Evolution in Disease‐Associated Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022402]