Proteogenomics to discover the full coding content of genomes: A computational perspective

Abstract

Proteogenomics has emerged as a field at the junction of genomics and proteomics. It is a loose collection of technologies that allow the search of tandem mass spectra against genomic databases to identify and characterize protein-coding genes. Proteogenomic peptides provide invaluable information for gene annotation, which is difficult or impossible to ascertain using standard annotation methods. Examples include confirmation of translation, reading-frame determination, identification of gene and exon boundaries, evidence for post-translational processing, identification of splice-forms including alternative splicing, and also, prediction of completely novel genes. For proteogenomics to deliver on its promise, however, it must overcome a number of technological hurdles, including speed and accuracy of peptide identification, construction and search of specialized databases, correction of sampling bias, and others. This article reviews the state of the art of the field, focusing on the current successes, and the role of computation in overcoming these challenges. We describe how technological and algorithmic advances have already enabled large-scale proteogenomic studies in many model organisms, including arabidopsis, yeast, fly, and human. We also provide a preview of the field going forward, describing early efforts in tackling the problems of complex gene structures, searching against genomes of related species, and immunoglobulin gene reconstruction.

Inference and Validation of Protein Identifications

“…These considerations are more intricate in proteogenomic projects that aim at genome annotation and discovery of novel gene models from shotgun proteomic data (58,59). The nature of these projects entails the use of large sequence databases that account for all possible protein coding regions of a genome.…”

“…Proteogenomic studies for various model organisms resorted to six frame translated genomic databases and expressed sequence tag (EST) 1 databases to achieve this goal (60 -64). The number of peptides in such databases is in the order of billions and further grows by two orders of magnitude if single amino acid mutations are considered, too (58). Several strategies have been pursued to faithfully compress these databases.…”

Brain Proteomics of Anopheles gambiae

“…Proteogenomics strategy stands out as an important experimental tool to identify the protein coding potential of sequenced or unsequenced genomes of an organism (Castellana et al, 2010;Krug et al, 2011). Proteogenomically identified peptide data can provide invaluable information for gene annotation, which is almost impossible or difficult to predict using nucleotide sequence information alone.…”

GAPP: A Proteogenomic Software for Genome Annotation and Global Profiling of Post-translational Modifications in Prokaryotes

“…Over the last few years, computational proteomics has become a dramatically growing field, and a handful of tools have been developed to execute complete proteogenomic analyses (11,46,47). Two excellent reviews have described a comprehensive overview of the various problems commonly encountered and their current solutions for this growing research area (8,11).…”