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

Joseph P. Gyekis, Dean H. Lang, David J. Vandenbergh, Glenn S. Gerhard, James W. Griffith, Jeffery W. Dodds, Zakaria K. Shihabi, Mera K. Tilley, David A. Blizard

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)59-67
Number of pages9
JournalAging Clinical and Experimental Research
Volume28
Issue number1
DOIs
StatePublished - Feb 1 2016

Fingerprint

Chromosomes, Human, Pair 13
Alleles
Survival
Mortality
Lipidoses
Pathology
Premature Mortality
Malocclusion
Heterozygote
Islets of Langerhans
Gene Frequency
Hypertrophy
Breeding
Survivors
Tooth
Genotype
Kidney
Population

All Science Journal Classification (ASJC) codes

  • Aging
  • Geriatrics and Gerontology

Cite this

Gyekis, Joseph P. ; Lang, Dean H. ; Vandenbergh, David J. ; Gerhard, Glenn S. ; Griffith, James W. ; Dodds, Jeffery W. ; Shihabi, Zakaria K. ; Tilley, Mera K. ; Blizard, David A. / A Chromosome 13 locus is associated with male-specific mortality in mice. In: Aging Clinical and Experimental Research. 2016 ; Vol. 28, No. 1. pp. 59-67.
@article{de3f04d83f314d5d9a0a12fe61d1cdd8,
title = "A Chromosome 13 locus is associated with male-specific mortality in mice",
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.",
author = "Gyekis, {Joseph P.} and Lang, {Dean H.} and Vandenbergh, {David J.} and Gerhard, {Glenn S.} and Griffith, {James W.} and Dodds, {Jeffery W.} and Shihabi, {Zakaria K.} and Tilley, {Mera K.} and Blizard, {David A.}",
year = "2016",
month = "2",
day = "1",
doi = "10.1007/s40520-015-0370-z",
language = "English (US)",
volume = "28",
pages = "59--67",
journal = "Aging clinical and experimental research",
issn = "1594-0667",
publisher = "Springer Verlag",
number = "1",

}

Gyekis, JP, Lang, DH, Vandenbergh, DJ, Gerhard, GS, Griffith, JW, Dodds, JW, Shihabi, ZK, Tilley, MK & Blizard, DA 2016, 'A Chromosome 13 locus is associated with male-specific mortality in mice', Aging Clinical and Experimental Research, vol. 28, no. 1, pp. 59-67. https://doi.org/10.1007/s40520-015-0370-z

A Chromosome 13 locus is associated with male-specific mortality in mice. / Gyekis, Joseph P.; Lang, Dean H.; Vandenbergh, David J.; Gerhard, Glenn S.; Griffith, James W.; Dodds, Jeffery W.; Shihabi, Zakaria K.; Tilley, Mera K.; Blizard, David A.

In: Aging Clinical and Experimental Research, Vol. 28, No. 1, 01.02.2016, p. 59-67.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Chromosome 13 locus is associated with male-specific mortality in mice

AU - Gyekis, Joseph P.

AU - Lang, Dean H.

AU - Vandenbergh, David J.

AU - Gerhard, Glenn S.

AU - Griffith, James W.

AU - Dodds, Jeffery W.

AU - Shihabi, Zakaria K.

AU - Tilley, Mera K.

AU - Blizard, David A.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84962050418&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962050418&partnerID=8YFLogxK

U2 - 10.1007/s40520-015-0370-z

DO - 10.1007/s40520-015-0370-z

M3 - Article

C2 - 25995165

AN - SCOPUS:84962050418

VL - 28

SP - 59

EP - 67

JO - Aging clinical and experimental research

JF - Aging clinical and experimental research

SN - 1594-0667

IS - 1

ER -