title: Genomic landscape of rat strain and substrain variation.
abstract: BACKGROUND
  Since the completion of the rat reference genome in 2003, whole-genome sequencing data from more than 40 rat strains have become available. These data represent the broad range of strains that are used in rat research including commonly used substrains. Currently, this wealth of information cannot be used to its full extent, because the variety of different variant calling algorithms employed by different groups impairs comparison between strains. In addition, all rat whole genome sequencing studies to date used an outdated reference genome for analysis (RGSC3.4 released in 2004).
  
  
  RESULTS
  Here we present a comprehensive, multi-sample and uniformly called set of genetic variants in 40 rat strains, including 19 substrains. We reanalyzed all primary data using a recent version of the rat reference assembly (RGSC5.0 released in 2012) and identified over 12 million genomic variants (SNVs, indels and structural variants) among the 40 strains. 28,318 SNVs are specific to individual substrains, which may be explained by introgression from other unsequenced strains and ongoing evolution by genetic drift. Substrain SNVs may have a larger predicted functional impact compared to older shared SNVs.
  
  
  CONCLUSIONS
  In summary we present a comprehensive catalog of uniformly analyzed genetic variants among 40 widely used rat inbred strains based on the RGSC5.0 assembly. This represents a valuable resource, which will facilitate rat functional genomic research. In line with previous observations, our genome-wide analyses do not show evidence for contribution of multiple ancestral founder rat subspecies to the currently used rat inbred strains, as is the case for mouse. In addition, we find that the degree of substrain variation is highly variable between strains, which is of importance for the correct interpretation of experimental data from different labs.
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. rmthermsen@gmail.com.
authors.forename: Roel
authors.initials: R
authors.lastname: Hermsen
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. j.ligt@hubrecht.eu.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. wim.spee@gmail.com.
authors.forename: Wim
authors.initials: W
authors.lastname: Spee
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. f.blokzijl@hubrecht.eu.
authors.forename: Francis
authors.initials: F
authors.lastname: Blokzijl
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany. sebastian.schaefer@mdc-berlin.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schäfer
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany. eleonora.adami@mdc-berlin.de.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Adami
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. s.boymans@hubrecht.eu.
authors.forename: Sander
authors.initials: S
authors.lastname: Boymans
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, 12800 E. 19th Ave., Aurora, CO, USA. stephen.flink@ucdenver.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Flink
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. r.boxtel@hubrecht.eu.
authors.forename: Ruben
authors.initials: R
authors.lastname: van Boxtel
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. robinweide@gmail.com.
authors.forename: Robin H
authors.initials: RH
authors.lastname: van der Weide
authors.affiliation: Physiological Genomic and Medicine Group, MRC Clinical Sciences Centre, London, UK. tim.aitman@ed.ac.uk.
authors.forename: Tim
authors.initials: T
authors.lastname: Aitman
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany. nhuebner@mdc-berlin.de.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. m.simonis@hubrecht.eu.
authors.forename: Marieke
authors.initials: M
authors.lastname: Simonis
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, 12800 E. 19th Ave., Aurora, CO, USA. boris.tabakoff@ucdenver.edu.
authors.forename: Boris
authors.initials: B
authors.lastname: Tabakoff
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AD, Groningen, The Netherlands. v.guryev@umcg.nl.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands. e.cuppen@hubrecht.eu.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D000818:Animals; D004285:Dogs; D019143:Evolution, Molecular; D040961:Genetic Drift; D023281:Genomics; D054643:INDEL Mutation; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D051381:Rats / Q000235:genetics*; D013045:Species Specificity