title: Functional analysis and transcriptional output of the Göttingen minipig genome.
abstract: BACKGROUND
  In the past decade the Göttingen minipig has gained increasing recognition as animal model in pharmaceutical and safety research because it recapitulates many aspects of human physiology and metabolism. Genome-based comparison of drug targets together with quantitative tissue expression analysis allows rational prediction of pharmacology and cross-reactivity of human drugs in animal models thereby improving drug attrition which is an important challenge in the process of drug development.
  
  
  RESULTS
  Here we present a new chromosome level based version of the Göttingen minipig genome together with a comparative transcriptional analysis of tissues with pharmaceutical relevance as basis for translational research. We relied on mapping and assembly of WGS (whole-genome-shotgun sequencing) derived reads to the reference genome of the Duroc pig and predict 19,228 human orthologous protein-coding genes. Genome-based prediction of the sequence of human drug targets enables the prediction of drug cross-reactivity based on conservation of binding sites. We further support the finding that the genome of Sus scrofa contains about ten-times less pseudogenized genes compared to other vertebrates. Among the functional human orthologs of these minipig pseudogenes we found HEPN1, a putative tumor suppressor gene. The genomes of Sus scrofa, the Tibetan boar, the African Bushpig, and the Warthog show sequence conservation of all inactivating HEPN1 mutations suggesting disruption before the evolutionary split of these pig species. We identify 133 Sus scrofa specific, conserved long non-coding RNAs (lncRNAs) in the minipig genome and show that these transcripts are highly conserved in the African pigs and the Tibetan boar suggesting functional significance. Using a new minipig specific microarray we show high conservation of gene expression signatures in 13 tissues with biomedical relevance between humans and adult minipigs. We underline this relationship for minipig and human liver where we could demonstrate similar expression levels for most phase I drug-metabolizing enzymes. Higher expression levels and metabolic activities were found for FMO1, AKR/CRs and for phase II drug metabolizing enzymes in minipig as compared to human. The variability of gene expression in equivalent human and minipig tissues is considerably higher in minipig organs, which is important for study design in case a human target belongs to this variable category in the minipig. The first analysis of gene expression in multiple tissues during development from young to adult shows that the majority of transcriptional programs are concluded four weeks after birth. This finding is in line with the advanced state of human postnatal organ development at comparative age categories and further supports the minipig as model for pediatric drug safety studies.
  
  
  CONCLUSIONS
  Genome based assessment of sequence conservation combined with gene expression data in several tissues improves the translational value of the minipig for human drug development. The genome and gene expression data presented here are important resources for researchers using the minipig as model for biomedical research or commercial breeding. Potential impact of our data for comparative genomics, translational research, and experimental medicine are discussed.
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. tobias.heckel@roche.com.
authors.forename: Tobias
authors.initials: T
authors.lastname: Heckel
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. roland.schmucki@roche.com.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmucki
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. marco.berrera@roche.com.
authors.forename: Marco
authors.initials: M
authors.lastname: Berrera
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. stephan.ringshandl@Synmikro.Uni-Marburg.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ringshandl
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. laura.badi@roche.com.
authors.forename: Laura
authors.initials: L
authors.lastname: Badi
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. guido.steiner@roche.com.
authors.forename: Guido
authors.initials: G
authors.lastname: Steiner
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. morgane.ravon.mr1@roche.com.
authors.forename: Morgane
authors.initials: M
authors.lastname: Ravon
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. erich.kueng@roche.com.
authors.forename: Erich
authors.initials: E
authors.lastname: Küng
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. bernd.kuhn@roche.com.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. nicole_a.kratochwil@roche.com.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Kratochwil
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. georg.schmitt@roche.com.
authors.forename: Georg
authors.initials: G
authors.lastname: Schmitt
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. anna.kiialainen@roche.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Kiialainen
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. corinne.nowaczyk@roche.com.
authors.forename: Corinne
authors.initials: C
authors.lastname: Nowaczyk
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. hamina.daff@roche.com.
authors.forename: Hamina
authors.initials: H
authors.lastname: Daff
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. AzinwiPhina.Khan@uk-essen.de.
authors.forename: Azinwi Phina
authors.initials: AP
authors.lastname: Khan
authors.affiliation: International Livestock Research Institute (ILRI), PO Box 30709, Nairobi, 00100, Kenya. lekolool@kws.go.ke.
authors.forename: Isaac
authors.initials: I
authors.lastname: Lekolool
authors.affiliation: International Livestock Research Institute (ILRI), PO Box 30709, Nairobi, 00100, Kenya. r.pelle@cgiar.org.
authors.forename: Roger
authors.initials: R
authors.lastname: Pelle
authors.affiliation: International Livestock Research Institute (ILRI), PO Box 30709, Nairobi, 00100, Kenya. e.okoth@cgiar.org.
authors.forename: Edward
authors.initials: E
authors.lastname: Okoth
authors.affiliation: International Livestock Research Institute (ILRI), PO Box 30709, Nairobi, 00100, Kenya. r.bishop@cgiar.org.
authors.forename: Richard
authors.initials: R
authors.lastname: Bishop
authors.affiliation: Swiss Tropical and Public Health Institute (Swiss TPH), Socinstr. 57, CH 4002, Basel, Switzerland. claudia.daubenberger@unibas.ch.
authors.forename: Claudia
authors.initials: C
authors.lastname: Daubenberger
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. martin.ebeling@roche.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.affiliation: Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. ulrich.certa@roche.com.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Certa
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D002875:Chromosomes; D015870:Gene Expression; D020869:Gene Expression Profiling; D016678:Genome; D006801:Humans; D008099:Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011544:Pseudogenes; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004364:Pharmaceutical Preparations