Dataset Information

A resource of variant effect predictions of single nucleotide variants in model organisms.

ABSTRACT: The effect of single nucleotide variants (SNVs) in coding and noncoding regions is of great interest in genetics. Although many computational methods aim to elucidate the effects of SNVs on cellular mechanisms, it is not straightforward to comprehensively cover different molecular effects. To address this, we compiled and benchmarked sequence and structure-based variant effect predictors and we computed the impact of nearly all possible amino acid and nucleotide variants in the reference genomes of Homo sapiens, Saccharomyces cerevisiae and Escherichia coli Studied mechanisms include protein stability, interaction interfaces, post-translational modifications and transcription factor binding sites. We apply this resource to the study of natural and disease coding variants. We also show how variant effects can be aggregated to generate protein complex burden scores that uncover protein complex to phenotype associations based on a set of newly generated growth profiles of 93 sequenced S. cerevisiae strains in 43 conditions. This resource is available through mutfunc (www.mutfunc.com), a tool by which users can query precomputed predictions by providing amino acid or nucleotide-level variants.

SUBMITTER: Wagih O

PROVIDER: S-EPMC6301329 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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A resource of variant effect predictions of single nucleotide variants in model organisms.

Wagih Omar O Galardini Marco M Busby Bede P BP Memon Danish D Typas Athanasios A Beltrao Pedro P

Molecular systems biology 20181220 12

The effect of single nucleotide variants (SNVs) in coding and noncoding regions is of great interest in genetics. Although many computational methods aim to elucidate the effects of SNVs on cellular mechanisms, it is not straightforward to comprehensively cover different molecular effects. To address this, we compiled and benchmarked sequence and structure-based variant effect predictors and we computed the impact of nearly all possible amino acid and nucleotide variants in the reference genomes ...[more]

PMID: 30573687

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Project description:The targeted capture and sequencing of genomic regions has rapidly demonstrated its utility in genetic studies. Inherent in this technology is considerable heterogeneity of target coverage and this is expected to systematically impact our sensitivity to detect genuine polymorphisms. To fully interpret the polymorphisms identified in a genetic study it is often essential to both detect polymorphisms and to understand where and with what probability real polymorphisms may have been missed.Using down-sampling of 30 deeply sequenced exomes and a set of gold-standard single nucleotide variant (SNV) genotype calls for each sample, we developed an empirical model relating the read depth at a polymorphic site to the probability of calling the correct genotype at that site. We find that measured sensitivity in SNV detection is substantially worse than that predicted from the naive expectation of sampling from a binomial. This calibrated model allows us to produce single nucleotide resolution SNV sensitivity estimates which can be merged to give summary sensitivity measures for any arbitrary partition of the target sequences (nucleotide, exon, gene, pathway, exome). These metrics are directly comparable between platforms and can be combined between samples to give "power estimates" for an entire study. We estimate a local read depth of 13X is required to detect the alleles and genotype of a heterozygous SNV 95% of the time, but only 3X for a homozygous SNV. At a mean on-target read depth of 20X, commonly used for rare disease exome sequencing studies, we predict 5-15% of heterozygous and 1-4% of homozygous SNVs in the targeted regions will be missed.Non-reference alleles in the heterozygote state have a high chance of being missed when commonly applied read coverage thresholds are used despite the widely held assumption that there is good polymorphism detection at these coverage levels. Such alleles are likely to be of functional importance in population based studies of rare diseases, somatic mutations in cancer and explaining the "missing heritability" of quantitative traits.

Dataset Information

A resource of variant effect predictions of single nucleotide variants in model organisms.

Publications

A resource of variant effect predictions of single nucleotide variants in model organisms.

Similar Datasets

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