BIOL 101 Fall 2018 Dr.

Bergerson

Extra Credit Opportunity: Mutation Application (5 homework points)

Background: Remember what we learned about in terms of evolution. Mutations provide the
variation that natural selection works upon. Importantly, it is not the change in environment that
causes the mutation, but rather the mutation already exists. The change in environment now
results in the mutation being an advantage/disadvantage.

There are humans that live in high altitude. Some of these humans have ancestors that lived there
for thousands of years. The Tibetan plateau is about 4 kilometers (2.5 miles) in altitude. The
oxygen levels at this altitude are 60% of that at sea level.

Producing more red blood cells and hemoglobin is an effective way to carry more oxygen to the
body; however, it has several negative effects. An increase in red blood cells makes the blood too
viscous (thick). This can cause the red blood cells to block blood vessels, making the person
more prone to heart attacks and strokes. Additionally, pregnant women who travel to areas of
high altitude are prone to preeclampsia, a form of high blood pressure that is particularly
dangerous in pregnant women.

So, how have the Tibetans who have lived in the mountains for thousands of years dealt with this
problem? There is a gene called ELGN1. When it is transcribed and translated it produces a
protein (PHD2) that regulates the number of red blood cells in the blood. In high oxygen
environments, there is plenty of oxygen and so PHD2 prevents the production of red blood cells.
In low oxygen conditions, the PHD2 protein becomes less active, allowing for more red blood
cells to be produced.

High oxygen Active PHD2 Fewer red blood cells

Low oxygen Inactive PHD2 More red blood cells

1. When a human from lower elevation travels to the Tibetan plateau, their body responds by
producing more red blood cells and hemoglobin. The hemoglobin in red blood cells carries
oxygen. Why would a normal human respond this way? What process requires oxygen?
What does this process make?

A normal human may respond this way because their body is trying to carry more oxygen to
the body in this area of low-oxygen. The process that requires oxygen is cellular respiration.
During cellular respiration, glucose is broken down in the presence of oxygen to produce carbon
dioxide and water. Energy released during the reaction is captured by the energy-carrying
molecule ATP (adenosine triphosphate).

2. Remember, on the Tibetan plateau, the oxygen levels are about 60% of that found at sea level. So,
when a lower altitude person travels to high altitudes they are experiencing a low oxygen

Lorenzo, F. R., Huff, C., Myllymäki, M., Olenchock, B., Swierczek, S., Tashi, T., & ... Prchal, J.T. 2014. A genetic mechanism
for Tibetan high-altitude adaptation. Nature Genetics. 46(9): 951-956. doi:10.1038/ng.3067
BIOL 101 Fall 2018 Dr. Bergerson

environment. What will happen to the PHD2 protein in an average human when they travel to the
Tibetan plateau?

The PHD2 protein in an average human when they travel to the Tibetal plateau will becomes
less active, allowing for more red blood cells to be produced.

This response, along with its increased health risks would not be advantageous to the average
Tibetan. Recent data suggests that Tibetans have a different DNA sequence for ELGN1.

3. At nucleotide 12 in the gene they have a DNA nucleotide change in the template from 3’
CTG 5’ to 3’ CTC 5’. What happens to the amino acid sequence when this mutation occurs?
Show the result of transcription and translation. How would that affect the protein
structure?

The amino acid sequence goes from 3’ CTG 5’ to 3’ CTC 5’. When transcribed it then goes
from GAC to GAG. The translation of this amino acid goes from Asp originally to Glu after the
mutation occurs. This would affect the structure of this protein because Glutamic acid (Glu) has
an additional CH2 on the molecule.

4. At nucleotide 380 they have a change in the template DNA from 3’ ACG 5’ to 3’ AGG 5’.
What happens to the amino acid sequence when this mutation occurs? Show the result of
transcription and translation. How would that affect the protein structure?

The amino acid sequence goes from 3’ ACG 5’ to 3’ AGG 5’. When transcribed it goes
from UGC to UCC. The translation of this amino acid goes from Cysteine originally to
Serine after the mutation occurs. This would affect the proteins structure because it goes
from SH at the top of the molecule to OH.

Lorenzo, F. R., Huff, C., Myllymäki, M., Olenchock, B., Swierczek, S., Tashi, T., & ... Prchal, J.T. 2014. A genetic mechanism
for Tibetan high-altitude adaptation. Nature Genetics. 46(9): 951-956. doi:10.1038/ng.3067
BIOL 101 Fall 2018 Dr. Bergerson

The DNA mutations, and therefore amino acid changes, alter the oxygen binding of PHD2. This
allows for there to be fewer red blood cells in a low oxygen environment. These mutations are
associated with protection from polycythemia, a disease state in which the proportion of blood
volume that is occupied by red blood cells increases, in low oxygen environments. This allows
the native Tibetans to live in a low oxygen environment, without the negative effects of blood
that is too thick.

5. What type of selection occurred in the Tibetan population (in evolutionary terms)? Is this a
gain-of-function or loss-of-function mutation?

The type of selection that occurred in the Tibetan population was natural selection. This
is a loss-of-function mutation because the Tibetans lost the PHD2 gene which originally
would have made their blood too thick which caused serious side effects.

Lorenzo, F. R., Huff, C., Myllymäki, M., Olenchock, B., Swierczek, S., Tashi, T., & ... Prchal, J.T. 2014. A genetic mechanism
for Tibetan high-altitude adaptation. Nature Genetics. 46(9): 951-956. doi:10.1038/ng.3067