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Proc Natl Acad Sci U S A DOI:10.1073/pnas.0810388105

Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis.

Publication TypeJournal Article
Year of Publication2008
AuthorsShao, H, Burrage, LC, Sinasac, DS, Hill, AE, Ernest, SR, O'Brien, W, Courtland, H-W, Jepsen, KJ, Kirby, A, Kulbokas, EJ, Daly, MJ, Broman, KW, Lander, ES, Nadeau, JH
JournalProc Natl Acad Sci U S A
Date Published2008 Dec 16
KeywordsAnimals, Body Weight, Disease, Epistasis, Genetic, Mice, Mice, Congenic, Mice, Inbred C57BL, Phenotype, Quantitative Trait Loci, Rats

The genetic architecture of complex traits underlying physiology and disease in most organisms remains elusive. We still know little about the number of genes that underlie these traits, the magnitude of their effects, or the extent to which they interact. Chromosome substitution strains (CSSs) enable statistically powerful studies based on testing engineered inbred strains that have single, unique, and nonoverlapping genetic differences, thereby providing measures of phenotypic effects that are attributable to individual chromosomes. Here, we report a study of phenotypic effects and gene interactions for 90 blood, bone, and metabolic traits in a mouse CSS panel and 54 traits in a rat CSS panel. Two key observations emerge about the genetic architecture of these traits. First, the traits tend to be highly polygenic: across the genome, many individual chromosome substitutions each had significant phenotypic effects and, within each of the chromosomes studied, multiple distinct loci were found. Second, strong epistasis was found among the individual chromosomes. Specifically, individual chromosome substitutions often conferred surprisingly large effects (often a substantial fraction of the entire phenotypic difference between the parental strains), with the result that the sum of these individual effects often dramatically exceeded the difference between the parental strains. We suggest that strong, pervasive epistasis may reflect the presence of several phenotypically-buffered physiological states. These results have implications for identification of complex trait genes, developmental and physiological studies of phenotypic variation, and opportunities to engineer phenotypic outcomes in complex biological systems.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID19066216
PubMed Central IDPMC2604967
Grant ListT32 GM008613 / GM / NIGMS NIH HHS / United States
R56 AR044927 / AR / NIAMS NIH HHS / United States
R01 AR044927 / AR / NIAMS NIH HHS / United States
AR44927 / AR / NIAMS NIH HHS / United States
GM08613 / GM / NIGMS NIH HHS / United States
P40 RR012305 / RR / NCRR NIH HHS / United States
RR12305 / RR / NCRR NIH HHS / United States
T32 GM07250 / GM / NIGMS NIH HHS / United States
R29 AR044927 / AR / NIAMS NIH HHS / United States
T32 GM007250 / GM / NIGMS NIH HHS / United States