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INTRODUCTION 11

variants, their effects, and their fluctuations in frequency. With resolu-
tion per site, one can also evaluate the interaction between variants at
different sites. I then turn around the causal pathway: the phenotype
of a variant—progression and incidence—influences the rate at which
that variant increases or decreases within the population. The limited
data appear to match expectations: variants that cause a strong shift
of incidence to earlier ages occur at low frequency; variants that only
sometimes lead to disease occur more frequently.
I finish Chapter 11 by addressing a central question of biomedical ge-
netics: Does inherited disease arise mostly from few variants that occur
at relatively high frequency in populations or from many variants that
each occur at relatively low frequency? Inheritance of cancer provides
the best opportunity for progress on this key question.
Chapter 12 focuses on somatic variants. Mitotic rate drives the origin
of new variants and the relative risk of cancer in different tissues. For
example, epithelial tissues often renew throughout life; about 80–90%
of human cancers arise in epithelia. The shape of somatic cell lineages
in renewing tissues affects how variants accumulate over time. Rare
stem cells divide occasionally, each division giving rise on average to
one replacement stem cell for future renewal and to one transit cell.
The transit cell undergoes multiple rounds of division to produce the
various short-lived, differentiated cells. Each transit lineage soon dies
out; only the stem lineage remains over time to accumulate heritable
variants. I review the stem-transit architecture of cell lineages in blood
formation (hematopoiesis), gastrointestinal and epidermal renewal, and
in sex-specific tissues such as the sperm, breast, and prostate.
I finish Chapter 12 by analyzing stem cells divisions and the origin
of heritable variations. In some cases, stem cells divide asymmetrically,
one daughter determined to be the replacement stem cell, and the other
determined to be the progenitor of the short-lived transit lineage. New
heritable variants survive only if they segregate to the daughter stem
cell. Recent studies show that some stem cells segregate old DNA tem-
plate strands to the daughter stem cells and newly made DNA copies
to the transit lineage. Most replication errors probably arise on the
new copies, so asymmetric division may segregate new mutations to
the short-lived transit lineage. This strategy reduces the mutation rate
in the long-lived stem lineage, a mechanism to protect against increased
disease with age.