The JAX Synteny Browser for mouse-human comparative genomics

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the browser is limited to the reference genomes for the laboratory mouse and human, the software platform is intentionally genome agnostic. The JAX Synteny Browser software can be deployed for any two genomes where genome coordinates for syntenic blocks are defined and for which biological attributes of the features in one or both genomes are available in widely used standard bioinformatics file formats. The JAX Synteny Browser is available at: http://syntenybrowser.jax.org/. The code base is available from GitHub: https://github.com/TheJacksonLaboratory/syntenybrowser and is distributed under the Creative Commons Attribution license (CC BY). Electronic supplementary material The online version of this article (10.1007/s00335-019-09821-4) contains supplementary material, which is available to authorized users.

The basic workflow for using the JAX Synteny Browser involves four steps: (1) selecting the Reference genome, (2) specifying a region of interest on the Reference, (3) visualizing the region of interest and its corresponding conserved syntenic block(s) in the Comparison genome, and (4) selectively highlighting genes in the Reference and Comparison genomes based on their biological attributes.
Two use cases described below serve to demonstrate this workflow. As the user interfaces for the JAX Synteny Browser evolve with software updates, this document illustrating different use cases will be updated. The most recent version will be available here: http://syntenybrowser.jax.org/docs.html

Use Case #1: Identify candidate genes in a mapped interval for human lung cancer susceptibility
A region of human chromosome 6 (6q23-25; GRCm38 chr6: 130300000-161000000 bp) was identified previously as a linkage interval associated with human lung cancer susceptibility (Bailey-Wilson, et al., 2004). Because this linkage interval also overlaps regions of allelic loss observed in several cancers, the authors hypothesized that genes involved in regulating apoptosis would be good candidates for the susceptibility phenotype.
The first step in using the JAX Synteny Browser to find potential candidate genes for the lung cancer susceptibility locus is to select human as the Reference genome.
Next, the user navigates to the region of interest on chromosome 6 using one of two options. For the first option, human chromosome 6 is selected in the Synteny Genome View graphic. Clicking on the View button in this panel results in the entire chromosome being displayed in the Syntenic Block Detail window. The display interval can then be refined interactively using the slider on the chromosome overview graphic. Alternatively, the coordinates of a genomic interval for the Reference genome can be entered in the appropriate dialog box within the Settings menu. When the "Update View" button is selected, the userspecified genomic region is then displayed in the Syntenic Block Detail panel.
Once the Syntenic Block Detail View display is finalized, searches for genome features according to their biological and functional annotations can be performed using the Syntenic Block Features Display Filters function. For the lung cancer susceptibility interval, a search for genome features that are annotated to the GO function term of "positive regulation of cell death" in either genome results in eight genes (CCN2, MAP3K5, BCLAF1, IL20RA, LATS1, FNDC1, IGR2R, and PRKN) being highlighted in the Syntenic Block Detail View. Four of these genes (IGR2R, PRKN, CCN2, and IL20RA) were identified by the authors of the mapping paper as likely candidate genes. Clicking on a genome feature opens a dialog box with links to external resources with detailed annotations about the feature (MGI for mouse genes; NCBI for human genes).

Use Case #2: Identifying candidate genes for Type 2 diabetes
The Quantitative Trait Locus (QTL) T2dm2sa (type 2 diabetes mellitus 2 in SMXA RI mice) was identified as a region of mouse chromosome 2 associated with impaired glucose tolerance, hyperinsulinemia, and high body mass index (BMI) (Kobayashi et al. 2006). To identify possible candidate genes in the QTL interval using prior biological knowledge about the genome features in this chromosomal region, a user would first use the To explore annotated functions and phenotype associations of mouse genes within and around the QTL region the researcher could limit the annotation searches to the mouse (Reference) genome and then use the Syntenic Block Features Display Filters tool to find genes annotated to relevant phenotype terms from the Mammalian Phenotype (MP) ontology (Smith and Eppig 2012). A search for the MP term, impaired glucose tolerance, identifies thirteen genes that fall within the boundaries of the T2dm2sa QTL interval: Pkn3, Lcn2,Dpm2,Zbtb43,Bbs5,Commd9,Hipk3,Pax6,Hdc,Ap4e1,Chgb,and Pcsk2. Search results are automatically displayed in the Syntenic Block Detail View panel.