ArticleGenetics in medicine : official journal of the American College of Medical Genetics2016
Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- Conformational changes in the Niemann-Pick type C1 protein NCR1 drive sterol translocation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Shedding light on theFrontiers in molecular biosciences · 2024Article
- Evolutionary history of MEK1 illuminates the nature of deleterious mutations.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Evolutionary association of receptor-wide amino acids with G protein-coupling selectivity in aminergic GPCRs.Life science alliance · 2022Article
- Article
- Computational Insights into the Deleterious Impacts of Missense Variants onInternational journal of molecular sciences · 2021Article
- Phylostat: a web-based tool to analyze paralogous clade divergence in phylogenetic trees.Turkish journal of biology = Turk biyoloji dergisi · 2021Article
- Identification and Characterization of a NovelGenes · 2020Article
- Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18Journal of clinical medicine · 2020Article
- Curated multiple sequence alignment for the Adenomatous Polyposis Coli (APC) gene and accuracy of in silico pathogenicity predictions.PloS one · 2020Article
- Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study.EBioMedicine · 2020Article
- Utility of primary cells to examine NPC1 receptor expression in Mops condylurus, a potential Ebola virus reservoir.PLoS neglected tropical diseases · 2020Article
- Variation benchmark datasets: update, criteria, quality and applications.Database : the journal of biological databases and curation · 2020Article
- Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases.Scientific reports · 2019Article
- Characterization of Squamous Cell Lung Cancers from Appalachian Kentucky.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2019Article
- From prioritisation to understanding: mechanistic predictions of variant effects.Molecular systems biology · 2018Article
- Article
- A novelCold Spring Harbor molecular case studies · 2018Article
- Revealing Alzheimer's disease genes spectrum in the whole-genome by machine learning.BMC neurology · 2018Article
- Assessing predictions of fitness effects of missense mutations in SUMO-conjugating enzyme UBE2I.Human mutation · 2017Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
purposePredicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease.
methodsWe identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism's fitness.
resultsRemoving the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions.
conclusionThe results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well.Genet Med 18 10, 1029-1036.
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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 Socratic graph.