Mammalian Genome

, Volume 16, Issue 6, pp 414–423 | Cite as

QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival

  • Ferrin C. Wheeler
  • Liliana Fernandez
  • Kerri M. Carlson
  • Matthew J. Wolf
  • Howard A. Rockman
  • Douglas A. MarchukEmail author


The progression from myocardial hypertrophy to heart failure is a complex process, involving genetic and environmental factors. Elucidating the genetic components contributing to heart failure has been difficult, largely because of the heterogeneity of human populations. We have employed a strategy to map genetic loci that modify the heart failure phenotype in a transgenic mouse model of cardiomyopathy caused by cardiac-specific overexpression of calsequestrin. Strain-specific differences in both cardiac function and survival are observed when the transgene is moved into different inbred mouse strains. We have previously reported linkage results from mapping in reciprocal backcrosses between C57/BL6 (BL6) and DBA/2J (DBA) and a backcross between DBA/AKR and AKR. Here we report the results of a genome-wide linkage scan in the reciprocal backcross between DBA/AKR and DBA. We identified one novel locus on Chromosome (Chr) 18 that affects heart function and a second on Chr 3 that shows significant linkage to both survival and heart function. Intriguingly, the Chr 3 allele of AKR shows a susceptibility effect on phenotype, whereas the overall effect of the AKR genetic background is protective. The Chr 3 locus also completely overlaps the Hrtfm2 locus, which was previously mapped in crosses between DBA and BL6. Mapping the same QTL in two different crosses allowed us to use ancestral haplotypes to narrow the candidate gene interval from 9 to 2 Mb. Identification of the genes at these QTLs in the mouse will provide novel candidate genes that can be evaluated for their role in human heart failure.


Heart Function Haplotype Block Likelihood Ratio Statistic Human Heart Failure Reciprocal Backcross 
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The authors thank Dr. Lan Mao for her expert technique of echocardiography and Christopher Clayton, Kristine Porter, and Holly Roberts for their technical assistance with mouse handling. This work was supported by NIH grants R01-HL-69230 and R01-HL-68963 and American Heart Association Fellowship 0425520U (F.C.W.).


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Copyright information

© Springer Science+Business Media Inc. 2005

Authors and Affiliations

  • Ferrin C. Wheeler
    • 1
  • Liliana Fernandez
    • 2
  • Kerri M. Carlson
    • 1
  • Matthew J. Wolf
    • 2
  • Howard A. Rockman
    • 1
    • 2
  • Douglas A. Marchuk
    • 1
    Email author
  1. 1.Department of Molecular Genetics and MicrobiologyDuke University Medical CenterDurhamUSA
  2. 2.Department of MedicineDuke University Medical CenterDurhamUSA

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