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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).

Identification of genetic variants that influence susceptibility to pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with persistent pain, we measured late-phase response to formalin injection in 275 male and female Diversity Outbred mice genotyped for over 70,000 single nucleotide polymorphisms. One quantitative trait locus reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus, Nociq4 (nociceptive sensitivity quantitative trait locus 4; MGI: 5661503), harbors the well-known pain gene Trpa1 (transient receptor potential cation channel, subfamily A, member 1). Trpa1 is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of Diversity Outbred founder strain allele effects revealed a significant effect of the CAST/EiJ allele at Trpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the 7 other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants in Trpa1 by assessing channel conductance, TRPA1-TRPV1 interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained by Trpa1 isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.

We report here a semi-automated process by which mouse genome feature predictions and curated annotations (i.e., genes, pseudogenes, functional RNAs, etc.) from Ensembl, NCBI and Vertebrate Genome Annotation database (Vega) are reconciled with the genome features in the Mouse Genome Informatics (MGI) database (http://www.informatics.jax.org) into a comprehensive and non-redundant catalog. Our gene unification method employs an algorithm (fjoin--feature join) for efficient detection of genome coordinate overlaps among features represented in two annotation data sets. Following the analysis with fjoin, genome features are binned into six possible categories (1:1, 1:0, 0:1, 1:n, n:1, n:m) based on coordinate overlaps. These categories are subsequently prioritized for assessment of annotation equivalencies and differences. The version of the unified catalog reported here contains more than 59,000 entries, including 22,599 protein-coding coding genes, 12,455 pseudogenes, and 24,007 other feature types (e.g., microRNAs, lincRNAs, etc.). More than 23,000 of the entries in the MGI gene catalog have equivalent gene models in the annotation files obtained from NCBI, Vega, and Ensembl. 12,719 of the features are unique to NCBI relative to Ensembl/Vega; 11,957 are unique to Ensembl/Vega relative to NCBI, and 3095 are unique to MGI. More than 4000 genome features fall into categories that require manual inspection to resolve structural differences in the gene models from different annotation sources. Using the MGI unified gene catalog, researchers can easily generate a comprehensive report of mouse genome features from a single source and compare the details of gene and transcript structure using MGI's mouse genome browser.

Mouse genetics is a powerful approach for discovering genes and other genome features influencing human pain sensitivity. Genetic mapping studies have historically been limited by low mapping resolution of conventional mouse crosses, resulting in pain-related quantitative trait loci (QTL) spanning several megabases and containing hundreds of candidate genes. The recently developed Diversity Outbred (DO) population is derived from the same eight inbred founder strains as the Collaborative Cross, including three wild-derived strains. DO mice offer increased genetic heterozygosity and allelic diversity compared to crosses involving standard mouse strains. The high rate of recombinatorial precision afforded by DO mice makes them an ideal resource for high-resolution genetic mapping, allowing the circumvention of costly fine-mapping studies. We utilized a cohort of ~300 DO mice to map a 3.8 Mbp QTL on chromosome 8 associated with acute thermal pain sensitivity, which we have tentatively named Tpnr6. We used haplotype block partitioning to narrow Tpnr6 to a width of ~230 Kbp, reducing the number of putative candidate genes from 44 to 3. The plausibility of each candidate gene's role in pain response was assessed using an integrative bioinformatics approach, combining data related to protein domain, biological annotation, gene expression pattern, and protein functional interaction. Our results reveal a novel, putative role for the protein-coding gene, Hydin, in thermal pain response, possibly through the gene's role in ciliary motility in the choroid plexus-cerebrospinal fluid system of the brain. Real-time quantitative-PCR analysis showed no expression differences in Hydin transcript levels between pain-sensitive and pain-resistant mice, suggesting that Hydin may influence hot-plate behavior through other biological mechanisms.

Historically our ability to identify genetic variants underlying complex behavioral traits in mice has been limited by low mapping resolution of conventional mouse crosses. The newly developed Diversity Outbred (DO) population promises to deliver improved resolution that will circumvent costly fine-mapping studies. The DO is derived from the same founder strains as the Collaborative Cross (CC), including three wild-derived strains. Thus the DO provides more allelic diversity and greater potential for discovery compared to crosses involving standard mouse strains. We have characterized 283 male and female DO mice using open-field, light-dark box, tail-suspension and visual-cliff avoidance tests to generate 38 behavioral measures. We identified several quantitative trait loci (QTL) for these traits with support intervals ranging from 1 to 3 Mb in size. These intervals contain relatively few genes (ranging from 5 to 96). For a majority of QTL, using the founder allelic effects together with whole genome sequence data, we could further narrow the positional candidates. Several QTL replicate previously published loci. Novel loci were also identified for anxiety- and activity-related traits. Half of the QTLs are associated with wild-derived alleles, confirming the value to behavioral genetics of added genetic diversity in the DO. In the presence of wild-alleles we sometimes observe behaviors that are qualitatively different from the expected response. Our results demonstrate that high-precision mapping of behavioral traits can be achieved with moderate numbers of DO animals, representing a significant advance in our ability to leverage the mouse as a tool for behavioral genetics., (© 2013 The Authors. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Fibromyalgia (FM) is a chronic widespread pain condition that is estimated to affect 5 million US adults. Several molecular pathophysiologies are thought to contribute to the symptoms of FM, complicating the development of effective clinical management techniques. It is now known that abnormalities in both nociceptive and central pain processing systems are necessary (but perhaps not sufficient) to condition the onset and maintenance of FM, producing associated neuropsychologic symptoms such as pronounced fatigue, sleep abnormalities, cognitive difficulties, stress sensitivity, anxiety, and depression. Current treatment strategies are focused primarily on correcting the pathophysiologic mechanisms underlying these nervous system abnormalities. Clinical studies demonstrate the safety and efficacy of three drugs recently approved for the treatment of FM: pregabalin (an alpha-2-delta ligand), and duloxetine and milnacipran (serotonin/norepinephrine reuptake inhibitors). This review describes these pharmaceuticals in detail and discusses their current roles in FM management.

Competing Interests: This work was supported by the National Science Foundation, IGERT training grant # 0221625. The author declares no conflicts of interest.

Fibromyalgia syndrome (FMS) is a chronic widespread pain syndrome that is estimated to affect 4-8 million US adults. The exact molecular mechanisms underlying this illness remain unclear, rendering most clinical treatment and management techniques relatively ineffective. It is now known that abnormalities in both nociceptive and central pain processing systems are necessary (but perhaps not sufficient) to condition the onset and maintenance of FMS. These same systemic abnormalities are thought to be responsible for the loss of cephalic gray matter density observed in all FMS patients groups studied to date. The current scope of FMS treatment focuses largely on analgesia and does not clearly address potential neuroprotective strategies. This article proposes a combined treatment of pregabalin and memantine to decrease the pain and rate of gray matter atrophy associated with FMS. This dual-drug therapy targets the voltage-gated calcium ion channel (VGCC) and the N-methyl d-aspartate receptor (NMDAR) (respectively), two primary components of the human nociceptive and pain processing systems.