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Complex traits: intersection of genes and environment “Discontinuous” (single-gene) traits vs. “continuous” (multi-genic) traits – how much is due to genetic component and how much to environment? heritability Many, perhaps most, human clinical traits of importance are complex – but most understanding is coming from mouse genetics Examples of human complex traits Coronary artery disease (CAD) – a very low frequency of this can be simply explained by familial hypercholesterolemia (LDL receptor mutations) – most is multigenic with variable susceptibility Cancers, e.g., BRCA1/BRCA2 The mouse as a model for study of obesity Cloning of the mouse ob and db genes – role of parabiosis experiments to identify circulating and non-circulating factors – ob encodes leptin – Db encodes the leptin receptor Other influencing mouse genes, including those encoding a leptin transporter, neuropeptide Y and melanocortin 4, reveal complexity The mouse as a model for study of cancer Murine multiple intestinal neoplasia (Min) – ENU-induced mutation in APC (important in human colon cancer) – major modifier mapped to chr. 4 - Mom (modifier of Min), encoding a secrretory phospholipase A2 The mouse as a model for study of cancer - mapping modifier QTLs The system: transgene-induced mammary tumor model The observation: backgrounddependent latency, tumor growth and metastatic progression The resource: backcross mapping panel The result: identification of QTLs controlling latency, metastasis, etc.