Critical assessment of missense variant effect predictors on disease-relevant variant data

Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Abstract Regular, systematic, and independent assessments of computational tools that are used to predict the pathogenicity missense variants necessary evaluate their clinical research utility guide future improvements. The Critical Assessment Genome Interpretation (CAGI) conducts ongoing Annotate-All-Missense (Missense Marathon) challenge, in which variant effect predictors (also called impact predictors) evaluated on added disease-relevant databases following prediction submission deadline. Here we assess submitted CAGI 6 commonly genetics, recently developed deep learning methods. We examine performance across a range settings relevant for applications, focusing different subsets evaluation data as well high-specificity high-sensitivity regimes. Our evaluations reveal notable advances current methods relative older, well-cited field. While meta-predictors tend outperform constituent individual predictors, several newer perform comparably meta-predictors. Predictor varies between regimes, highlighting may be optimal use cases. also characterize two potential sources bias. Predictors incorporate allele frequency predictive feature have reduced when distinguishing pathogenic from very rare benign variants, trained labels curated often inherit gene-level label imbalances. findings help illuminate modern identify areas development.

Language: Английский

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Introgression of regulatory alleles and a missense coding mutation drive plumage pattern diversity in the rock pigeon

eLife, Journal Year: 2018, Volume and Issue: 7

Published: July 17, 2018

Birds and other vertebrates display stunning variation in pigmentation patterning, yet the genes controlling this diversity remain largely unknown. Rock pigeons (Columba livia) are fundamentally one of four color pattern phenotypes, decreasing order melanism: T-check, checker, bar (ancestral), or barless. Using whole-genome scans, we identified NDP as a candidate gene for variation. Allele-specific expression differences indicate cis-regulatory divergence between ancestral melanistic alleles. Sequence comparisons suggest that derived alleles originated speckled pigeon guinea), providing striking example introgression. In contrast, barless rock have an increased incidence vision defects and, like human families with hereditary blindness, carry start-codon mutations NDP. summary, find both coding regulatory same drives wing diversity, post-domestication introgression supplied potentially advantageous to feral populations ubiquitous urban bird.

Language: Английский

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Positive-unlabelled learning of glycosylation sites in the human proteome

BMC Bioinformatics, Journal Year: 2019, Volume and Issue: 20(1)

Published: March 6, 2019

As an important type of post-translational modification (PTM), protein glycosylation plays a crucial role in stability and function. The abundance ubiquity across three domains life involving Eukarya, Bacteria Archaea demonstrate its roles regulating variety signalling metabolic pathways. Mutations on the proximity sites are highly associated with human diseases. Accordingly, accurate prediction can complement laboratory-based methods greatly benefit experimental efforts for characterization understanding functional glycosylation. For this purpose, number supervised-learning approaches have been proposed to identify sites, demonstrating promising predictive performance. To train conventional model, both reliable positive negative samples required. However, practice, large portion (i.e. non-glycosylation sites) mislabelled due limitation current technologies. Moreover, supervised algorithms often fail take advantage volumes unlabelled data, which aid model learning conjunction experimentally verified sites).

Language: Английский

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Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Sept. 12, 2019

Abstract Each human genome carries tens of thousands coding variants. The extent to which this variation is functional and the mechanisms by they exert their influence remains largely unexplored. To address gap, we leverage ExAC database 60,706 exomes investigate experimentally impact 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, 421 SNVs segregate at > 1% allele frequency in populations. We find that interaction-disruptive are prevalent both rare common frequencies. Furthermore, these results suggest 10.5% carried per individual disruptive, a higher proportion than previously reported; indicates each individual’s genetic makeup may be significantly more complex expected. Finally, demonstrate candidate disease-associated mutations can identified through shared perturbations between interest known disease mutations.

Language: Английский

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Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

Biological Psychiatry, Journal Year: 2019, Volume and Issue: 87(2), P. 100 - 112

Published: June 29, 2019

Language: Английский

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