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Originally published as Genetics Published Articles Ahead of Print on September 1, 2006.

Genetics, Vol. 174, 999-1007, October 2006, Copyright © 2006
doi:10.1534/genetics.106.059717

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Complex Genetic Architecture Revealed by Analysis of High-Density Lipoprotein Cholesterol in Chromosome Substitution Strains and F2 Crosses

Ioannis M. Stylianou*, Shirng-Wern Tsaih*, Keith DiPetrillo*,{dagger}, Naoki Ishimori*,{ddagger}, Renhua Li{dagger}, Beverly Paigen* and Gary Churchill*,1

* The Jackson Laboratory, Bar Harbor, Maine 04609, {dagger} Novartis Institutes for BioMedical Research, East Hanover, New Jersey 07936 and {ddagger} Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

1 Corresponding author: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609.
E-mail: gary.churchill{at}jax.org

Intercrosses between inbred lines provide a traditional approach to analysis of polygenic inheritance in model organisms. Chromosome substitution strains (CSSs) have been developed as an alternative to accelerate the pace of gene identification in quantitative trait mapping. We compared a classical intercross and three CSS intercrosses to examine the genetic architecture underlying plasma high-density lipoprotein cholesterol (HDL) levels in the C57BL/6J (B) and A/J (A) mouse strains. The B x A intercross revealed significant quantitative trait loci (QTL) for HDL on chromosomes 1, 4, 8, 15, 17, 18, and 19. A CSS survey revealed that many have significantly different HDL levels compared to the background strain B, including chromosomes with no significant QTL in the intercross and, in some cases (CSS-1, CSS-17), effects that are opposite to those observed in the B x A intercross population. Intercrosses between B and three CSSs (CSS-3, CSS-11, and CSS-8) revealed significant QTL but with some unexpected differences from the B x A intercross. Our inability to predict the results of CSS intercrosses suggests that additional complexity will be revealed by further crosses and that the CSS mapping strategy should be viewed as a complement to, rather than a replacement for, classical intercross mapping.




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