Author's School

Graduate School of Arts & Sciences

Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Human and Statistical Genetics

Author's Department/Program

Biology and Biomedical Sciences: Human and Statistical Genetics

Language

English (en)

Date of Award

1-15-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Patrick Jay, James Cheverud, D.C. Rao, David Ornitz, Robert Mecham, Kelle Moley

Abstract

While a clear heritable risk has been observed for congenital heart disease, there is considerable variation in penetrance and presentation likely due to multiple genetic and environmental risk factors. To identify causative factors and interactions responsible for variability in heart development, greater than 4,200 hearts from Nkx2-5 heterozygous knockout mice have been collected and examined. Nkx2-5+/- mice in the inbred strain background C57Bl/6 frequently have atrial and ventricular septal defects. The incidences are substantially reduced in the Nkx2-5+/- progeny of first-generation: F1) outcrosses to the strains FVB/N or A/J. Defects recur in the second generation: F2) of the F1xF1 intercross or backcrosses to the parental strains. All 3 strains carry susceptibility alleles at different loci for atrial and ventricular septal defects. Relative to the other 2 strains, A/J carries polymorphisms that confer greater susceptibility to atrial septal defect: ASD) and atrioventricular septal defects and C57Bl/6 to muscular ventricular septal defects: VSD). Genome wide linkage analysis was conducted on 306 mice from the FVB/n F2 intercross and 80 mice from the A/J F2 intercross diagnosed with VSD to map main effect and interacting loci that correlate with risk. Additionally the possibility of environmental interactions was explored in this analysis by including maternal and paternal age and litter size as terms in the models tested. Significantly linked genomic regions were identified from the FVB/n population on chromosomes 6, 8 and 10 implicating genes in these positions as important candidates for VSD risk. Linkage analysis on the A/J cross identified both shared and unique modifiers from the FVB/N cross scan. Maternal age was found to significantly correlate with VSD risk in FVB/N crosses but not A/J providing evidence for strain specific susceptibility to a non-heritable risk factor. The findings in this study implicate modifier genes as major factors in cardiac developmental pathways by buffering against genetic and environmental insults in the majority while directing the manifestation of disease in a few. Characterization of the genetic architecture of congenital heart disease in a mouse model will provide a deeper understanding of its multifactorial nature and possibly lead to novel strategies for prognosis and prevention.

DOI

https://doi.org/10.7936/K78P5XJV

Comments

Permanent URL: http://dx.doi.org/10.7936/K78P5XJV

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