1. Mutations, DNA, and Protein

In a previous module, we examined how natural selection can increase the frequency of helpful alleles within a gene pool, and decrease the frequency of harmful alleles. But evolution isn’t only about the increase or decrease of already existing alleles. Through mutation, new alleles can enter gene pools.

A mutation is a random change in a nucleotide sequence (or in an entire chromosome, though that’s beyond the scope of what we’ll be discussing below). For example, examine this nucleotide sequence.

 

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DNA Nucleotides ATG GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACT
Amino Acid START Val His Leu Thr Pro Glu Glu Lys Ser Ala Val Thr

The As, Ts, Cs, and Gs on the row labeled “DNA nucleotides” represent the nitrogenous bases which carry genetic information in DNA. The three letters on the amino acid row represent one of the twenty amino acids, or some genetic code “punctuation,” such as “start.” The numbers on top organize the nucleotides into triplets, reflecting the way that the genetic code uses groups of three nucleotides to code for one amino acid. The 13 triplets shown above code for the start of hemoglobin (the same oxygen-carrying protein we discussed in a previous tutorial in relationship to ice fish).

Now examine the wild type hemoglobin sequence and the mutated (changed) hemoglobin sequence below it. Before reading on, try to find the mutation.

Original (wild type) Sequence for Hemoglobin

 

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DNA Nucleotides ATG GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACT
Amino Acid START Val His Leu Thr Pro Glu Glu Lys Ser Ala Val Thr

Mutated Sequence for Hemoglobin

 

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DNA Nucleotides ATG GTG CAC CTG ACT CCT GTG GAG AAG TCT GCC GTT ACT
Amino Acid START Val His Leu Thr Pro Val Glu Lys Ser Ala Val Thr
Effects of sickle cell mutation. Source: National Institutes of Health, http://www.nhlbi.nih.gov/health/health-topics/topics/sca

It doesn’t seem like much: just one nucleotide in the 7th triplet, with the triplet GAG changed to GTG. However, that one change results in the 7th  amino acid being Valine instead of Glutamic Acid. And the effects of that change are catastrophic. Because valine is a non-polar amino acid and glutamic acid is ionic, the substitution changes hemoglobin’s chemical and physical properties. The mutation causes adjacent mutated hemoglobin molecules to weakly bond with one another, especially when the mutated hemoglobin is exposed to a low oxygen environment – something that can be brought on whenever blood oxygen levels drop. As a result, running, climbing stairs, or any other kind of exertion causes the mutant hemoglobin to crystallize into long fibers. This changes the shape of the red blood cells. Instead of smooth and roughly doughnut shaped, they become spiky and sickle shaped. This shape causes them to clog up in small blood vessels, damaging the tissue on the other side of the blockage, and causing debilitating pain.

Note that the way that biologists use the word “mutation” can be confusing. In the case of sickle cell anemia, the mutation happened long ago, and, for reasons we’ll soon see, rose to a relatively high frequency in certain human gene pools. In other words, the phrase “sickle cell mutation” is essentially the same as the phrase “sickle cell allele.”

 

In my DNA Rap, I explain this as follows. See if you can drag the right words into the right place.

[qwiz qrecord_id=”sciencemusicvideosMeister1961-Pop-gen: Mutation Interactive Lyrics”]

[q labels = “top”]

Hundreds of bases spell one __________ piece
Hundreds of A’s, G’s, __ and Cs
The gene starts CAC-GTG-CAC
Then TGA-GGA-CTC-CTC 

The key is these bases are ____________
For hemoglobin’s function and conformation
Hundreds of bases, in a predetermined ________
A single change brings on a major disorder

Change T to A in one _________ spot
This little point _________ might not seem like a lot
Thymine to Adenine might not seem that big to ya’
But baby that’s the cause of ________ cell anemia!

[l]hemoglobin

[fx] No, that’s not correct. Please try again.

[f*] Good!

[l]information

[fx] No. Please try again.

[f*] Correct!

[l]mutation

[fx] No, that’s not correct. Please try again.

[f*] Great!

[l]order

[fx] No, that’s not correct. Please try again.

[f*] Correct!

[l]sickle

[fx] No. Please try again.

[f*] Correct!

[l]single

[fx] No, that’s not correct. Please try again.

[f*] Excellent!

[l]Ts

[fx] No, that’s not correct. Please try again.

[f*] Excellent!

[/qwiz]

2. Mutations can have three types of consequences

2a. Mutations are mostly harmful

Firstly, as in the example of sickle cell anemia, a mutation might take a working protein and make it stop working. This is especially true if the mutation results in STOP codon being inserted anywhere in the protein, or if the mutation shifts the reading frame. Then either part or all of the protein won’t be made (in the case of a stop codon), or it will be made with many incorrect amino acids. In the both cases, the mutation causes the loss of a functioning protein.

