Essential Cell Biology 5th edition

680 CHAPTER 19 Sexual Reproduction and Genetics
population. The more time that has elapsed since the origin of a relatively
common polymorphism like a SNP, the smaller should be the haplotype
block that surrounds it: that’s because, over the course of many generations,
crossover events will have had many chances to separate an
ancient allele from other variants nearby. Thus by comparing the sizes of
haplotype blocks from different human populations, it is possible to estimate
how many generations have elapsed since the origin of a specific
neutral mutation. By combining such genetic comparisons with archaeological
findings, scientists have been able to deduce the most probable
routes our ancestors took when they left Africa (see Figure 9−37).
Genome analyses can also be used to estimate when and where humans
acquired mutations that have conferred an evolutionary benefit, such as
resistance to infection. Such favorable mutations will rapidly accumulate
in the population because individuals that carry them will be more likely
to survive an epidemic and pass the mutation on to their offspring. A haplotype
analysis can be used to “date” the appearance of such a favorable
mutation. If it cropped up in the population relatively recently, there will
have been fewer opportunities for recombination to break up the DNA
sequence around it, so the surrounding haplotype block will be large.
Such is the case for sickle-cell anemia, a disorder caused by a single
nucleotide substitution that changes a glutamic acid to a valine in one of
the protein subunits of hemoglobin (see Figure 6–32). Although individuals
who are homozygous for this allele experience the harmful effects
of anemia, heterozygotes who carry one normal and one sickle-cell
allele show no ill effects and, in addition, are resistant to malaria. This
allele—which confers a benefit under the right set of circumstances—is
widespread in Africa, where malaria is rife. A comparison of numerous
human genes reveals that the sickle-cell allele is embedded in an unusually
large haplotype block, indicating that it arose relatively recently in
the African gene pool—probably about 2000 years ago. In this way, analyses
of modern human genomes can highlight important events in human
evolution, including our initial exposures to specific infections.
Genetic Studies Aid in the Search for the Causes of
Human Diseases
Like the wrinkled peas studied by Mendel, our susceptibility to disease is
a phenotypic trait—albeit an unfortunate one. Thus, for many diseases,
the causes are rooted in our genomes. In some cases, the genetic underpinnings
of disease are clear and unequivocal. For example, mutations in
specific genes give rise, in a reproducible way, to clearly defined conditions
such as congenital deafness, albinism, hemophilia, and sickle-cell
anemia. Other times, the genetic connections are more complex. Many of
the most common human disorders, such as diabetes or arthritis, involve
many genes working together to give rise to the “disease phenotype.”
Most diseases are also influenced by environmental factors: availability
of nutrition or exposure to toxins, carcinogens, infectious viruses or
microorganisms—even to sunlight (see Figure 6−25). Yet even diseases
that are clearly environmental in nature, such as infection by specific
pathogens can be modified by genetic factors. For example, individuals
bearing a sickle-cell allele are resistant to malaria, as we discussed
earlier. Others carry an allele that renders them genetically resistant to
infection with HIV, the virus that causes AIDS, as we discuss shortly. The
ultimate outcome, in terms of disease phenotype, thus depends on an
intricate interplay amongst genetic and environmental factors.
Despite these complexities, genetic studies—particularly those that
involve a comparison of human genome sequences—are expanding
our understanding of the fundamental causes of human disease. In the