TY - JOUR
T1 - Heterogeneous stock rat: A unique animal model for mapping genes influencing bone fragility
AU - Alam, Imranul
AU - Koller, Daniel L.
AU - Sun, Qiwei
AU - Roeder, Ryan K.
AU - Cañete, Toni
AU - Blázquez, Gloria
AU - López-Aumatell, Regina
AU - Martínez-Membrives, Esther
AU - Vicens-Costa, Elia
AU - Mont, Carme
AU - Díaz, Sira
AU - Tobeña, Adolf
AU - Fernández-Teruel, Alberto
AU - Whitley, Adam
AU - Strid, Pernilla
AU - Diez, Margarita
AU - Johannesson, Martina
AU - Flint, Jonathan
AU - Econs, Michael J.
AU - Turner, Charles H.
AU - Foroud, Tatiana
PY - 2011/5/1
Y1 - 2011/5/1
N2 - 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. © 2010 Elsevier Inc.
AB - 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. © 2010 Elsevier Inc.
KW - Bone density
KW - Bone strength
KW - Genetics
KW - Heterogeneous stock rat
KW - Osteoporosis
U2 - 10.1016/j.bone.2011.02.009
DO - 10.1016/j.bone.2011.02.009
M3 - Article
SN - 8756-3282
VL - 48
SP - 1169
EP - 1177
JO - Bone
JF - Bone
IS - 5
ER -