On account of this, the most likely thing that a mutation will do is cause genetic disorders. Cystic fibrosis, the most common genetic disorder among Americans of European descent, is caused by a deletion of three nucleotides in a gene that codes for a very large membrane protein (to learn more about cystic fibrosis, click herethe link will open in new tab). Tay Sachs disease (discussed in a previous tutorial) is caused by a variety of mutations. The one most common in Jews of Eastern European descent involves a four base insertion in the gene for an enzyme. The insertion causes a change in the reading frame, making the resulting enzyme completely non-functional (click here to read more about Tay Sachs).

2b. Mutations can be silent

Secondly, the mutation might change the DNA, but not the amino acid being coded for. This can happen because the genetic code has a lot of redundancy. For example, the DNA triplets ACT, ACC, ACA, and ACG all code for the amino acid threonine. These kind of mutations, which change DNA but not the protein being coded for, are known as silent mutations. Because they have no effect on the phenotype, they won’t be acted upon by natural selection.

2c.Mutations can be beneficial

Thirdly, the mutation might improve the protein. It might, for example, improve the efficiency with which an enzyme binds to its substrate. Or, as Sean Carroll points out in his book The Making Of The Fittest, it might change a light receptor in an animal’s eye so that it can see a slightly different frequency of light energy, making it able to perceive prey that others without this mutation can’t see.

Frequency of sickle cell anemia allele in Africa. Areas in blue have the highest frequency, then gray, then green, then white

The beneficial nature of some mutations explains why the allele for sickle cell anemia is in such high frequency in parts of sub-Saharan Africa. In Nigeria, for example, up to 2% of newborns are affected by this disease. The disease is caused by a recessive allele, and over 10% of the Nigerian population may be carriers (heterozygotes).You can see this in the map on the left: areas shaded represent populations where the allele frequency for sickle cell anemia exceeds 10%.

Incidence of malaria in Africa. Darker colors have higher incidence. Compare with the sickle cell incidence map.

The high frequency of the disease is explained by the fact that this area is also a central region for malaria, a serious blood disease caused by a parasite that is carried from person to person by mosquitoes. While heterozygotes are, when viewed from outside, mostly symptom free, on the inside (in their blood cells), the presence of the mutated hemoglobin disrupts the life cycle of the malaria causing parasite. In other words, having the allele, if you’re a heterozygote, will be selected for, even while being a homozygote is selected against. You can see the incidence of malaria in the map to the right. Compare it with the map on the left to see how the incidence of malaria correlates with the frequency of the sickle cell allele.

This phenomenon, where harmful recessive alleles are in higher-than expected frequency because having one copy of the allele is a selective advantage, is called heterozygote advantage (the link takes you to a Wikipedia article in a new tab). Heterozygote advantage is well established as an explanation for the high frequency of the sickle cell allele in parts of Africa with malaria. It has also been proposed to explain the high frequency of the cystic fibrosis allele in European populations, where approximately 1 in 25 people is a carrier. The idea is that being heterozygous for the cystic fibrosis allele confers a possible survival advantage in the face of the bacterial diseases cholera and tuberculosis, though this idea is controversial. No known heterozygote advantage has been identified for Tay-Sachs disease, which is carried by about 1 in 27 Jews of European descent.

Heterozygote advantage is a specific example of a wider theme: how variation is the raw material that natural selection acts upon to make populations adapted. While mutations are mostly harmful, on the vast timescale of evolution, they play a role of increasing variation in a gene pool, which increases a population’s ability to adapt.

3. Checking Understanding

The key concepts in this module were

  1. What mutations are
  2. The impact of mutations on phenotype
  3. Heterozygote advantage
  4. Mutation and Variation

If you feel that you understand these concepts well, take this brief quiz. If not, carefully re-read the material above, and then take the quiz.

[qwiz qrecord_id=”sciencemusicvideosMeister1961-Pop-gen: Gene Pools and Mutation”]

[h]Gene Pools and Mutation

[!!!!!!] question 1 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]A change in a nucleotide sequence of a gene is called a (n)

[c] transformation.

[c*] mutation.

[c] recombination

[f] No. While ‘transformation’ is roughly synonymous with ‘change,’ there’s a better match for the definition above. Additionally, there’s a special biological definition of ‘transformation:’ putting new DNA into a cell. Next time, choose another term.

[f] That’s correct. A mutation is a change in the nucleotide sequence of a gene.

[f] Recombination does involve changes in DNA, as DNA from different sources is mixed together. But there’s a better term to match the definition above.

[!!!!!!] question 2 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]True or false? When the environment changes, a population will evolve new mutations in order to be able to adapt.

