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

HOW GENOMES EVOlvE
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compared. For example, typical human and chimpanzee DNA sequences differ
from one another by about 1%. In contrast, when the same region of the genome
is sampled from two randomly chosen humans, the differences are typically about
0.1%. For more distantly related organisms, the interspecies differences outshine
intraspecies variation even more dramatically. However, each “fixed difference”
between the human and the chimpanzee (in other words, each difference that is
now characteristic of all or nearly all individuals of each species) started out as a
new mutation in a single individual. If the size of the interbreeding population in
which the mutation occurred is N, the initial allele frequency for a new mutation
would be 1/(2N) for a diploid organism. How does such a rare mutation become
fixed in the population, and hence become a characteristic of the species rather
than of a few scattered individuals?
The answer to this question depends on the functional consequences of the
mutation. If the mutation has a significantly deleterious effect, it will simply be
eliminated by purifying selection and will not become fixed. (In the most extreme
case, the individual carrying the mutation will die without producing progeny.)
Conversely, the rare mutations that confer a major reproductive advantage on
individuals who inherit them can spread rapidly in the population. Because
humans reproduce sexually and genetic recombination occurs each time a gamete
is formed (discussed in Chapter 5), the genome of each individual who has
inherited the mutation will be a unique recombinational mosaic of segments
inherited from a large number of ancestors. The selected mutation along with a
modest amount of neighboring sequence—ultimately inherited from the individual
in which the mutation occurred—will simply be one piece of this huge mosaic.
The great majority of mutations that are not harmful are not beneficial either.
These selectively neutral mutations can also spread and become fixed in a population,
and they make a large contribution to evolutionary change in genomes.
For example, as we saw earlier, they account for most of the DNA sequence differences
between apes and humans. The spread of neutral mutations is not as
rapid as the spread of the rare strongly advantageous mutations. It depends on
a random variation in the number of mutation-bearing progeny produced by
each mutation-bearing individual, causing changes in the relative frequency of
the mutant allele in the population. Through a sort of “random walk” process, the
mutant allele may eventually become extinct, or it may become commonplace.
This can be modeled mathematically for an idealized interbreeding population,
on the assumption of constant population size and random mating, as well as
selective neutrality for the mutations. While neither of the first two assumptions
is a good description of human population history, study of this idealized case
reveals the general principles in a clear and simple way.
When a new neutral mutation occurs in a population of constant size N that
is undergoing random mating, the probability that it will ultimately become fixed
is approximately 1/(2N). This is because there are 2N copies of the gene in the
diploid population, and each of them has an equal chance of becoming the predominant
version in the long run. For those mutations that do become fixed, the
mathematics shows that the average time to fixation is approximately 4N generations.
Detailed analyses of data on human genetic variation have suggested an
ancestral population size of approximately 10,000 at the time when the current
pattern of genetic variation was largely established. With a population that has
reached this size, the probability that a new, selectively neutral mutation would
become fixed is small (1/20,000), while the average time to fixation would be on
the order of 800,000 years (assuming a 20-year generation time). Thus, while we
know that the human population has grown enormously since the development
of agriculture approximately 15,000 years ago, most of the present-day set of common
human genetic variants reflects the mixture of variants that was already present
long before this time, when the human population was still small.
Similar arguments explain another phenomenon with important practical
implications for genetic counseling. In an isolated community descended from
a small group of founders, such as the people of Iceland or the Jews of Eastern