title: Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility.
abstract: Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility.
authors.affiliation: Indiana University School of Medicine, Indiana University Indianapolis, IN, USA. ialam@iupui.edu
authors.forename: Imranul
authors.initials: I
authors.lastname: Alam
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Koller
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Sun
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Roeder
authors.forename: Toni
authors.initials: T
authors.lastname: Cañete
authors.forename: Gloria
authors.initials: G
authors.lastname: Blázquez
authors.forename: Regina
authors.initials: R
authors.lastname: López-Aumatell
authors.forename: Esther
authors.initials: E
authors.lastname: Martínez-Membrives
authors.forename: Elia
authors.initials: E
authors.lastname: Vicens-Costa
authors.forename: Carme
authors.initials: C
authors.lastname: Mont
authors.forename: Sira
authors.initials: S
authors.lastname: Díaz
authors.forename: Adolf
authors.initials: A
authors.lastname: Tobeña
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernández-Teruel
authors.forename: Adam
authors.initials: A
authors.lastname: Whitley
authors.forename: Pernilla
authors.initials: P
authors.lastname: Strid
authors.forename: Margarita
authors.initials: M
authors.lastname: Diez
authors.forename: Martina
authors.initials: M
authors.lastname: Johannesson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
authors.forename: Charles H
authors.initials: CH
authors.lastname: Turner
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000502:physiology; D001835:Body Weight / Q000235:genetics; D015519:Bone Density / Q000502:physiology; D001842:Bone and Bones / Q000033:anatomy & histology / Q000502:physiology*; D002874:Chromosome Mapping; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000502:physiology; D005272:Femur Neck / Q000502:physiology; D058685:Genetic Pleiotropy; D040582:Inheritance Patterns / Q000235:genetics; D008159:Lumbar Vertebrae / Q000033:anatomy & histology / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009929:Organ Size / Q000502:physiology; D010641:Phenotype; D025341:Principal Component Analysis; D051381:Rats; D011919:Rats, Inbred Strains; D012727:Sex Characteristics