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Endocrinology, Metabolism and Clinical Nutrition

Pleiotropy and Physiologic Integration

Because of the Blank lab’s interest in the integration of the various aspects of biomechanical performance, we have particular interest in the relationships among various bone traits. These clearly display covariation, and the nature of that covariation provides insight into the physiologic mechanisms by which biomechanical performance is achieved and maintained.

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Regression of Young's Modulus (tissue-level stiffness) on Femoral Perimeter.

Load bearing by the skeleton (e.g. walking, jumping) stimulates bone growth, while unloading (e.g. space flight, prolonged bed rest, paralysis) stimulates bone resorption. Bone is thereby physiologically adapted to its usual loading environment. Bone may also be lost in conditions in which calcium or phosphate balance can’t be maintained. When bone is out of balance either nutritionally or mechanically, a response occurs to try and reestablish balance. The details of which mechanisms dominate the response, bone will develop a characteristic size, shape, and tissue-level properties. These details are largely determined by genetic constitution, as illustrated by the mouse strains HcB-8 and HcB-23, which were developed by Peter Demant.

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Micro-CT scans of femora from HcB-8 and HcB-23 male mice. Note the difference in size and shape. Scale bar = 1 mm.

The covariation of various bone traits causes many of the genes that influence bone biomechanical performance to affect multiple traits, rather than just one. This phenomenon is called pleiotropy. Pleiotropy is illustrated by the genetic linkage map of mouse chromosome 10 shown here, which shows that multiple traits are controlled by a gene In the same region of the chromosome.

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Linkage Map of Chromosome 10. Ten Traits are linked to this chromosome. The X axis shows position on chromosome 10. The Y axis shows the LOD score, a statistic that shows the strength of genetic linkage. LOD scores are logarithmic, so each change of 1 represents a 10-fold difference in the linkage signal. Each curve represents genetic linkage for a different bone trait. The horizontal lines at LOD ~ 2.8 represent the significance thresholds for each of the traits, some of which are not visible because they are superimposed. LOD scores above the line are positive findings. The superposition of the peaks for all these traits is an example of pleiotropy.

Some of the genes affecting bone biomechanics work differently in males and females. This is true in both humans and mice. This linkage map of mouse chromosome 6 illustrates this; there is a pleiotropic gene affecting multiple traits in males, but it has no effect in females.

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Linkage Map of Mouse Chromosome 6 in Males. The X axis shows positions along the chromosome, while the Y axis shows the LOD score, a statistic that shows the strength of genetic linkage. LOD scores are logarithmic, so each change of 1 represents a 10-fold difference in the linkage signal. Each curve represents genetic linkage for a different bone trait. The horizontal lines at LOD~2.8 represent the significance thresholds for each of the traits, some of which are not visible because they are superimposed. LOD scores above the line are positive findings. The superposition of the peaks for all these traits is an example of pleiotropy. In females, none of these traits displays a peak above the significance threshold. Note the difference in the scale of the Y axes in the 2 plots. The difference between the male and female linkage maps is an example of a genotype x sex interaction.

In collaboration with Narayan Yoganandan, we are studying how pleiotropic bone genes affect bone growth in response to mechanical loading under reproducible experimental conditions.

Ongoing work with Marc Drezner seeks to understand the mechanisms that lead to osteomalacia and phosphate wasting in X-linked hypophosphatemia. See his page for additional information about this work.

New projects will look to extend our findings in mice to humans. These clinical efforts will be conducted through the Clinical and Translational Science Institute.

The lines of investigation summarized on this page are part of our effort not just to identify genes that affect bone properties, but to understand how their varied functions are integrated.