How can functional annotations be derived from profiles of phenotypic annotations?

Beatriz Serrano-Solano,Juan A G Ranea,Antonio Díaz Ramos,Jean-Karim Hériché

doi:10.1186/s12859-017-1503-5

Abstract

BackgroundLoss-of-function phenotypes are widely used to infer gene function using the principle that similar phenotypes are indicative of similar functions. However, converting phenotypic to functional annotations requires careful interpretation of phenotypic descriptions and assessment of phenotypic similarity. Understanding how functions and phenotypes are linked will be crucial for the development of methods for the automatic conversion of gene loss-of-function phenotypes to gene functional annotations.ResultsWe explored the relation between cellular phenotypes from RNAi-based screens in human cells and gene annotations of cellular functions as provided by the Gene Ontology (GO). Comparing different similarity measures, we found that information content-based measures of phenotypic similarity were the best at capturing gene functional similarity. However, phenotypic similarities did not map to the Gene Ontology organization of gene function but to functions defined as groups of GO terms with shared gene annotations.ConclusionsOur observations have implications for the use and interpretation of phenotypic similarities as a proxy for gene functions both in RNAi screen data analysis and curation and in the prediction of disease genes.

Highlights

Loss-of-function phenotypes are widely used to infer gene function using the principle that similar phenotypes are indicative of similar functions
Comparison of phenotypic similarity measures As we wished to link phenotypic similarity to gene function, the first question we addressed is which measure of phenotypic similarity to use for the task
The availability of Cellular Microscopy Phenotype Ontology (CMPO) allows for a semantic information content-based approach to phenotypic similarity, analoguous to what has been used with Gene

Summary

Introduction

Loss-of-function phenotypes are widely used to infer gene function using the principle that similar phenotypes are indicative of similar functions. A central tenet of experimental approaches to assigning functions to genes posits that genes involved in the same biological process show similar loss-of-function phenotypes This provides the rationale for performing loss-offunction genetic screens and is used by the Gene Ontology consortium in their gene annotation process (i.e. for annotations with evidence code IMP: Inferred from Mutant Phenotype, The Gene Ontology Evidence Tree). In contrast to more traditional experiments that have been addressing a single phenotype closely associated with a function, systems microscopy approaches increasingly use phenotypic profiling, the description of phenotypes by multi-parameter measurements. While this increases the amount of usable information, the cost is that functional associations become less evident. Large RNAi screens performed in human cells haven’t been used to annotate genes with Gene Ontology terms from the biological process domain and this contributes to a lower level of experimentally-supported annotations of genes cellular functions than the number of reported functional assays

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