Nowak, M. (1990). HIV mutation rate. Nature. 347:522.
Shankarappa, R. Margolick, J. B., Gange, S. J., Rodrigo, A. G.,
Upchurch, D., . . . Mullins, J. I. (1999). Consistent viral
evolutionary changes associated with the progression of Human
Immunodeficiency Virus Type 1 infection. Journal of Virology. 73:
10489-10502.
Xue, Y., Wang, Q., Long, Q., Ng, B. L., Swedlow, H., Burton, J.
. . . Tyler-Smith, C. (2009). Human Y chromosome base-substitution
mutation rate measured by direct sequencing in a deep-rooting
pedigree. Current Biology. 19: 1453-1457.Evolution connection: DNA
replication
Weve just studied how DNA is copied and some of the different
ways the system guards against errors (mutations). The specificity
of the genetic code is an important first step in maintaining the
fidelity of the sequence; however, as weve learned, many additional
mechanisms have evolved DNA polymerase compares each newly added
base against the template, in a sense, proofreading its own work.
If a mistake is found, it is corrected before moving on.
This image shows the replication fork with DNA polymerase
attached.Mismatch repair can catch mistakes shortly after
replication by recognizing which strand was used as the template
and fixing mismatched bases on the newly synthesized strand.In
excision repair, a section of the DNA surrounding damaged bases or
damaged nucleotides are cut out and replaced, based on the
non-damaged strand.
Other cellular mechanisms, such as double-strand break repair,
have also evolved and repair different sorts of damage.
Cells go to extreme lengths to make sure that their DNA is
copied accurately and that the DNA sequence is maintained with
fidelity after that. The end result of this is impressive. (CLICK)
Recent estimates suggests that, in humans, mistakes slip by only
once in every 30 million base pairs or so.DNA proofreading and
repair mechanisms evolved because, on average, mutations decrease
the fitness of the individual carrying them. Most mutations are
neutral or deleterious. But there are exceptions. Sometimes,
mutations are advantageous, as in the case of antibiotic resistant
bacteria (CLICK) or the peppered moth (CLICK), where a mutation
that caused dark body color allowed moths to survive better in
their polluted environment.
(CLICK) Mutation generates genetic variation in populations, and
natural selection acts on this variation, weeding out the
deleterious mutations and increasing the frequency of the
advantageous ones. Genetic variation is the raw material of
evolution.What happens when some of these repair mechanisms are
missing? Retroviruses (like HIV, shown here) are a case in point.
They have single-stranded RNA (not DNA) as their genetic material.
In order to make copies of themselves, they use an enzyme called
reverse transcriptase. This enzyme makes a DNA copy of RNA. But
unlike DNA polymerase, reverse transcriptase cannot proof-read.
(Note to instructor: If you wish, this is an opportunity to go
into greater depth on how HIV reproduces by invading a cell and
using reverse transcriptase to make a DNA copy of their RNA. This
DNA is then integrated into the hosts genome in that cell and
directs the hosts cellular machinery to produce copies of the
virus.)
What happens without proofreading? Each time reverse
transcriptase copies HIVs genome, it makes many mistakesas many as
one mistake per thousand base pairs copied. This high mutation rate
(combined with the viruss rapid rate of reproduction) means that
HIV evolves at lightning fast speeds.
Organisms that use proof-reading DNA polymerase (which only
makes a mistake once every billion base pairs or so in eukaryotic
cells) have much lower mutation rates and evolve much more
slowly.
What does this mean in terms of our evolution?Its a tradeoff.
For high fidelity copiers (like humans), very few of our offspring
carry damaging mutations. On the other hand, little new variation
is generated each generation to contribute to our future evolution.
Retroviruses, on the other hand, produce a lot of offspring with
deleterious mutationsbut they are also evolutionarily nimble. They
have lots of standing genetic variation and can evolve quickly when
faced with new environmental conditions.
This has direct implications for human health.HIV-1 genomes
evolve about a million times as quickly eukaryotic DNA genomes do.
This phylogeny tracks the evolutionary history of an HIV infection
within a single patient over the course of 10 years. This rapid
pace of HIV evolution has enormous implications for our ability to
fight the virus:
HIV evolves to evade the antibodies our immune systems produce
to attack it.HIV evolves resistance to the drugs we develop against
it. This puts medical researchers in an arms race against the
virus. New drugs must be constantly developed, and patients often
need to take cocktails of drugs to slow the evolution of resistance
and keep viral loads low.Finally, because the virus is so
genetically variable and changes so quickly, researchers have not
yet managed to develop a vaccine that works against the virus
consistently.
In this case, small differences at the molecular level (like
using reverse transcriptase instead of DNA polymerase to copy ones
genetic material) have a big impact on evolution and on human
health. The evolutionary trade-off of sloppy copying is worth it
for HIV and means that it can evolve remarkably quicklyand this
rapid evolution is what makes the virus so difficult for us to
fight.
