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A Chromosome 13 locus is associated with male-specific mortality in mice

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Abstract

Background and aim

Mortality is a highly complex trait influenced by a wide array of genetic factors.

Methods

We examined a population of 1200 mice that were F2 generation offspring of a 4-way reciprocal cross between C57BL6/J and DBA2/J strains. Animals were sacrificed at age 200, 500, or 800 days and genotyped at 96 markers. The 800 days old cohort, which were the survivors of a much larger breeding group, were examined for enriched frequency of alleles that benefit survival and depletion of alleles that reduce survival.

Results

Loci on Chr 13 in males and on Chr X in females were significantly distorted from Mendelian expectations, even after conservative correction for multiple testing. DBA2/J alleles between 35 and 80 Mb on Chr 13 were underrepresented in the age 800 male animals. D2 genotypes in this region were also associated with premature death during behavioral testing. Furthermore, confirmatory analysis showed BXD recombinant inbred strains carrying the D2 alleles in this region had shorter median survival. Exploration of available pathology data indicated that a syndrome involving dental malocclusions, pancreatic islet hypertrophy, and kidney lipidosis may have mediated the effects of DBA alleles on mortality specifically in male mice. The heterozygote advantage locus on the X Chr was not found to be associated with any pathology.

Conclusions

These results suggest a novel locus influencing survival in the B6/D2 genetic background, perhaps via a metabolic disorder that emerges by 200 days of age in male animals.

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Acknowledgments

We acknowledge the encouragement of Jerry McClearn Principal Investigator on P01-AG-14731 which supported this research. T32-AG-00276 provided stipends for graduate students. Jeanne Spicer provided superb database management. Thanks to Susan E. Lingenfelter, Kim A. Seymour, David A. Bienus, Gee-Sue Park, and Olivia Nourie for their excellent technical assistance and writing support.

Conflict of interest

All authors declare we have no financial conflicts of interest.

Human and Animal Rights

All animals were maintained according to protocols approved by the Institutional Animal Care and Use Committee of Penn State University.

Informed consent

This article does not report results of human subjects research.

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Authors and Affiliations

  1. Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, 16802, USA

    Joseph P. Gyekis, David J. Vandenbergh, Mera K. Tilley & David A. Blizard

  2. Department of Kinesiology and School of Engineering Design, Technology, and Professional Programs, Penn State University, University Park, PA, 16802, USA

    Dean H. Lang

  3. Penn State Institute for the Neurosciences, Pennsylvania State University, University Park, PA, 16802, USA

    David J. Vandenbergh

  4. Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, 19140, USA

    Glenn S. Gerhard

  5. Institute of Comparative Medicine, Pennsylvania State University, Hershey, PA, 17033, USA

    James W. Griffith

  6. Animal Resource Program, Pennsylvania State University, University Park, PA, 16802, USA

    Jeffery W. Dodds

  7. Department of Pathology, Wake Forest University Medical Center, Winston-Salem, NC, 27103, USA

    Zakaria K. Shihabi

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  1. Joseph P. Gyekis
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  2. Dean H. Lang
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  7. Zakaria K. Shihabi
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  8. Mera K. Tilley
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  9. David A. Blizard
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Correspondence to Joseph P. Gyekis.

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Gyekis, J.P., Lang, D.H., Vandenbergh, D.J. et al. A Chromosome 13 locus is associated with male-specific mortality in mice. Aging Clin Exp Res 28, 59–67 (2016). https://doi.org/10.1007/s40520-015-0370-z

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  • DOI: https://doi.org/10.1007/s40520-015-0370-z

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