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Review
. 2022 Jan;31(1):8-22.
doi: 10.1002/pro.4218. Epub 2021 Nov 25.

PANTHER: Making genome-scale phylogenetics accessible to all

Paul D Thomas  1 , Dustin Ebert  1 , Anushya Muruganujan  1 , Tremayne Mushayahama  1 , Laurent-Philippe Albou  1 , Huaiyu Mi  1
Affiliations
Review

PANTHER: Making genome-scale phylogenetics accessible to all

Paul D Thomas et al. Protein Sci. 2022 Jan.

Abstract

Phylogenetics is a powerful tool for analyzing protein sequences, by inferring their evolutionary relationships to other proteins. However, phylogenetics analyses can be challenging: they are computationally expensive and must be performed carefully in order to avoid systematic errors and artifacts. Protein Analysis THrough Evolutionary Relationships (PANTHER; http://pantherdb.org) is a publicly available, user-focused knowledgebase that stores the results of an extensive phylogenetic reconstruction pipeline that includes computational and manual processes and quality control steps. First, fully reconciled phylogenetic trees (including ancestral protein sequences) are reconstructed for a set of "reference" protein sequences obtained from fully sequenced genomes of organisms across the tree of life. Second, the resulting phylogenetic trees are manually reviewed and annotated with function evolution events: inferred gains and losses of protein function along branches of the phylogenetic tree. Here, we describe in detail the current contents of PANTHER, how those contents are generated, and how they can be used in a variety of applications. The PANTHER knowledgebase can be downloaded or accessed via an extensive API. In addition, PANTHER provides software tools to facilitate the application of the knowledgebase to common protein sequence analysis tasks: exploring an annotated genome by gene function; performing "enrichment analysis" of lists of genes; annotating a single sequence or large batch of sequences by homology; and assessing the likelihood that a genetic variant at a particular site in a protein will have deleterious effects.

Keywords: gene ontology; genome analysis; hidden Markov model; molecular evolution; omics data analysis; phylogenetic tree; protein function annotation; protein function evolution.

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Figures

FIGURE 1
FIGURE 1
List of unconnected proteins for the GO class (“Wnt signaling pathway” (GO:0016055) (left panel), compared to connected components of the PANTHER Pathway P00057 “Wnt signaling pathway” (right panel). Each pathway component is a generalized protein (a group of one or more specified clades of related proteins in the knowledgebase) that participate in sequential steps/reactions in the pathway
FIGURE 2
FIGURE 2
Overview of the content of the Protein Analysis THrough Evolutionary Relationships (PANTHER) KB. Individual proteins (right) are annotated with knowledge derived from the annotated PANTHER families (left), and with knowledge imported from external resources (green). All information is updated yearly, except for imported gene ontology (GO) annotations, which are updated monthly to synchronize with official GO releases
FIGURE 3
FIGURE 3
The interleukin 1 family in Protein Analysis THrough Evolutionary Relationships (PANTHER) (PTHR10078). Green circles represent speciation events, while orange circles represent duplication. Diamonds are expanded subfamily nodes, and triangles are collapsed nodes. Most family members are cytokines from the ancestral annotation from the root node of the tree (green arrow), but a phylogenomic analysis suggests that, following gene duplication (orange arrow), two subfamilies of mammalian genes (IL36RN and IL1RN, red arrows) adopted modified functions and now all subfamily members are likely to act as receptor antagonists rather than agonists. Note that we have collapsed some nodes (shown with triangles) here to simplify the diagram by hiding some descendant subtrees. Different colors correspond to different subfamilies. The full family tree can be explored at www.pantherdb.org/treeViewer/treeViewer.jsp?book=PTHR10078
FIGURE 4
FIGURE 4
The Protein Analysis THrough Evolutionary Relationships (PANTHER) pipeline transforms raw protein sequence data into knowledge about gene family and function evolution. The major direction of data flow shown with solid arrows. Blue arrows indicate automated computational processes, while orange indicates manually curated processes. QA processes are shown as dashed lines in the reverse direction. Gray boxes and black arrows show external data inputs
FIGURE 5
FIGURE 5
The Protein Analysis THrough Evolutionary Relationships (PANTHER) knowledgebase interoperates with many resources, via regular knowledge transfer and exchange (solid arrows) or hyperlinks (dashed arrows)
FIGURE 6
FIGURE 6
Citations of Protein Analysis THrough Evolutionary Relationships (PANTHER) for analysis of different types of experimental data. With the continued growth in RNA‐seq experiments, the increase in gene expression and epigenomics analysis has increased even more rapidly in the past 5 years or so
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