ArticlePLoS computational biology2016
The Loss and Gain of Functional Amino Acid Residues Is a Common Mechanism Causing Human Inherited Disease.
Article in PLoS computational biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
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- Mining cancer genomes for change-of-metabolic-function mutations.Communications biology · 2023Article
- Prioritizing de novo autism risk variants with calibrated gene- and variant-scoring models.Human genetics · 2022Article
- Computational and experimental methods for classifying variants of unknown clinical significance.Cold Spring Harbor molecular case studies · 2022Article
- dCas9-VPR-mediated transcriptional activation of functionally equivalent genes for gene therapy.Nature protocols · 2022Review
- Assessment of methods for predicting the effects of PTEN and TPMT protein variants.Human mutation · 2019Article
- Gain-of-Function Mutations: An Emerging Advantage for Cancer Biology.Trends in biochemical sciences · 2019Review
- Pathogenicity and functional impact of non-frameshifting insertion/deletion variation in the human genome.PLoS computational biology · 2019Article
- Spatial distribution of disease-associated variants in three-dimensional structures of protein complexes.Oncogenesis · 2017Article
- Missense variant pathogenicity predictors generalize well across a range of function-specific prediction challenges.Human mutation · 2017Article
- The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.Human genetics · 2017Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Elucidating the precise molecular events altered by disease-causing genetic variants represents a major challenge in translational bioinformatics. To this end, many studies have investigated the structural and functional impact of amino acid substitutions. Most of these studies were however limited in scope to either individual molecular functions or were concerned with functional effects (e.g. deleterious vs. neutral) without specifically considering possible molecular alterations. The recent growth of structural, molecular and genetic data presents an opportunity for more comprehensive studies to consider the structural environment of a residue of interest, to hypothesize specific molecular effects of sequence variants and to statistically associate these effects with genetic disease. In this study, we analyzed data sets of disease-causing and putatively neutral human variants mapped to protein 3D structures as part of a systematic study of the loss and gain of various types of functional attribute potentially underlying pathogenic molecular alterations. We first propose a formal model to assess probabilistically function-impacting variants. We then develop an array of structure-based functional residue predictors, evaluate their performance, and use them to quantify the impact of disease-causing amino acid substitutions on catalytic activity, metal binding, macromolecular binding, ligand binding, allosteric regulation and post-translational modifications. We show that our methodology generates actionable biological hypotheses for up to 41% of disease-causing genetic variants mapped to protein structures suggesting that it can be reliably used to guide experimental validation. Our results suggest that a significant fraction of disease-causing human variants mapping to protein structures are function-altering both in the presence and absence of stability disruption.
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