Evolution and Natural Selection
Depending on the level at which one looks at evolution there is more than one way to define evolution.
However, it is important to remember that evolution is a population process that occurs from
generation to generation. It is not an individual process (i.e. an individual cannot evolved, only
populations can.
Microevolution: Any change in the inherited traits (genetic structure) of a population that occurs from
one generation to the next.
Macroevolution: Change in the morphology of organisms over time and/or the origin of new species.
Macroevolutionary changes are the result of microevolutionary changes in genetic structure of a
population over time.
Why study evolution?
Evolution explains the diversity of life. All living things are related to each other and are the products of
millions of years of evolution.
Understanding evolution allows us to understand why the living world is the way it is. We can
understand e.g., the similarities and differences between species, as well as their adaptations and their
distributions.
There are also practical reasons to study evolution. Evolution allows us to understand the evolution of
disease organisms such as viruses and bacteria and combat them.
Evolution also gives us insight into such “big” questions as: “How did we get here?” and “How did
thought and language evolve?”
Natural Selection and Evolution in action
Evolution in viruses. Viruses go through many generations in a short period of time so they provide an
excellent example of evolution in action. Your text has a nice discussion of the evolution of the flu virus.
You need to read it and be familiar with it.
We will discuss a different example in class– the HIV virus to illustrate the process of natural selection.
HIV Virus and AIDS
Acquired immune deficiency syndrome (AIDS) is caused by Human Immunodeficiency Virus (HIV). The
virus is transmitted through transfer of bodily fluids (e.g. blood, semen). The virus attacks the immune
system and the victim dies of secondary infections. Projected worldwide mortality from HIV by 2020 is
90 million lives. Sub-Saharan Africa in particular has been devastated by the disease.
HIV, like all viruses, is an intracellular parasite. It parasitizes macrophages and T-cells of the immune
system. It uses the cell’s own enzymatic machinery to make copies of itself. When the virus emerges
from the cell it kills the host cell.
HIV gains entry to the cell’s interior by binding to two protein receptors on the cell’s surface : CD4 and a
coreceptor, usually CCR5. The host cell’s membrane and the viral coat fuse and the virus contents enter
cell.
The virus inserts in entire RNA genome and three enzymes that carry out essential tasks to make new
virus.
Reverse transcriptase: transcribes viral RNA into DNA. This copies the virus’s information into a form
that can be inserted into the hosts DNA
Integrase: this enzyme splices DNA into host DNA. This enzymes cuts the host’s DNA so the viral DNA
can be inserted into the host’s DNA.
Protease: this enzyme involved in production of viral proteins that form the outer shell of the virus.
The viral DNA inserted in host DNA produces HIV mRNA and all components of virus. The viral particles
self assemble from the available components and bud from host cell.
HIV is difficult to treat because HIV hijacks the host’s own enzymatic machinery: ribosomes, transfer
RNAs, polymerases, etc. Drugs that targeted these enzymes would target every cell in the host’s body,
which would be very debilitating for the host.
How HIV causes AIDS
Human body responds to infection with HIV by mobilizing the immune system. The immune system
destroys virus particles floating in bloodstream and also destroys cells infected with virus.
Unfortunately, the cells that HIV infects are critical to immune system function.
HIV invades immune system cells especially helper T cells. These helper T cells have a vital role in the
immune system. When a helper T cell is activated (by having an antigen [a piece of foreign protein]
presented to it, it begins to divide into memory T cells and effector T cells.
Memory T cells do not engage in current fight against the virus. Instead they are long-lived and can
generate an immune response quickly if the same foreign protein is encountered again.
Effector T cells attack the virus. They produce signaling molecules called chemokines that stimulate B
cells to produce antibodies to the virus.
Effector T cells also stimulate macrophages to ingest cells infected with the virus.
In addition effector T cells stimulate killer T cells to destroy infected cells displaying viral proteins.
First round of infection with HIV reduces the pool of CD4 Helper T cells (those that can recognize and
attack HIV).
Loss of CD4 cells costly, but immune system now primed to recognize viral protein.
What’s the problem? Why isn’t HIV eliminated?
Virus mutates and the proteins on its outer surface (gp120 and gp41) change.
These different surface proteins are not recognized by the immune systems’ memory cells. Thus, the
mutants survive the immune system onslaught and begin a new round of infection
Each round of infection reduces the numbers of helper T cells because they are infected by virus and
destroyed. Furthermore, because each lineage of T cells has a limited capacity for replication after a
finite number of rounds of replication the body’s supply of helper T cells becomes exhausted and the
immune system eventually is overwhelmed and collapses. The patient then vulnerable to secondary
infections.
AZT
AZT (azidothymidine) was the first HIV wonder drug. AZT works by interfering with HIV’s reverse
transcriptase, which is the enzyme the virus uses to convert its RNA into DNA so it can be inserted in the
host’s genome.
DNA is made up of repeating patterns of 4 nucleotides that contain one of four bases (adenine, guanine,
cytosine and thymine)
AZT is similar to thymine (one of the 4 bases of DNA) but it has an azide group (N3) in place of hydroxyl
group (OH).
If an AZT molecule is inserted into a DNA strand that is being assembled it prevents the strand from
growing. The azide group will not bond with the next nucleotide in the chain so it the completion of the
DNA molecule. If the DNA cannot be completed, viral proteins cannot be made.
AZT was successful in tests although with it had serious side effects. However, patients quickly stopped
responding to treatment and the evolution of AZT-resistant HIV in patients usually took only about 6
months.
