title: Genome-based analysis of the nonhuman primate Macaca fascicularis as a model for drug safety assessment.
abstract: The long-tailed macaque, also referred to as cynomolgus monkey (Macaca fascicularis), is one of the most important nonhuman primate animal models in basic and applied biomedical research. To improve the predictive power of primate experiments for humans, we determined the genome sequence of a Macaca fascicularis female of Mauritian origin using a whole-genome shotgun sequencing approach. We applied a template switch strategy that uses either the rhesus or the human genome to assemble sequence reads. The sixfold sequence coverage of the draft genome sequence enabled discovery of about 2.1 million potential single-nucleotide polymorphisms based on occurrence of a dimorphic nucleotide at a given position in the genome sequence. Homology-based annotation allowed us to identify 17,387 orthologs of human protein-coding genes in the M. fascicularis draft genome, and the predicted transcripts enabled the design of a M. fascicularis-specific gene expression microarray. Using liver samples from 36 individuals of different geographic origin we identified 718 genes with highly variable expression in liver, whereas the majority of the transcriptome shows relatively stable and comparable expression. Knowledge of the M. fascicularis draft genome is an important contribution to both the use of this animal in disease models and the safety assessment of drugs and their metabolites. In particular, this information allows high-resolution genotyping and microarray-based gene-expression profiling for animal stratification, thereby allowing the use of well-characterized animals for safety testing. Finally, the genome sequence presented here is a significant contribution to the global "3R" animal welfare initiative, which has the goal to reduce, refine, and replace animal experiments.
authors.affiliation: Translational Research Sciences, F. Hoffmann-La Roche AG, Pharmaceutical Research and Early Development, 4070 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.forename: Erich
authors.initials: E
authors.lastname: Küng
authors.forename: Angela
authors.initials: A
authors.lastname: See
authors.forename: Clemens
authors.initials: C
authors.lastname: Broger
authors.forename: Guido
authors.initials: G
authors.lastname: Steiner
authors.forename: Marco
authors.initials: M
authors.lastname: Berrera
authors.forename: Tobias
authors.initials: T
authors.lastname: Heckel
authors.forename: Leonardo
authors.initials: L
authors.lastname: Iniguez
authors.forename: Thomas
authors.initials: T
authors.lastname: Albert
authors.forename: Roland
authors.initials: R
authors.lastname: Schmucki
authors.forename: Hermann
authors.initials: H
authors.lastname: Biller
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Certa
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004353:Drug Evaluation, Preclinical; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis / Q000235:genetics*; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D027361:Organic Anion Transporters / Q000235:genetics; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D027361:Organic Anion Transporters; D004247:DNA; D003577:Cytochrome P-450 Enzyme System