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 4 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, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Conflict of Interest: All authors have no conflicts of interest. NIH Public Access Author ManuscriptBone. Author manuscript; available in PMC 2012 May 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from 5 of the 8 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.

Genetic architecture of bone quality variation in layer chickens revealed by a genome-wide association study

“…Factors influencing these traits include nutrition, sex, age, exercising, genetics and disease. Genetics as a contributing factor of bone breaking strength has been testified by a number of studies and the heritability of BMD ranged from 0.39 to 0.59 567. Genetic improvement of bone strength has been carried out in an experimental flock.…”

Genetics of osteoporosis and bone disease (ASBMR 2012)

“…This population captures huge amounts of genetic variation and can facilitate genetic mapping with high resolution and precision. 8 Alam et al 7 used the HS rats to map quantitative trait loci for both BMD and bone structure phenotypes that are comparatively difficult to measure in humans and discovered many sex-specific loci for these phenotypes. These loci are reasonably small in size, allowing for rapid candidate gene identification.…”

Genetics of aging bone

“…The HS descends from eight genetically diverse strains: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N, and WN/N (77). This genetic mapping population revealed a high degree of heritability for femoral strength phenotypes measured at mid-diaphysis and the femoral neck (78). With increasing genetic mapping resolution afforded by higher density of genetic recombinations, this HS population was used to identify QTLs for structural dimensions and measures of femoral strength (79).…”