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

232 Chapter 4: DNA, Chromosomes, and Genomes
disease survivors
or migrants
individual with
rare allele
original population founder group new population
Figure 4–78 How founder effects
determine the set of genetic variants in
a population of individuals belonging to
the same species. This example illustrates
how a rare allele (red) can become
established in an isolated population,
even though the mutation that produced
it has no selective advantage—or is mildly
deleterious.
Europe, genetic variants that are rare in the human population as a whole can
often be present at a high frequency, even if those variants are mildly deleterious
(Figure 4–78).
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A Great Deal Can Be Learned from Analyses of the Variation
Among Humans
Even though the common variant gene alleles among modern humans originate
from variants present in a comparatively tiny group of ancestors, the total number
of variants now encountered, including those that are individually rare, is very
large. New neutral mutations are constantly occurring and accumulating, even
though no single one of them has had enough time to become fixed in the vast
modern human population.
From detailed comparisons of the DNA sequences of a large number of modern
humans located around the globe, scientists can estimate how many generations
have elapsed since the origin of a particular neutral mutation. From such
data, it has been possible to map the routes of ancient human migrations. For
example, by combining this type of genetic analysis with archaeological findings,
scientists have been able to deduce the most probable routes that our ancestors
took when they left Africa 60,000 to 80,000 years ago (Figure 4–79).
We have been focusing on mutations that affect a single gene, but these are not
the only source of variation. Another source, perhaps even more important but
missed for many years, lies in the many duplications and deletions of large blocks
of human DNA. When one compares any individual human with the standard
reference genome in the database, one will generally find roughly 100 differences
involving gain or loss of long sequence blocks, totaling perhaps 3 million nucleotide
pairs. Some of these copy number variations (CNVs) will be very common,
presumably reflecting relatively ancient origins, while others will be present in
only a small minority of people (Figure 4–80). On average, nearly half of the CNVs
contain known genes. CNVs have been implicated in many human traits, including
color blindness, infertility, hypertension, and a wide variety of disease susceptibilities.
In retrospect, this type of variation is not surprising, given the prominent
role of DNA addition and DNA loss in vertebrate evolution.
The intraspecies variations that have been most extensively characterized,
however, are single-nucleotide polymorphisms (SNPs). These are simply points
in the genome sequence where one large fraction of the human population has
one nucleotide, while another substantial fraction has another. To qualify as
Figure 4–79 Tracing the course of
human history by analyses of genome
sequences. The map shows the
routes of the earliest successful human
migrations. Dotted lines indicate two
alternative routes that our ancestors are
thought to have taken out of Africa. DNA
sequence comparisons suggest that
modern Europeans descended from a
small ancestral population that existed
about 30,000 to 50,000 years ago.
In agreement, archaeological findings
suggest that the ancestors of modern
native Australians (solid red arrows)—and
of modern European and Middle Eastern
populations—reached their destinations
about 45,000 years ago. Even more recent
studies, comparing the genome sequences
of living humans with those of Neanderthals
and another extinct population from
southern Siberia (the Denisovans), suggest
that our exit from Africa was a bit more
convoluted, while also revealing that a
number of our ancestors interbred with
these hominid neighbors as they made
their way across the globe. (Modified from
P. Forster and S. Matsumura, Science
308:965–966, 2005.)
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