Interpreting functional effects of coding variants

Challenges in proteome-scale prediction, annotation and assessment

Khader Shameer, Lokesh P. Tripathi, Krishna R Kalari, Joel T. Dudley, Ramanathan Sowdhamini

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Accurate assessment of genetic variation in human DNA sequencing studies remains a nontrivial challenge in clinical genomics and genome informatics. Ascribing functional roles and/or clinical significances to single nucleotide variants identified from a next-generation sequencing studyis an important stepin genome interpretation.Experimental characterization ofall the observed functional variants is yet impractical;thus, the prediction offunctional and/or regulatoryimpacts ofthe various mutations using in silico approaches is an important step toward the identification of functionally significant or clinically actionable variants. The relationships between genotypes and the expressed phenotypes aremultilayered and biologically complex; such relationships present numerous challenges and at the same time offer various opportunities for the design of in silico variant assessment strategies. Over the past decade,many bioinformatics algorithms have been developed to predict functional consequences of single nucleotide variants in the protein coding regions. In this review, we provide an overview of the bioinformatics resources for the prediction, annotation and visualization of coding single nucleotide variants. We discuss the currently available approaches andmajor challenges fromthe perspective of protein sequence, structure, function and interactions that require consideration when interpreting the impact of putatively functional variants.We also discuss the relevance of incorporating integrated workflows for predicting the biomedical impact of the functionally important variations encoded in a genome, exome or transcriptome. Finally, we propose a framework to classify variant assessment approaches and strategies for incorporation of variant assessment within electronic health records.

Original languageEnglish (US)
Pages (from-to)841-862
Number of pages22
JournalBriefings in Bioinformatics
Volume17
Issue number5
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Proteome
Nucleotides
Genes
Genome
Bioinformatics
Computational Biology
Proteins
Computer Simulation
Exome
Informatics
Workflow
Electronic Health Records
Genomics
DNA Sequence Analysis
Transcriptome
Open Reading Frames
DNA
Visualization
Genotype
Health

Keywords

  • Functional genomics
  • Functional variant
  • Human genome
  • Human proteome
  • Human variation
  • Mutation
  • Nonsynonymous mutations
  • Prediction algorithms
  • Sequence analysis
  • Structure analysis
  • Variant interpretation

ASJC Scopus subject areas

  • Information Systems
  • Molecular Biology

Cite this

Interpreting functional effects of coding variants : Challenges in proteome-scale prediction, annotation and assessment. / Shameer, Khader; Tripathi, Lokesh P.; Kalari, Krishna R; Dudley, Joel T.; Sowdhamini, Ramanathan.

In: Briefings in Bioinformatics, Vol. 17, No. 5, 01.09.2016, p. 841-862.

Research output: Contribution to journalArticle

Shameer, Khader ; Tripathi, Lokesh P. ; Kalari, Krishna R ; Dudley, Joel T. ; Sowdhamini, Ramanathan. / Interpreting functional effects of coding variants : Challenges in proteome-scale prediction, annotation and assessment. In: Briefings in Bioinformatics. 2016 ; Vol. 17, No. 5. pp. 841-862.
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