[c] True

[c*] False

[f] No. Mutations are random. Evolutionary adaptation is about previously existing variations being selected by the environment, and allele frequencies shifting in response.

[f] That’s correct. Mutations are random. Evolutionary adaptation is about previously existing variations being selected by the environment, and allele frequencies shifting in response.

[!!!!!!] question 3 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]A nucleotide sequence changes from

TGAGGTCTCCTC

to

TGAGGCCTCCTC

Of the terms below, this change is best described as a

[c] nucleotide shift.

[c*] mutation.

[c] gene alteration.

[f] No. While the nucleotide sequence has changed, there’s a better term than ‘shift’ to describe what happened.

[f] That’s correct. A mutation is a change in the nucleotide sequence of a gene, which is what you see above.

[f] No. While the change above would alter a gene, there’s a better term to describe what happened.

[!!!!!!] question 4 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]A mutation causes a nucleotide sequence to change from

TGAGGTCTCCTC

to

TGAGGCCTCCTC

Both sequences code for the same amino acid sequence.

This type of mutation is known as a(n)

[c] insertion mutation.

[c] deletion mutation.

[c*] silent mutation.

[c] frameshift mutation.

[f] No. An insertion mutation would add a new nucleotide somewhere in the nucleotide sequence, and push all the other nucleotides over one position. The main consequence of this is that it changes the reading frame, and changes every codon downstream of the mutation. Next time, choose a type of mutation with a less drastic effect.

[f] No. A deletion mutation would remove a nucleotide somewhere in the nucleotide sequence, and pull all the other nucleotides one position forward. The main consequence of this is that it changes the reading frame, and changes every codon downstream of the mutation. Next time, choose a type of mutation with a less drastic effect.

[f] Exactly. A silent mutation changes the DNA, but doesn’t change the amino acids that the sequence is coding for.

[f] A frameshift mutation results from either inserting or deleting a base. These insertions change the reading frame during translation, and cause many of the amino acids in the protein that the gene codes for to be changed. In the example above, what we have is a simple substitution, and one that doesn’t change even one amino acid. Choose another answer next time.

[!!!!!!] question 5 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]What’s the most likely effect of a mutation that deletes one nucleotide near the start of a gene?

[c] The mutation will cause a single amino acid to be changed in the protein that this gene codes for.

[c*] The mutation will cause a series of changes in the amino acids that the gene codes for.

[c] The mutation will cause no change in the resulting protein.

[f] No. If a single nucleotide is deleted near the start of a gene, then the ‘reading frame’ for all subsequent codons will be shifted. Almost all the codons will be incorrectly read, changing many amino acids in that protein.

[f] That’s the most likely result. If a single nucleotide is deleted near the start of a gene, then the ‘reading frame’ for all subsequent codons will be shifted. Almost all the codons will be incorrectly read, changing many amino acids in that protein.

[f] That’s not correct. If a single nucleotide is deleted near the start of a gene, then the ‘reading frame’ for all subsequent codons will be shifted. Almost all the codons will be incorrectly read, changing many amino acids in that protein. It looks like you were thinking about a ‘silent mutation,’ which is when a mutation changes the DNA, but not the protein. This can happen when one nucleotide is substituted for another, and it happens because many codons are synonymous, and code for the same amino acid. Deletions, by contrast, are almost never silent.

[!!!!!!] question 6 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]Insertion or deletion of a single nucleotide in a DNA sequence results in a

[c*] frameshift mutation.

[c] silent mutation.

[c] point mutation that doesn’t change the reading frame.

[f] Terrific! Insertions or deletions in the nucleotide sequence either push all the nucleotides down, or pull them all forward. The main consequence of this is that it changes the reading frame, and changes every codon downstream of the mutation.

[f] No. A silent mutation changes the DNA, without changing any of the amino acids the gene codes for. Insertions or deletions  in the nucleotide sequence either push all the nucleotides down, or pull them all forward. The main consequence of this is that it changes the reading frame, and changes every codon downstream of the mutation. See if you can find a choice that, in a single word, captures what happens with insertions or deletions.

[f] No. The key point here is that inserting or deleting a nucleotide from a DNA sequence shifts every nucleotide forward or backward. This does change the reading frame. Next time, choose another answer.

[!!!!!!] question 7 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]Which type of mutation is most likely to be acted upon by natural selection?

[c] A silent mutation (which only changes the DNA)

[c*] An active mutation (which changes the DNA, and the protein the DNA codes for)

[f] No. Silent mutations have no effect on an organism’s phenotype. Since natural selection only acts on the phenotype, silent mutation can’t be acted on by natural selection.

[f] That’s correct. Active mutations change protein, which changes an organism’s phenotype. Since natural selection acts on an organism’s phenotype, active mutations become targets for selection.

