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Phenotypic integration of skeletal traits during growth buffers genetic variants affecting the slenderness of femora in inbred mouse strains

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Abstract

Compensatory interactions among adult skeletal traits are critical for establishing strength but complicate the search for fracture susceptibility genes by allowing many genetic variants to exist in a population without loss of function. A better understanding of how these interactions arise during growth will provide new insight into genotype-phenotype relationships and the biological controls that establish skeletal strength. We tested the hypothesis that genetic variants affecting growth in width relative to growth in length (slenderness) are coordinated with movement of the inner bone surface and matrix mineralization to match stiffness with weight-bearing loads during postnatal growth. Midshaft femoral morphology and tissue-mineral density were quantified at ages of 1 day and at 4, 8, and 16 weeks for a panel of 20 female AXB/BXA recombinant inbred mouse strains. Path Analyses revealed significant compensatory interactions among outer-surface expansion rate, inner-surface expansion rate, and tissue-mineral density during postnatal growth, indicating that genetic variants affecting bone slenderness were buffered mechanically by the precise regulation of bone surface movements and matrix mineralization. Importantly, the covariation between morphology and mineralization resulted from a heritable constraint limiting the amount of tissue that could be used to construct a functional femur. The functional interactions during growth explained 56-99% of the variability in adult traits and mechanical properties. These functional interactions provide quantitative expectations of how genetic or environmental variants affecting one trait should be compensated by changes in other traits. Variants that impair this process or that cannot be fully compensated are expected to alter skeletal growth leading to underdesigned (weak) or overdesigned (bulky) structures.

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Acknowledgments

This project was supported by grants AR44927 and RR12305 from the National Institutes of Health.

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Authors and Affiliations

  1. Leni and Peter W. May Department of Orthopaedics, Mount Sinai School of Medicine, Box 1188, One Gustave L. Levy Place, New York, NY, 10029, USA

    Karl J. Jepsen, Bin Hu, Hayden-William Courtland, Christopher Price & Matthew Cordova

  2. New York Center for Biomedical Engineering, CUNY Graduate School, Department of Biomedical Engineering, City College of New York, New York, NY, 10031, USA

    Steven M. Tommasini

  3. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Joseph H. Nadeau

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  1. Karl J. Jepsen
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  2. Bin Hu
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Correspondence to Karl J. Jepsen.

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Jepsen, K.J., Hu, B., Tommasini, S.M. et al. Phenotypic integration of skeletal traits during growth buffers genetic variants affecting the slenderness of femora in inbred mouse strains. Mamm Genome 20, 21–33 (2009). https://doi.org/10.1007/s00335-008-9158-1

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  • DOI: https://doi.org/10.1007/s00335-008-9158-1

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