ArticlePLoS genetics2010
The use of orthologous sequences to predict the impact of amino acid substitutions on protein function.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
31 citing papers in PubMed, 48 citations in OpenAlex.
- Exploring molecular mechanisms of aminoglycoside resistance in Escherichia coli MG1655 using the antibiotic resistance growth plate.Scientific reports · 2026Article
- Prognostic Modeling of Deleterious IDUA Mutations L238Q and P385R in Hurler Syndrome Through Molecular Dynamics Simulations.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Meta-EA: a gene-specific combination of available computational tools for predicting missense variant effects.Nature communications · 2025Article
- Development of a novel and viable knock-in factor V deficiency murine model: Utility for an ultra-rare disease.PloS one · 2025Article
- Low nucleotide diversity of the Plasmodium falciparum AP2-EXP2 gene among clinical samples from Ghana.Parasites & vectors · 2024Article
- Variant Impact Predictor database (VIPdb), version 2: trends from three decades of genetic variant impact predictors.Human genomics · 2024Article
- Variant Impact Predictor database (VIPdb), version 2: Trends from 25 years of genetic variant impact predictors.bioRxiv : the preprint server for biology · 2024Article
- Genome wide and evolutionary analysis of heat shock protein 70 proteins in tomato and their role in response to heat and drought stress.Molecular biology reports · 2022Article
- Humanized yeast to model human biology, disease and evolution.Disease models & mechanisms · 2022Review
- VIPdb, a genetic Variant Impact Predictor Database.Human mutation · 2019Article
- Evolutionary Analysis of Makorin Ring Finger Protein 3 Reveals Positive Selection in Mammals.Evolutionary bioinformatics online · 2019Article
- Comparative Genomics Approaches Accurately Predict Deleterious Variants in Plants.G3 (Bethesda, Md.) · 2018Article
- In silico mutational analysis and identification of stability centers in human interleukin-4.Molecular biology research communications · 2018Article
- Positive selection drives the evolution of endocrine regulatory bone morphogenetic protein system in mammals.Oncotarget · 2018Article
- Maximum-likelihood approaches reveal signatures of positive selection in BMP15 and GDF9 genes modulating ovarian function in mammalian female fertility.Ecology and evolution · 2017Article
- Objective assessment of the evolutionary action equation for the fitness effect of missense mutations across CAGI-blinded contests.Human mutation · 2017Review
- Substitutional Analysis of Orthologous Protein Families Using BLOCKS.Bioinformation · 2017Article
- Review
- An extended set of yeast-based functional assays accurately identifies human disease mutations.Genome research · 2016Article
- Efforts to make and apply humanized yeast.Briefings in functional genomics · 2016Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Computational predictions of the functional impact of genetic variation play a critical role in human genetics research. For nonsynonymous coding variants, most prediction algorithms make use of patterns of amino acid substitutions observed among homologous proteins at a given site. In particular, substitutions observed in orthologous proteins from other species are often assumed to be tolerated in the human protein as well. We examined this assumption by evaluating a panel of nonsynonymous mutants of a prototypical human enzyme, methylenetetrahydrofolate reductase (MTHFR), in a yeast cell-based functional assay. As expected, substitutions in human MTHFR at sites that are well-conserved across distant orthologs result in an impaired enzyme, while substitutions present in recently diverged sequences (including a 9-site mutant that "resurrects" the human-macaque ancestor) result in a functional enzyme. We also interrogated 30 sites with varying degrees of conservation by creating substitutions in the human enzyme that are accepted in at least one ortholog of MTHFR. Quite surprisingly, most of these substitutions were deleterious to the human enzyme. The results suggest that selective constraints vary between phylogenetic lineages such that inclusion of distant orthologs to infer selective pressures on the human enzyme may be misleading. We propose that homologous proteins are best used to reconstruct ancestral sequences and infer amino acid conservation among only direct lineal ancestors of a particular protein. We show that such an "ancestral site preservation" measure outperforms other prediction methods, not only in our selected set for MTHFR, but also in an exhaustive set of E. coli LacI mutants.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.