The International Complex Trait Consortium

Integrated Polygene Discovery with Long-Term Selection Lines

Daniel Pomp

Department of Animal Science, University of Nebraska, Lincoln, NE 68583 USA

Body weight and fatness are complex traits controlled by relatively equal contributions of polygenic and environmental influences. Many experimental paradigms have been used to understand the quantitative genomic nature of such complex characters; however, elucidation of the identity and nature of the underlying polygenes has remained elusive. Long-term selective breeding is a powerful approach to concentrate allelic variants explaining significant variation for quantitative traits. We study body weight, fatness and energy balance using two sets of such selection lines. The M16 line was selected 27 generations for rapid 3-6 wk weight gain (Gene Eisen, NCSU), while the MH/ML lines were selected 16 generations for high/low heat loss using direct calorimetry (Merlyn Nielsen, UNL). Marker genotyping has identified regions harboring putative polygenes regulating relevant phenotypes in these lines. Fine mapping of QTL is progressing using a combination of congenic lines, advanced intercrosses and recombinant progeny testing. Gene expression analysis using ddPCR and microarrays is defining correlated responses to selection in the transcriptome, while a parallel approach evaluates selection response in the proteome. These efforts are combined with detailed physiological and metabolomic phenotyping in an integrated approach to polygene discovery. For example, key transcriptional, proteomic, metabolomic and endocrine pathways are being phenotyped in large, segregating F2 (n=1,200) and AIL (n=2,000) populations for which STR genotypes are available. Such analysis will facilitate correlation of predisposition (QTL) genes with those regulating key physiological events controlling body weight and fatness, will enable estimation of heritabilities and genetic correlations among multiple sub-phenotypes, and will lead to a better understanding of the overall genetic architecture of complex traits. Bridging the gap between predisposition and physiology will be required to overcome the substantial obstacles that have thus far rendered polygene discovery an elusive goal.

[This work is partially supported by a grant from NIH-NIGMS and by funds from the Nebraska Agricultural Research Station. Many primary collaborators have contributed to these long term efforts, including Gene Eisen and Merlyn Nielsen who developed the selection lines, and Kari Elo, John Rocha, Mark Allan, Nancy Jerez, Stephanie Wesolowski and Diane Moody who participated in population development, data collection and analysis]