Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

238 Chapter 5: DNA Replication, Repair, and Recombination
sugar, such as glucose, and testing them subsequently to see how many have lost
the ability to survive on a lactose diet. The fraction of damaged genes underestimates
the actual mutation rate because many mutations are silent (for example,
those that change a codon but not the amino acid it specifies, or those that
change an amino acid without affecting the activity of the protein coded for by the
gene). After correcting for these silent mutations, one finds that a single gene that
encodes an average-sized protein (~10 3 coding nucleotide pairs) accumulates a
mutation (not necessarily one that would inactivate the protein) approximately
once in about 10 6 bacterial cell generations. Stated differently, bacteria display
a mutation rate of about three nucleotide changes per 10 10 nucleotides per cell
generation.
Recently, it has become possible to measure the germ-line mutation rate
directly in more complex, sexually reproducing organisms such as humans. In
this case, the complete genomes from a family—parents and offspring—were
directly sequenced, and a careful comparison revealed that approximately 70 new
single-nucleotide mutations arose in the germ lines of each offspring. Normalized
to the size of the human genome, the mutation rate is one nucleotide change
per 10 8 nucleotides per human generation. This is a slight underestimate because
some mutations will be lethal and will therefore be absent from progeny; however,
because relatively little of the human genome carries critical information, this
consideration has only a small effect on the true mutation rate. It is estimated that
approximately 100 cell divisions occur in the germ line from the time of conception
to the time of production of the eggs and sperm that go on to make the next
generation. Thus, the human mutation rate, expressed in terms of cell divisions
(instead of human generations), is approximately 1 mutation/10 10 nucleotides/
cell division.
Although E. coli and humans differ greatly in their modes of reproduction and
in their generation times, when the mutation rates of each are normalized to a
single round of DNA replication, they are both extremely low and within a factor
of three of each other. We shall see later in the chapter that the basic mechanisms
that ensure these low rates of mutation have been conserved since the very early
history of cells on Earth.
Low Mutation Rates Are Necessary for Life as We Know It
Since many mutations are deleterious, no species can afford to allow them to
accumulate at a high rate in its germ cells. Although the observed mutation frequency
is low, it is nevertheless thought to limit the number of essential proteins
that any organism can depend upon to perhaps 30,000. More than this, and the
probability that at least one critical component will suffer a damaging mutation
becomes catastrophically high. By an extension of the same argument, a mutation
frequency tenfold higher would limit an organism to about 3000 essential genes.
In this case, evolution would have been limited to organisms considerably less
complex than a fruit fly.
The cells of a sexually reproducing animal or plant are of two types: germ cells
and somatic cells. The germ cells transmit genetic information from parent to offspring;
the somatic cells form the body of the organism (Figure 5–1). We have
seen that germ cells must be protected against high rates of mutation to maintain
the species. However, the somatic cells of multicellular organisms must also be
protected from genetic change to properly maintain the organized structure of the
body. Nucleotide changes in somatic cells can give rise to variant cells, some of
which, through “local” natural selection, proliferate rapidly at the expense of the
rest of the organism. In an extreme case, the result is the uncontrolled cell proliferation
that we know as cancer, a disease that causes (in Europe and North America)
more than 20% of human deaths each year. These deaths are due largely to
an accumulation of changes in the DNA sequences of somatic cells, as discussed
in Chapter 20. A significant increase in the mutation frequency would presumably
cause a disastrous increase in the incidence of cancer by accelerating the rate
at which somatic-cell variants arise. Thus, both for the perpetuation of a species