ABSTRACT Most phenotypes with agricultural or biomedical relevance are multifactorial traits controlled by complex contributions of genetics and environment. Genetic predisposition results from combinations of relatively small effects due to variations within a large number of genes, known as QTL. Well over 200 QTL have been reported for growth and body composition traits in the mouse, which likely represent at least 50 to 100 distinct genes. Molecular biology has yielded significant advances in understanding these traits at the metabolic and physiological levels; however, little has been learned regarding the identity and nature of the underlying polygenes. In addition to the significantly poor precision inherent to QTL localization, it is very difficult to differentiate between co-localization and coincidence when comparing QTL with other QTL and with potential candidate genes. The wide gap between our knowledge of physiological mechanisms underlying complex traits and the nature of genetic predisposition significantly impairs discovery of genes underlying QTL. Identification and genetic mapping of key transcriptional, proteomic, metabolomic, and endocrine events will uncover large lists of significant positional candidate genes for growth and body composition. However, integration of experimental approaches to jointly evaluate predisposition and physiology will increase success of QTL identification by merging the power of recombination with functional analysis. Measuring physiologically relevant subphenotypes within a structured QTL mapping population will not only facilitate pathway-specific prioritization among candidate genes, but may also directly identify genes underlying QTL. This would advance our understanding of the genetic architecture of complex traits by testing the central hypothesis that genes controlling predisposition to a quantitative trait are primarily involved in trans-regulation of the primary physiological pathways that regulate the trait.
Key Words: Body Fat, Body Weight, Complex Traits, Gene Expression, Genetic Architecture, Quantitative Trait Loci
© 2004, by the American Society of Animal Science. All rights reserved.
J. Anim. Sci. 2004. 82(E. Suppl.):E300-E312
Implications
The paradigm of “quantitative genomics,” whereby large-scale subphenotyping at the transcriptional, proteomic, and metabolomic levels is performed within the context of a quantitative trait loci mapping population, will be a powerful force in dissecting the genetic architecture of complex trait predisposition. Carcass and body composition traits constitute extremely important considerations for modern livestock production systems where consumer health concerns and marketing perspectives play increasingly prominent roles. An estimated 65% of U.S. adults are overweight, and 31% are obese, substantially increasing the risk for numerous other heath concerns. Understanding the roles of specific loci in genetic susceptibility to obesity is critical to improving human health and quality of life. Enhanced understanding of how complex traits are controlled will also aid in elucidating the nature of predisposition for other diseases, including certain forms of cancer, and will be broadly applicable to many important relevant phenotypes in agriculture and biomedicine.
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