Essential Cell Biology 5th edition

686 CHAPTER 19 Sexual Reproduction and Genetics
well as genetic factors play an important part in determining which individuals
will develop the disease.
Disappointingly, most of the DNA polymorphisms identified through this
strategy increase the risk of disease only slightly. Many of them fall within
regulatory DNA sequences and only subtly alter the expression of the
genes they control. However, by identifying these “risky alleles,” such
studies provide insights into the molecular mechanisms underlying these
complex disorders, these results are leading to an improved understanding
of the molecular basis of common inherited diseases.
We Still Have Much to Learn about the Genetic Basis
of Human Variation and Disease
The polymorphisms that have thus far allowed us to track our ancestors
and identify genes that increase our risk of disease have to be relatively
common to be detected by the methods we have described. Because they
arose so long ago in our evolutionary past they are now present, in one
form or another, in a substantial portion (1% or more) of the population.
Such genetic variants are thought to account for about 90% of the differences
between one person’s genome and another. But when we try to tie
these common alterations to differences in disease susceptibility or other
heritable traits, such as height, we find that they do not have as much
predictive power as we had anticipated: thus, for example, most confer
relatively small increases—less than twofold—in the risk of developing a
common disease.
Part of the problem is that many of the mutations that are directly
responsible for complex human diseases appeared more recently in
our evolutionary history—during a period when the human population
underwent an explosive expansion in size, from the few million individuals
that existed a mere 10,000 years ago to the 7 billion or so that inhabit
the planet today. Because such mutations occur more rarely than the
ancient polymorphisms that are common in the human population, they
could slip through the type of GWAS approach just described.
Now that the price of DNA sequencing has plummeted, the most efficient
and cost-effective way to identify these recent mutations is by sequencing
and comparing the genomes of many thousands of individuals—those
affected by diseases and those who are not. Such DNA sequencing must
be very accurate, so that rare DNA variants in the population can be
unambiguously identified (and distinguished from sequencing errors).
Once these variants are identified, the next challenge is to determine how
they affect the phenotype of the individuals that carry them. When a variant
falls within the coding region of a gene, it is simple to assess whether
it would alter the amino acid sequence of the resulting protein. However,
as we have seen, many important DNA variants lie outside coding
regions. This mechanism could help explain why many alleles have only
a small, but statistically significant, effect on the probability of precipitating
a particular disease. It is often difficult to predict—from inspection of
a genome sequence alone—what the effect of such variants might be; in
these cases, additional experiments in cultured cells or animal models
are needed to determine the consequences of such a mutation.
As genome sequencing efforts continue, we are discovering many previously
unreported genetic variants in people affected by disease—and in
apparently healthy individuals. Based on one study, each of us harbors
about 100 loss-of-function mutations in protein-coding genes—some of
which eliminate the activity of both gene copies. This surprising result
means that our genome still holds many secrets, and that we can develop