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Complex traits: intersection of
genes and environment
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“Discontinuous” (single-gene) traits vs.
“continuous” (multi-genic) traits
– how much is due to genetic component
and how much to environment? heritability
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Many, perhaps most, human clinical
traits of importance are complex
– but most understanding is coming from
mouse genetics
Examples of human complex
traits
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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
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Cancers, e.g., BRCA1/BRCA2
The mouse as a model for study
of obesity
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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
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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
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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
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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.