Resistant HIV strains had reverse transcriptase genes that differed genetically from non-resistant strains.
The mutations were located in the active site (the part of the enzyme that picks up nucleotides) of the
reverse transcriptase. These changes selectively blocked the binding of AZT to DNA but allowed other
nucleotides including thymine to be added.
How did resistance develop?
The HIV reverse transcriptase is very error prone. As a result ,about half of all DNA transcripts produced
contain an error (mutation). HIV actually has the highest mutation rate known for any biological entity.
There is thus enormous VARIATION in the HIV population in a patient.
The high mutation rate makes the occurrence just by chance of AZT-resistant mutations almost certain.
NATURAL SELECTION now starts to act in the presence of AZT
The presence of AZT in the environment (i.e. the patient’s body) suppresses the replication of nonresistant strains. The resistant strains, however, are BETTER ADAPTED to the environment and can still
reproduce. Consequently, resistant strains reproduce more rapidly. There is thus DIFFERENTIAL
REPRODUCTIVE SUCCESS of HIV strains. Resistant strains produce more offspring.
Resistant strains replicate and pass on their resistant genes to the next generation. Thus resistance is
HERITABLE.
As a result of out-reproducing the non-resistant strains the AZT-resistant strains quickly replace nonresistant strains. The HIV gene pool changes from one generation to the next. EVOLUTION has
occurred: Remember evolution is change in the gene pool from one generation to the next.
Recall the necessary steps for the process of Natural Selection to work and we can see the HIV example
is a beautiful example of natural selection in action.
There must be variation in population – individuals differ in their traits or characteristics. In the HIV
example, virus particles differ in the structure of the active site of their reverse transcriptase enzyme.
The variation must be heritable. We know the shape of the enzyme reverse transcriptase is directly
coded for by the viral genome, so we know the variation is heritable.
The variation (the traits that organisms possess) affects reproductive success – there is differential
reproductive success because the variation that some individuals possess makes them better adapted
than others. In this case, individual virus particles that have active sites on their reverse transcriptase
that don’t pick up AZT have an advantage in reproducing over virus particles that pick up AZT.
As a result, more copies of the beneficial alleles are passed to offspring and those alleles become more
common in next generation.
Using selection to devise better treatment regimens.
Several different types of drugs have been developed to treat HIV. These include
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Reverse transcriptase inhibitors (e.g. AZT).
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Protease inhibitors (prevent HIV from producing final viral proteins from precursor
proteins).
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Fusion inhibitors prevent HIV entering cells.
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Integrase inhibitors prevent HIV from inserting HIV DNA into host’s genome.
Because HIV mutates so rapidly treatment with a single drug will not be successful for long. Is there a
better way to treat patients?
Most successful approach has been to use multi-drug cocktails (referred to as HAART [Highly Active AntiRetroviral Treatments]. HAART cocktails usually use three different drugs in combination (e.g. two
reverse transcriptase inhibitors and a protease inhibitor).
Using multi-drug cocktails sets the evolutionary bar higher for HIV. To be resistant a virus particle must
possess mutations against all three drugs. The chances of this occurring in a single virus particle are very
low.
If the same drugs were provided in sequence to an HIV population each time it faced a new drug it
would need only a single mutation to gain resistance, which would then spread through the population.
Offering drugs one at a time is analagous to providing a stairway that HIV must climb. Offering multiple
drugs at once requires HIV to leap from the bottom to the top in a single bound, which is much more
difficult
Multi-drug treatments have proven very successful in reducing viral load and reducing mortality of
patients. However, HIV infection is not cured. Reservoir of HIV hides in resting white blood cells.
Patients who go off HAART therapy experience increased HIV loads.
For patients on HAART whether HIV replication is stopped completely or not is crucial. In some HIV
appears dormant and no replication means no evolution. In other patients replication occurs, although
slowly. However, this allows HIV to mutate and resistance to develop. So far, few HAART regimens are
effective for more than 3 years.
A downside of HAART therapy is that many patients experience severe side effects. These patients have
difficulties maintaining their treatment regimen. Because of severe side effects of HAART therapy some
doctors have advocated “drug holidays” for their patients (i.e. to have patients stop taking drugs for a
while).
From an evolutionary perspective does this seem like a good idea or not?
Because a drug holiday allows HIV to replicate it is likely to be a very bad idea. Every time HIV replicates
it produces new mutants and this increases the chance that a resistant form of HIV will be produced.
Origins of HIV
Where did HIV come from? HIV is similar to a type of virus in monkeys and apes called SIV (simian
immunodeficiency virus). To identify the ancestry of HIV scientists have sequenced various HIV strains
and compared them to various SIV strains.
HIV-1 is most similar to an SIV found in chimps and HIV-2 is most similar to an SIV found in a monkey
called the sooty mangabey.
HIV-1 occurs in three different subgroups (called M,N and O) and each appears closely related to a
different chimpanzee SIV strain. Thus it appears that HIV-1 jumped to humans from chimps on at least
three occasions. HIV therefore was most likely acquired through killing and butchering chimps and
monkeys in the “bushmeat” trade.
When did HIV first infect humans?
Sequence data from several group M strains has been used estimate when HIV moved from chimps to
humans. Korber et al. (2000) analyzed nucleotide sequence data for 159 samples of HIV-1 strain M.
They constructed a phylogenetic tree showing relatedness to a common ancestor of the 159 samples.
Based on rates of change observed in different strains of HIV it is believed that subgroup M probably
infected humans in the early 1930’s.