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INHERITANCE 241

individuals, r ≈ 0.5 (Huson et al. 1989). Thus, qpr ≈ 10 −4 , which implies
a high germline mutation rate.
Few families transmit a mutation through several generations, and
most cases arise from new mutations (Gutmann and Collins 2002). A
wide variety of DNA lesions occur in the gene, including translocations,
large chromosomal deletions, smaller deletions within the gene, small
rearrangements within the gene, and point mutations. No particular
mutational hotspots have been detected. This large gene spans almost
9 kb of coding DNA over at least 57 exons and, including the intron
regions, approximately 300 kb of total DNA. Perhaps the large size con-
tributes to the high rate at which loss of function mutations arise. It will
be interesting to learn if other special attributes of this gene cause the
apparently elevated mutation rate.

Hereditary breast cancer.—Mutations in BRCA1, which has an impor-
tant function in the repair of double-strand DNA breaks, confer a high
probability of developing breast or ovarian cancer (Couch and Weber
2002). Current estimates for the penetrance of breast cancer in carriers
of BRCA1 mutations range from 56% to 86% (Couch and Weber 2002).
Lack of functional BRCA1 leads to chromosomal abnormalities (Welcsh
and King 2001), a common feature of cancer cells. The median age of
onset is approximately 50 years (Ford et al. 1998), which is later than for
most of the other cancers that follow dominant Mendelian inheritance.
The frequency of BRCA1 mutant alleles and associated cases varies in
different populations over the range 10 −3 –10 −2 (Tonin et al. 1995; Couch
and Weber 1996; Struewing et al. 1997; Couch and Weber 2002). No data
measure the decrease in reproduction in carriers of BRCA1 mutations:
a reasonable guess would be in the range 10 −2 –10 −1 . These values give
an estimate for qpr of 10 −5 –10 −3 , which is somewhat higher than the
standard assumption of 10 −6 –10 −5 for the mutation rate.
Welcsh and King (2001) suggested that BRCA1 may have an elevated
somatic mutation rate because of the high density of repetitive DNA
elements in the gene. Those repeats may also cause a higher germline
mutation rate, which would explain the higher than expected frequency
of variants in populations.
Alternatively, Harpending and Cochran (2006) argued that natural se-
lection of BRCA1 variants may be more strongly affected by that gene’s
role in early brain growth and development rather than in DNA repair.