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: background-

dependent latency, tumor growth and metastatic progression

The resource: backcross mapping panel The result: identification of QTLs

controlling latency, metastasis, etc.