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

STUDYING GENE EXPRESSION AND FUNCTION
493
Polymorphisms Can Aid the Search for Mutations Associated with
Disease
Mutations that give rise, in a reproducible way, to rare but clearly defined abnormalities,
such as albinism, hemophilia, or congenital deafness, can often be identified
by studies of affected families. Such single-gene, or monogenic, disorders
are often referred to as Mendelian because their pattern of inheritance is easy to
track. Moreover, individuals who inherit the causative mutation will exhibit the
abnormality irrespective of environmental factors such as diet or exercise. But for
many common diseases, the genetic roots are more complex. Instead of a single
allele of a single gene, such disorders stem from a combination of contributions
from multiple genes. And often, environmental factors have strong influences
on the severity of the disorder. For these multigenic conditions, such as diabetes
or arthritis, population studies are often helpful in tracking down the genes that
increase the risk of getting the disease.
In population studies, investigators collect DNA samples from a large number
of people who have the disease and compare them to samples from a group of
people who do not have the disease. They look for variants—SNPs, for example—
that are more common among the people who have the disease. Because DNA
sequences that are close together on a chromosome tend to be inherited together,
the presence of such SNPs could indicate that an allele that increases the risk of
the disease might lie nearby (Figure 8–51). Although, in principle, the disease
could be caused by the SNP itself, the culprit is much more likely to be a change
that is merely linked to the SNP as part of a haplotype block.
Such genome-wide association studies have been used to search for genes that
predispose individuals to common diseases, including diabetes, coronary artery
disease, rheumatoid arthritis, and even depression. For many of these conditions,
the DNA polymorphisms identified increase the risk of disease only slightly.
Moreover, environmental factors (diet, exercise, for example) play an important
role in the onset and severity of the disease. Nonetheless, the identification of
genes affected by these polymorphisms is leading to a mechanistic understanding
of some of our most common disorders.
Genomics Is Accelerating the Discovery of Rare Mutations That
Predispose Us to Serious Disease
The genetic variants that have thus far allowed us to identify some of the genes
that increase our risk of disease are common ones. They arose long ago in our evolutionary
past and are now present, in one form or another, in a substantial portion
(1% or more) of the population. Such polymorphisms are thought to account
healthy individuals
individual A
B
C
D
E
affected individuals
individual A
B
C
D
E
Figure 8–51 Genes that affect the
risk of developing a common disease
can often be tracked down through
linkage to SNPs. Here, the patterns
of SNPs are compared between two
sets of individuals—a set of healthy
controls and a set affected by a particular
common disease. A segment of a
typical chromosome is shown. For most
polymorphic sites in this segment, it is
a random matter whether an individual
has one SNP variant (red vertical bars)
or another (blue vertical bars); this same
randomness is seen both for the control
group and for the affected individuals.
However, in the part of the chromosome
that is shaded in darker gray, a bias is
seen: most normal individuals have the
blue SNP variants, whereas most affected
individuals have the red SNP variants.
This suggests that this region contains,
or is close to, a gene that is genetically
linked to these red SNP variants and that
predisposes individuals to the disease.
Using carefully selected controls and
thousands of affected individuals, this
approach can help track down diseaserelated
genes, even when they confer only
a slight increase in the risk of developing
the disease.