ANS 378 Animal Genetics
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Research Journal Report #05
11/23/04
Research Topic: Epistasis and Pleiotropy
Animal Species: Mouse
Title of the Paper: Genetic dissection of femur breaking strength in a large population (MRL/MpJ x SJL/J) of F2 mice: single QTL effects, epistasis, and pleiotropy
Author(s): Li, X.; Masinde, G.; Gu, W.; Wergedal, J.; Mohan, S.; Baylink, D. J.
Abstract: Bone breaking strength is an ultimate measurement of the risk of fracture. For a practical reason, bone mineral density (BMD) has been commonly used for predicting the risk instead. To identify genetic loci influencing femur-breaking strength (FBS), which was measured by three-point bending using an Instron DynaMight Low-Force Testing System, the whole-genome scan was carried out using 119 polymorphic markers in 633 (MRL x SJL) F2 female mice. We identified six significant quantitative trait loci (QTL) affecting bone breaking strength on chromosomes 1, 2, 8, 9, 10, and 17, which together explained 23% of F2 variance. Of those, the QTL on chromosomes 2, 8, and 10 seem to be unique to bone breaking strength, whereas the remaining three QTL are concordant with femur BMD QTL. Genetic analysis suggests that, of these six FBS QTL, three influence BMD, two influence bone quality, and one influences bone size. We found evidence that pleiotropic effect might represent a common genetic mechanism to coordinately regulate bone-related phenotypes. Pleiotropic analysis also suggests that our current threshold level for significant QTL may be too high to detect biologically significant QTL with small effect. Together with epistatic interactions, these undetected small QTL could explain 30% of genetic variance that remains unaccounted for in this study (heritability estimate for FBS is 68%). Our findings in single QTL effects, epistasis, and pleiotropy demonstrate that partially overlapped but distinct combinations of genetic loci in MRL/MpJ and SJL/J inbred strains of mice regulate bone strength and bone density. Identification of the genes unique to FBS may have an impact on prediction of osteoporosis in human.
Keywords: Bone mineral density, bone strength, epistasis, heritability, and pleiotropy.
Reference: Li, X., G. Masinde, W. Gu, J. Wergedal, S. Mohan, and D.J. Baylink. 2002. Genetic dissection of femur breaking strength in a large population (MRL/MpJ x SJL/J) of F2 mice: single QTL effects, epistasis, and pleiotropy. Genomics. 79:734-740.
Bone mineral density (BMD), bone size, and bone quality all contribute to the measurement of bone strength. Bone strength itself can be used to determine resistance to fracturing. It would be beneficial to the scientific and medical communities to know what affects bone breaking strength, and to be able to accurately determine bones’ fracture resistance. As a start to this, the authors of this paper studied the femur breaking strength (FBS) in the F2 generation of an MRL/MpJ x SJL/J cross in mice. The mice were raised in standard conditions until seven weeks of age, at which time they were humanely killed. Body weights were recorded at necropsy, as well as the removal and preservation of the liver for future DNA extraction. BMD and breaking strength were determined for each of the femurs, muscle size was measured using the forearm (due to easier analysis), each mouse was genotyped, and QTL (quantitative trait loci) and statistical analyses were performed. Epistatic, pleiotropic, and single QTL effects were also ascertained.
The purpose of this research was to find an effective way to determine bone breaking strength in mice so that it might be applied in other species, such as humans. Epistatic, pleiotropic, and QTL effects all bear importance in this determination by effecting BMD and/or bone strength either directly or indirectly through various gene loci interactions.
Six QTL were found to be significant in regulating bone breaking strength. These locations accounted for 23% of the phenotypic variance found in the F2 generation of the mice. Epistatic interactions were found to account for another 14.6% of the variance observed. However, this still leaves 30.4% of the broad heritability value of 68% unaccounted for. The remaining portion of variance could be due to more complex epistatic interactions not accounted for in this experiment. Pleiotropy was documented to occur in ways that affected the strength of the bone. FBS QTL, Fbs17P6.6L8.4, was determined to have a large effect on bone-related phenotypes, femur length, and femur mid-shaft periosteal circumference.
Data observed in experiments such as this have the distinct possibility of being applied in other areas of medicine and science, specifically humans in this case. Determining epistatic and pleiotropic effects on bone development allows us to better understand how their density and strength are affected by genes. Knowing this, we can hopefully be able to better treat diseases, such as osteoporosis in humans, in the future.
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