[!!!!!!] question 8 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]The most common consequence of an active mutation is for there to be

[c] improvement of the protein, making it more effective and increasing an organism’s probability of survival.

[c] no impact on the organism’s phenotype.

[c*] damage to a functioning protein, resulting in disease for the organism that bears the mutation.

[f] No. While this is possible, and an important part of evolution, it’s very unlikely. Mutations are random changes, and random changes are more likely to break things than to fix them.

[f] No. By definition, an active mutation is changing a protein. Proteins, on some level, are what make up an organism’s phenotype (either directly, or through enzymes that control development).

[f] Yes. Mutation is the cause of many genetic diseases. Their most likely impact of a mutation is to take a protein that’s working, and to diminish or destroy its function.

[!!!!!!] question 9 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]In a population, a specific gene has two alleles, ‘A’ and ‘a.’ Individuals with genotype ‘aa’ die in early childhood. Individuals with genotype ‘Aa’ have a higher rate of surviving and reproducing than individuals with genotype ‘AA.’ This phenomenon is called

[c] mutation selection.

[c*] heterozygote advantage.

[c] allele selection.

[f] No. While this will alter the frequency of alleles in this population in favor of the lethal allele, that’s not the name that’s used. Think about which genotype has the survival advantage.

[f] Yes. This situation, where heterozygotes survive at higher rates, even though they carry a lethal allele, is called heterozygote advantage.

[f] No. On a population genetic level, the lethal allele will wind up with a much higher frequency than would be expected for a lethal allele. But that’s not the name for this phenomenon. Think about which genotype has the survival advantage.

[!!!!!!] question 10 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]For this question, let ‘S’ represent the normal hemoglobin allele, and ‘s’ represent the sickle cell allele. In areas affected by malaria, which of the following sequences of genotypes correctly shows which genotype has the highest survival rate, followed by the second highest, followed by the lowest survival rate.

[c] SS, Ss, ss

[c] ss, SS, Ss

[c] SS, ss, Ss

[c*] Ss, SS, ss

[f] No. ‘SS’ is the normal hemoglobin genotype, but individuals with this genotype suffer from malaria. You’re correct in putting ‘ss’ last, since it results in sickle cell anemia, a serious disease. Think about which genotype produces a phenotype that does best in malaria-affected areas, and choose another sequence.

[f] No. ‘ss’ is for sickle cell anemia, a serious disease. with a low survival rate. ‘ss’ should go last. ‘SS’ is the normal hemoglobin genotype, but individuals with this genotype suffer from malaria. Think about which genotype produces a phenotype that does best in malaria-affected areas, and choose another sequence.

[f] No. ‘SS’ is the normal hemoglobin genotype, but this individuals with this genotype suffer from malaria. ‘ss’ is for sickle cell anemia, a serious disease with high mortality (’ss’ should go last). Think about which genotype produces a phenotype that does best in malaria-affected areas, and choose another sequence.

[f] Excellent. Heterozygotes have the advantage, and survive at the highest rate. ‘SS’ is for normal hemoglobin, but the normal phenotype is vulnerable to malaria, a very serious disease that can be deadly. While ‘ss’ is not exactly ‘lethal,’ it results in sickle cell anemia, a disease with lowered survival rates.

[!!!!!!] question 11 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]Which of the following statements about the role of mutation in a population’s gene pool is most correct?

[c*] Mutations can add variation to a population’s gene pool, making that population more able to adapt to change.

[c] Mutations have only negative effects on a population’s gene pool.

[c] Populations encourage mutations in order to respond to environmental challenges.

[f] Yes. While on an individual basis, mutations are mostly harmful, on a population level mutations are an important source of the variation that makes adaptation possible.

[f] No. While on an individual basis, mutations are mostly harmful, on a population level mutations are an important source of the variation that makes adaptation possible.

[f] No. Mutations are completely random. Neither individuals nor populations have any control over when mutations happen, and whether those mutations will be harmful or beneficial.

[!!!!!!] question 12 +++++++++[/!!!!!!]

[q topic= “gene_pools_and_mutation”]The gene pools of two populations of the same species are compared. For the genes studied, almost all of the genes for all the alleles in population ‘A’ are fixed. Population ‘B’ has many more genes with two or more alleles. Which population will have difficulty adapting to environmental change?

[c*] Population A

[c] Population B

[f] Yes. Variation is the raw material that nature acts upon to select new adaptations. Population ‘A,’ with its many fixed alleles, seems to have little variability. Adapting to environmental change will be very difficult.

[f] No. Variation is the raw material that nature acts upon to select new adaptations. Population ‘B,’ with two or more alleles for many genes, will have more variation, enabling it to have a better chance at adapting to changes in its environment.

[x]

[restart]

[/qwiz]

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