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

492 Chapter 8: Analyzing Cells, Molecules, and Systems
population is so large, spontaneous, nonlethal mutations have arisen in all human
genes—many times over. A substantial proportion of these remain in the genomes
of present-day humans. The most deleterious of these mutations are discovered
when the mutant individuals call attention to themselves by seeking medical help.
With the recent advances that have enabled the sequencing of entire human
genomes cheaply and quickly, we can now identify such mutations and study
their evolution and inheritance in ways that were impossible even a few years ago.
By comparing the sequences of thousands of human genomes from all around the
world, we can begin to identify directly the DNA differences that distinguish one
individual from another. These differences hold clues to our evolutionary origins
and can be used to explore the roots of disease.
Linked Blocks of Polymorphisms Have Been Passed Down from
Our Ancestors
When we compare the sequences of multiple human genomes, we find that any
two individuals will differ in roughly 1 nucleotide pair in 1000. Most of these variations
are common and relatively harmless. When two sequence variants coexist
in the population and both are common, the variants are called polymorphisms.
The majority of polymorphisms are due to the substitution of a single nucleotide,
called single-nucleotide polymorphisms or SNPs (Figure 8–50). The rest are due
largely to insertions or deletions—called indels when the change is small, or copy
number variations (CNVs) when it is large. Although these common variants can
be found throughout the genome, they are not scattered randomly—or even independently.
Instead, they tend to travel in groups called haplotype blocks—combinations
of polymorphisms that are inherited as a unit.
To understand why such haplotype blocks exist, we need to consider our evolutionary
history. It is thought that modern humans expanded from a relatively
small population—perhaps around 10,000 individuals—that existed in Africa
about 60,000 years ago. Among that small group of our ancestors, some individuals
will have carried one set of genetic variants, others a different set. The chromosomes
of a present-day human represent a shuffled combination of chromosome
segments from different members of this small ancestral group of people. Because
only about two thousand generations separate us from them, large segments of
these ancestral chromosomes have passed from parent to child, unbroken by the
crossover events that occur during meiosis. As described in Chapter 5, only a few
crossovers occur between each set of homologous chromosomes during each
meiosis (see Figure 5–53).
As a result, certain sets of DNA sequences—and their associated polymorphisms—have
been inherited in linked groups, with little genetic rearrangement
across the generations. These are the haplotype blocks. Like genes that exist in
different allelic forms, haplotype blocks also come in a limited number of variants
that are common in the human population, each representing a combination of
DNA polymorphisms passed down from a particular ancestor long ago.
~1000 nucleotide pairs
individual A
individual B
individual C
individual D
T
A
T
A
T
A
T
A
G T
G A C
C G T
C A
C T G
G C A
A T
G T C C A T
T A
C A G
G T A
A T
G A C C A T
T A
C T G
G T A
G T
G A C C A T
C A
C T G G T A
SNP1 SNP2 SNP3
Figure 8–50 Single-nucleotide polymorphisms (SNPs) are sites in the genome where two or
more alternative choices of a nucleotide are common in the population. Most such variations
in the human genome occur at locations where they do not significantly affect a gene’s function.