Page 257 - 20dynamics of cancer

242 CHAPTER 11

Such pleiotropy could explain the elevated frequency of BRCA1 if the
variants had beneficial effects on brain development. In particular, Harp-
ending and Cochran (2006) argue that heterozygotes for BRCA1 variants
can in some environments have beneficial neural effects, but the variant
homozygotes would be at a disadvantage. A mild heterozygote advan-
tage balanced against strongly deleterious effects in the variant homozy-
gotes could explain the observed frequency of BRCA1 variants. The age
of variant BRCA1 alleles may provide clues about the forces that affect
allele frequencies.

THE AGE OF ALLELES: A COMPARATIVE PREDICTION

Variants that cause greater reproductive loss will disappear from the
population faster than variants that cause relatively lower reproductive
loss.
In the simplest case, each new variant causes early death before repro-
duction, and each variant only lives for a generation. Lower penetrance
or later onset imposes a weaker selective sieve against variants, allowing
the variants a longer time before extinction.
Soon, we will have enough data on the DNA sequences of variants to
allow reconstruction of their history and the time back to their com-
mon ancestor—the age of the allele. If the age of alleles is primarily
determined by a balance between the origin of novel variants by mu-
tation and clearance from the population by selection, then those ages
should follow the simple prediction that more deleterious alleles tend to
last a shorter period of time. Alternatively, forces other than mutation-
selection balance may determine the age of alleles.
Consider, for example, the two alternative hypotheses for BRCA1 vari-
ant frequency. If the elevated frequency of BRCA1 variants arises from
a higher germline mutation rate for that gene balanced against contin-
ual loss of variants by selection, then most variants at this locus should
be relatively young (recent in origin). By contrast, if the elevated fre-
quency arises from pleiotropic beneficial effects on neural development
balanced against deleterious effects on cancer progression, then most
variants at this locus should be relatively old.