Essential Cell Biology 5th edition

684
HOW WE KNOW
USING SNPs TO GET A HANDLE ON HUMAN DISEASE
For diseases that have their roots in genetics, finding the
gene or genes responsible can be the first step toward
improved diagnosis, treatment, and even prevention.
The task is not simple, but having access to polymorphisms
such as SNPs can help. In 1999, an international
group of scientists set out to collect and catalog 300,000
SNPs—the single-nucleotide polymorphisms that are
common in the human population (see Figure 9−38).
Today, the database has grown to include a catalog of
millions upon millions of genetic variations. These SNPs
do not only help to define the differences between one
individual and another; for geneticists, they also serve
as signposts that can point the way toward the genes
involved in common human disorders, such as diabetes,
obesity, asthma, arthritis, and even gallstones and restless
leg syndrome.
Making a map
One way that SNPs have facilitated the search for alleles
that predispose to disease is by providing the physical
markers needed to construct detailed genetic linkage
maps. A genetic linkage map displays the relative locations
of genetic markers along each chromosome. Such
maps are based on the frequency with which these markers
are co-inherited. Those that lie close to one another
on the same chromosome will be inherited together
much more frequently than those that lie farther apart.
By determining how often crossing-over separates two
markers, the relative distance between them can be calculated
(see Panel 19−1, p. 675).
The same sort of analysis can be used to discover linkage
between a SNP and an allele—for example, one that
might cause an inherited disease. We simply look for coinheritance
of the SNP with a certain phenotype—in this
case, the disease. Finding such a linkage indicates that
the mutation responsible for the phenotype is either the
SNP itself or, more likely, lies close to the SNP (Figure
19−39). And because we know the exact location in the
human genome sequence of every SNP we examine, the
linkage tells us the neighborhood in which the causative
mutation resides. A more detailed analysis of the
DNA in that region—to look for deletions, insertions, or
other functionally significant abnormalities in the DNA
sequence of affected individuals—can then lead to a
precise identification of the critical gene.
chromosome pair in
heterozygous mother
same chromosome pair
in heterozygous father
recessive
mutation
SNP a
SNP b
recessive
mutation
SNP a
egg
sperm
b
b
a a a b b a b b a b a a
–
bb
+
aa
–
ab
–
ba
–
bb
–
ab
+
aa
disease
SNP genotype
TESTS PERFORMED ON 7 OFFSPRING
OBSERVATION: Disease is seen only in progeny with SNP genotype aa.
CONCLUSION: Recessive mutation causing the disease is co-inherited with SNP a. If this same
correlation is observed in other families that have been examined, the mutation causing the disease
must lie close to SNP a.
Figure 19−39 SNP analysis can pin down the location of a mutation that causes a genetic disease. In this approach, one studies
the co-inheritance of a specific human phenotype (here a genetic disease) with a particular set of SNPs. The figure shows the logic for
the common case of a family in which both parents are carriers of a recessive mutation. If individuals with the disease, and only such
individuals, are homozygous for a particular SNP, then the SNP and the recessive mutation that causes the disease are likely to be close
together on the same chromosome, as shown here. To prove that an apparent linkage is statistically significant, a few dozen individuals
from such families may need to be examined. With more individuals and using more SNPs, it is possible to locate the mutation more
precisely. These days it can be just as fast and cheap to use whole-genome sequencing to find the mutation.
ECB5 e19.39/19.39