page1
The ongoing functional annotation of proteins relies upon the work of curators to capture experimental findings from scientific literature and apply them to protein sequence and structure data. However, with the increasing use of high-throughput experimental assays, a small number of experimental studies dominate the functional protein annotations collected in databases. Here we investigate just how prevalent is the ``few articles -- many proteins'' phenomenon.
1. 0.14% of articles providing the source of annotations for 25% of the proteins in the UniProt-GOA compilation.
2. Mass-spectrometry, microscopy and RNAi experiments dominate high throughput experiments.
Consequently, the functional information derived from these experiments is mostly of the subcellular location of proteins, and of the participation of proteins in embryonic developmental pathways.
3. For some organisms, the information provided by different studies overlap by a large amount.
4. the information provided by high throughput experiments is less specific than those provided by low throughput experiments.
Given the experimental techniques available, certain biases in protein function annotation due to high-throughput experiments are unavoidable. Knowing that these biases exist and understanding their characteristics and extent is important for database curators, developers of function annotation programs, and anyone who uses protein function annotation data to plan experiments.
Top 25 Papers—
The Set of Papers that Annotate the Most Proteins in GOA
Ontology abbreviations: BPO (Biological Process Ontology), CCO (Cellular Compartment Ontology), MFO (Molecular Function Ontology)
a
Molecular Function
Biological Process
Cellular Component
Information Content (bits)
The more proteins a paper describes, the less information is given per protein
1: one protein per paper; <10: 2-9 proteins/paper; <100: 10-100 proteins/paper; > 100: more than 100 proteins /paper
Biases in the Experimental Annotations of Protein Function and their Eﬀect on Our Understanding of Protein Function Space
Alexandra M Schnoes1, David C Ream2, Alexander W Thorman2, Patricia C Babbitt1, Iddo Friedberg*2,3
Dept of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA 2. Depts. of Microbiology, and
3. Computer Science and Software Engineering, Miami University, Oxford OH, USA
To remedy the bias created by high throughput annotations, the provenance of annotations should be described in more detail by curators and annotation software. Many function annotation algorithms rely on homology transfer as part of their pipeline to annotate query sequences. Knowing the annotation provenance, including the number of proteins annotated by the original paper can create less biased benchmarks or otherwise incorporate that information into the annotation procedure. The ECO ontology can be used to determine the source of the annotation, and the user or the algorithm can decide whether to rely upon any combinations of ``throughputness'' and experimental type. Of course, such approaches should be taken cautiously, as sweeping measures can cause the unintended loss of information. We hereby call upon the communities of annotators, computational biologists and experimental biologists to be mindful of the phenomenon of the experimental biases described in this study, and to work to understand its implications and impact.
Possible solution?
Distribution of the number of proteins annotated per article
Relative contribution of top-50 articles to the annotation of major model organisms
A circle represents the sum total of articles annotating each organism. Each colored arch is composed of all the proteins in a single article. A line is drawn between any two points on the circle if the proteins they represent have 100\% sequence identity. A black line is drawn if they are annotated with a different ontology (for example, in one article the protein is annotated with the MFO, and in another article with BPO); a red line if they are annotated in the same ontology. Example: S. pombe is described by two articles, one with few protein (light arch on bottom) and one with many (dark arch encompassing most of circle). Many of the same proteins are annotated by both articles.
Redundancy in proteins described by the top-50 articles.
Paper:
Contact:
friedbi@miamioh.edu: