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INHERITANCE 229

It is difficult to tell how reliable those conclusions are about polygenic
inheritance. Other models could be fit to the same data, with different
contributions of Mendelian loci, polygenic loci, and environment. I favor
the strong emphasis on polygenic inheritance, because most complex
quantitative traits in nature show extensive polygenic variation (Barton
and Keightley 2002; Houle 1992; Mousseau and Roff 1987). However,
statistical models are hard to test directly, because it is difficult to obtain
evidence that strongly supports one model and rules out other plausible
models. One is often left with conclusions that are based as much on
prior belief as on data.

DIRECT STUDIES OF VARIANTS AT MULTIPLE SITES
Ideally, one would like to know how particular genetic variants affect
the biochemistry of cells, and how those biochemical effects influence
progression to cancer. Although we are still a long way from this ideal,
recent studies of DNA repair genes provide hints about what could be
learned (Mohrenweiser et al. 2003).
Individuals vary in the ability of their cells to repair DNA damage
(Berwick and Vineis 2000). A relatively low repair efficiency is associated
with a higher risk of cancer. Presumably, the association arises because
higher rates of unrepaired somatic mutations and chromosomal aberra-
tions contribute to faster progression to cancer. Repair genes also play
a role in sensing genetic damage and initiating apoptosis.
Most studies of repair capacity measure the effects of mutagens on
DNA damage in lymphocytes. For example, a mutagen can be applied to
cultures of lymphocytes; after a period of time, damage can be measured
by the numbers of unrepaired single-strand or double-strand breaks, or
by incorporation of a radioisotope. To study the role of DNA repair
in cancer, measurements compare individuals with and without cancer.
Berwick and Vineis (2000) summarized 64 different studies that used
a variety of methods to quantify repair. In those studies, a relatively
low repair capacity was consistently associated with an approximately
2–10-fold increase in cancer risk.
Roughly speaking, repair efficiency has an inheritance pattern that is
typical of a quantitative trait. A few rare Mendelian disorders cause se-
vere deficiencies in repair capacity. Apart from those rare cases, repair
capacity shows a continuous pattern of variation and has a significant