ArticleMolecular biology and evolution2014
Why human disease-associated residues appear as the wild-type in other species: genome-scale structural evidence for the compensation hypothesis.
Article in Molecular biology and evolution, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 25 citations in OpenAlex.
- Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes.Human genomics · 2024Article
- Proteome-Wide Structural Computations Provide Insights into Empirical Amino Acid Substitution Matrices.International journal of molecular sciences · 2023Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Article
- MitImpact 3: modeling the residue interaction network of the Respiratory Chain subunits.Nucleic acids research · 2021Article
- Losses of human disease-associated genes in placental mammals.NAR genomics and bioinformatics · 2020Article
- Compensated pathogenic variants in coagulation factors VIII and IX present complex mapping between molecular impact and hemophilia severity.Scientific reports · 2019Article
- The evolution of gene regulatory networks controlling Arabidopsis thaliana L. trichome development.BMC plant biology · 2019Article
- Review
- Neutral Theory, Disease Mutations, and Personal Exomes.Molecular biology and evolution · 2018Article
- Compensatory mutations and epistasis for protein function.Current opinion in structural biology · 2018Review
- Epistasis Analysis Goes Genome-Wide.PLoS genetics · 2017Article
- Epistasis in protein evolution.Protein science : a publication of the Protein Society · 2016Review
- Causes of molecular convergence and parallelism in protein evolution.Nature reviews. Genetics · 2016Review
- Protein Destabilization as a Common Factor in Diverse Inherited Disorders.Journal of molecular evolution · 2016Article
- Are Convergent and Parallel Amino Acid Substitutions in Protein Evolution More Prevalent Than Neutral Expectations?Molecular biology and evolution · 2015Article
- Contingency and entrenchment in protein evolution under purifying selection.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
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2 authors at 1 institution in 1 country.
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Abstract
Many human-disease associated amino acid residues (DARs) appear as the wild-type in other species. This phenomenon is commonly explained by the presence of compensatory residues in these other species that alleviate the deleterious effects of the DARs. The general validity of this hypothesis, however, is unclear, because few compensatory residues have been identified. Here we test the compensation hypothesis by assembling and analyzing 1,077 DARs located in 177 proteins of known crystal structures. Because destabilizing protein structures is a primary reason why DARs are deleterious, we focus on protein stability in this analysis. We discover that, in species where a DAR represents the wild-type, the destabilizing effect of the DAR is generally lessened by the observed amino acid substitutions in the spatial proximity of the DAR. This and other findings provide genome-scale evidence for the compensation hypothesis and have important implications for understanding epistasis in protein evolution and for using animal models of human diseases.
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