Essential Cell Biology 5th edition

682 CHAPTER 19 Sexual Reproduction and Genetics
Some monogenic diseases are more common in certain populations
than in others. In some cases, this prevalence is due to natural selection.
The mutant hemoglobin allele that can provide resistance to malaria, for
example, is present in higher frequencies in geographic regions where
malaria is common. In other cases, the preponderance of a particular
mutation is likely due to a founder effect; that is, a subpopulation of
humans arose from a small number of individuals, some of which happened
to carry a particular mutation. As this subpopulation expanded,
the frequency of the mutant allele became higher than it is in the human
population as a whole. This appears to be the case for Tay-Sachs disease,
which is more prevalent in Ashkenazi Jews.
When we explore the mechanisms by which these rare, single-gene
mutations lead to disease, we find that monogenic disorders affect nearly
all aspects of cell and molecular biology. Tay-Sachs disease, for example,
is caused by loss-of-function mutations in the gene that encodes
the enzyme hexosaminidase. Without this enzyme, brain and nerve cells
become increasingly damaged, with tragic consequences. Another disease,
called cystic fibrosis, arises from mutations in the gene coding for
a specialized form of chloride channel. Some of these mutations prevent
the channel from opening, while others inhibit its proper folding, which
leads to the protein being destroyed. Knowing how a particular mutation
affects protein function can point the way toward the most effective treatment.
For example, certain drugs can help direct a misfolded channel to
its proper place in the plasma membrane and help it to function more
effectively. Such treatments can “rescue” mutant proteins and restore
enough of their activity to alleviate some of the worst symptoms of cystic
fibrosis. Although the consequences of such diseases can be devastating
to individuals, families, and communities, their study has provided critical
insights into the function of many human genes.
QUESTION 19–5
In a recent automated analysis,
thousands of SNPs across the
genome were analyzed in pooled
DNA samples from humans who had
been sorted into groups according
to their age. For the vast majority of
these sites, there was no change in
the relative frequencies of different
variants as these humans aged.
Sometimes, albeit rarely, a particular
variant at one position was found to
decrease in frequency progressively
for people over 50 years old. Which
of the possible explanations seems
most likely?
A. The nucleotide in that SNP
at that position is unstable, and
mutates with age.
B. Those people born more
than 50 years ago came from a
population that tended to lack the
disappearing SNP variant.
C. The SNP variant alters an
important gene product in a way
that shortens the human life-span, or
is linked to a neighboring allele that
has this effect.
Finally, it should be noted that not all loss-of-function mutations in
humans are deleterious. For example, individuals that are homozygous
for mutations that destroy a cell-surface receptor called CCR5 are resistant
to infection by HIV because the virus uses this receptor to enter
human immune cells. Although individuals lacking this receptor may be
slightly more sensitive to other viral infections, they appear normal in all
other respects. This mutation can thus be seen as largely beneficial in
a world in which HIV continues to be a major public health issue—and
could point toward therapeutic strategies for combatting the spread of
the virus.
Common Human Diseases Are Often Influenced by
Multiple Mutations and Environmental Factors
Although the monogenic disorders discussed above are rare, the genes
responsible tend to be relatively simple to track down. Analyzing the
genomes from an affected family—or a small population in which the
disease is prevalent—is often sufficient to locate the disease-causing
mutation. However, many of the most common human diseases—such as
type 2 diabetes, coronary artery disease, and obesity—are influenced by
many different genetic factors, as well as environmental conditions. For
such complex, multigenic conditions, no single allele—whether homozygous
or heterozygous—is sufficient to precipitate the disease. Instead, a
given allele might increase the risk of having the disease, but—in the
absence of other contributing alleles (or environmental factors)—would
be unlikely to cause it.
Unlike the relatively simple inheritance patterns associated with monogenic
disorders, those of multigenic disorders are often bewilderingly
complex: although the individual alleles involved are each inherited