Essential Cell Biology 5th edition

Exploring Human Genetics
679
With the recent advances that have enabled the sequencing of entire
human genomes rapidly and inexpensively (discussed in Chapter 10), 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 tens of thousands of human genomes, we can now
identify directly the DNA differences that distinguish one individual from
another. In this section, we discuss how analyses of DNA collected from
human families and populations all over the world are providing clues
about our evolutionary history and about the genes that influence our
susceptibility to disease.
Linked Blocks of Polymorphisms Have Been Passed
Down from Our Ancestors
As discussed in Chapter 9, when we compare the sequences of multiple
human genomes, we find that any two individuals will differ in about 1
nucleotide pair in 1000. Most of these variations are common and relatively
harmless. When two sequence variants coexist at the same site and
are common in the population, the variants are called polymorphisms.
The majority of polymorphisms are due to the substitution of a single
nucleotide, called single-nucleotide polymorphisms or SNPs (see
Figure 9−38). The rest are due largely to insertions or deletions—called
indels when the change is small, or copy number variants (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
or other DNA markers 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 200,000 years ago. Among that small group of our
ancestors, some individuals might 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. (Remember, only
a few crossovers occur between each set of homologous chromosomes,
as shown in Figure 19−12.)
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.
QUESTION 19–4
When two individuals from different
isolated, inbred subpopulations of
a species come together and mate,
their offspring often show “hybrid
vigor”: that is, they appear more
robust, healthy, and fertile than
either parent. Can you suggest
a possible explanation for this
phenomenon?
Polymorphisms Provide Clues to Our Evolutionary
History
A detailed examination of haplotype blocks has provided intriguing
insights into the history of human populations. Our DNA sequences are
constantly being altered by mutation; many of these changes will be
neutral, in that they will not affect the reproductive success of the individual.
Each of these variants has a chance of becoming common in the