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INHERITANCE 243

11.3 Few Common or Many Rare Variants?

I have discussed a small number of mutations in which carriers suffer
significantly earlier onset of disease. In those cases, a single mutation
greatly increases incidence. Such mutations often appear to occur in key
genes that directly affect progression of the particular type of cancer.
The search for single mutations of large effect has intensified over
the past few years. However, few new mutations have been discovered.
Most of the inherited predisposition to cancer remains unexplained. The
widespread heritability of cancer appears to be caused by several vari-
ants each of relatively small effect—what is often called polygenic inher-
itance.
Within this large, polygenic component of heritability, do genetic vari-
ants that cause disease tend to be common or rare? Are there relatively
few common, older variants or many rare, newer variants?
Much recent debate in biomedical genetics has turned on these ques-
tions, because methods for estimating genetic risk in particular individ-
uals depend on the frequency of variant alleles (Weiss and Terwilliger
2000; Lee 2002). If most genetic risk comes from a few relatively com-
mon alleles that are relatively old, then those alleles will be associated
with other polymorphisms in the genome that can be used as markers
of risk. Those associations arise because the original mutations will,
by chance, occur in regions in which other single nucleotide polymor-
phisms (SNPs) are located nearby.
By contrast, most genetic risk might come from many rare, young al-
leles. If so, then there will be no consistent association between known
SNPs and genetic predisposition. Each particular mutation will have its
own profile of linked marker polymorphisms, often specific for a par-
ticular population. Those linkage profiles will differ for each mutation.
Because there may be many mutations, with each making only a small
contribution to genetic risk, no overall association will occur between
known marker polymorphisms and total genetic risk.
The available data do not definitively distinguish between a few com-
mon, older variants and many rare, younger variants. Wright et al. (2003)
argued eloquently in favor of many rare variants; I agree with their logic.
However, the issue here does not turn on point of view, but rather on the
actual distribution of variants and their effects. I discuss two examples
that provide the first clues.