title: Minipig and beagle animal model genomes aid species selection in pharmaceutical discovery and development.
abstract: Improving drug attrition remains a challenge in pharmaceutical discovery and development. A major cause of early attrition is the demonstration of safety signals which can negate any therapeutic index previously established. Safety attrition needs to be put in context of clinical translation (i.e. human relevance) and is negatively impacted by differences between animal models and human. In order to minimize such an impact, an earlier assessment of pharmacological target homology across animal model species will enhance understanding of the context of animal safety signals and aid species selection during later regulatory toxicology studies. Here we sequenced the genomes of the Sus scrofa Göttingen minipig and the Canis familiaris beagle, two widely used animal species in regulatory safety studies. Comparative analyses of these new genomes with other key model organisms, namely mouse, rat, cynomolgus macaque, rhesus macaque, two related breeds (S. scrofa Duroc and C. familiaris boxer) and human reveal considerable variation in gene content. Key genes in toxicology and metabolism studies, such as the UGT2 family, CYP2D6, and SLCO1A2, displayed unique duplication patterns. Comparisons of 317 known human drug targets revealed surprising variation such as species-specific positive selection, duplication and higher occurrences of pseudogenized targets in beagle (41 genes) relative to minipig (19 genes). These data will facilitate the more effective use of animals in biomedical research.
authors.affiliation: Computational Biology, Quantitative Sciences, GlaxoSmithKline, Stevenage, UK. jessica.j.vamathevan@gsk.com
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Vamathevan
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
authors.forename: Samiul
authors.initials: S
authors.lastname: Hasan
authors.forename: Peter M
authors.initials: PM
authors.lastname: Woollard
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.forename: Yulan
authors.initials: Y
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Steve
authors.initials: S
authors.lastname: Kenny
authors.forename: James R
authors.initials: JR
authors.lastname: Brown
authors.forename: Julie
authors.initials: J
authors.lastname: Huxley-Jones
authors.forename: Jon
authors.initials: J
authors.lastname: Lyon
authors.forename: John
authors.initials: J
authors.lastname: Haselden
authors.forename: Jiumeng
authors.initials: J
authors.lastname: Min
authors.forename: Philippe
authors.initials: P
authors.lastname: Sanseau
mesh_terms: D000818:Animals; D001483:Base Sequence; D004285:Dogs / Q000235:genetics*; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D016678:Genome; D023421:Models, Animal; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013552:Swine; D013556:Swine, Miniature / Q000235:genetics*