Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, Justice M, O'Brien WE, Conti DV, Witte JS, Lander ES, Nadeau JH.
Genetic dissection of complex traits with chromosome substitution strains of mice.
Science. 2004 Apr 16;304(5669):445-8.
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Disclaimer: Bruce Lamb is assistant professor in the department chaired by senior author Joseph Nadeau.
The development of the chromosome substitution strains (CSSs) is truly a unique resource to study any number of quantitative traits that differ between the C57BL/6J (B6) and A/J parental strains. In the panel described in the Science paper, a single A/J chromosome is substituted for each B6 chromosome, yielding 22 total strains (19 autosomes, both sex chromosome and the mitochondria). The primary advantage of these strains for quantitative trait mapping is that they provide a permanent resource for both identifying specific chromosomes that contain genes that control specific traits of interest, and for further mapping these genes through the rapid generation of interval-specific congenics. In addition, there is genomic sequence available for both B6 (through the public sequencing efforts) and A/J (by Celera), including many of the polymorphisms that exist between these two parental strains, as well as BAC libraries for both strains.
Importantly, these strains also are included in numerous phenotypic measurements being deposited into the mouse (Phenome database). The CSSs will prove particularly invaluable for a variety of aging and age-related phenotypes. To name a few, this includes lifespan, behavior, and cholesterol metabolism, all of which are dramatically different between the B6 and A/J strains. In addition, it is quite likely that many neurodegenerative disease phenotypes will also differ between the B6 and A/J parental strains, providing a unique opportunity for the mapping of genes that regulate these phenotypes in vivo.
Indeed, my own laboratory is currently examining AD phenotypes in B6 and A/J congenic mouse strains that contain a mutant APP yeast artificial chromosome transgene. The availability of the CSS strains will provide a powerful resource to help identify unique modifier genes of AD phenotypes in this strain combination. Unfortunately, at present, this is the only complete set of CSSs in the mouse, so that identification of age-related modifiers in other strain combinations will still have to rely on standard (and extremely tedious) methods for identifying quantitative trait loci. In the future, additional CSSs will hopefully be generated for other strain combinations, which will greatly facilitate the mapping of complex traits in the mouse.
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