3.2: Consequences of mutations - Biology

3.2: Consequences of mutations - Biology

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The effect of a mutation will depend upon the function of the DNA sequence.

When mutations occur in coding sequences, we can predict the effect using the codon table.

  • Silent mutations: do not change the encoded amino acid
  • Nonsense mutations: change a codon to a STOP codon
  • Missense mutations: change a codon to a codon for a DIFFERENT amino acid
  • Frameshift mutations: add or remove bases to change all downstream codons

Three is the magic number

Adding or removing bases in multiples of three, will not cause a frameshift mutation. Why not?

Would mutations like this affect the protein? What additional information would you need to make a prediction about such a mutation?

Effect of Mutations on Protein Structure | Biology

Mutations may lead to addition, deletion, translocation or duplication of chromosomal segment. It may also involve addition, deletion or replacement of one or more base pairs of a gene.

Such mutations are clearly observed in proteins. Nitrogenous bases in DNA are changed due to physical mutagens like radiations (i.e., X- rays, UV rays, gamma rays) and some chemical mutagens.

By chemical mutations following changes’ are expected:

(i) Deamination of bases:

Chemicals like nitrous oxide deaminate (removal of NH2 group) from nitrogenous bases and therefore change the codon.

(ii) Incorporation of base analogue:

Two common base analogues are 5-bromouracil (5BU) and 5-fluorouracil (5FU). Both are analogous bases to thymine of DNA.

(iii) Methylating agent:

Some of the chemicals like nitrogen mustard cause addition of methyl group to the nitrogen bases of DNA.

Certain organic dyes as acridine orange and proflavin cause insertion or deletion of nitrogenous bases in a gene and may lead to frame-shift type of mutations.

By mutations, replication, transcription and translation mechanism of DNA molecule is disturbed. A-T base pair may get changed to G-C pair. Sometimes, cross-over and recombination between DNA strands may lead to chunks of DNA being added or deleted. Under special conditions, shuffling of genes from one location to another location may occur and such shuffling genes are called as jumping genes.

Changed proteins are formed in mutations due to the reason that mRNA transcribed from the mutated gene will lack a segment or a base or will have an additional or altered segment or base. The abnormal mRNA introduce different amino acids in the polypeptide chain formed with changed message.

In a gene, single base is altered, only one codon of mRNA will change and will lead to change in single amino acid in polypeptide chain. Sometimes, entire reading frame may change from the site of mutation and a protein molecule may be formed with new set of amino acids.

Such mutation has been called as frame shift mutation. Sometimes, mutation may lead to the formation of non­sense codon which acts as a stop signal. This may lead to the formation of incomplete polypeptide chain.

There are also cases, when a single base change may not form a new amino acid. It occurs usually when change occurs in the third base of triplet codon. Such codon still interacts with the anticodon of corresponding tRNA. This position of a codon is called Wobble position and phenomenon has been described as Wobble hypothesis (Crick). According to this hypothesis first two bases of tRNA anticodon specifically undergo for hydrogen bonding. However, third base can form unusual base pairing. Because, it can wobble, position is called Wobble position.

Point Mutation

The alteration that occurs to the nucleotide sequence present in the genome of a virus or an organism or extrachromosomal DNA is called a mutation. There are chances that mutation can either produce detectable changes that are observable in an organism or it cannot produce it. They can either prevent the genes from functioning properly or can have no effect or it can alter the product of the gene. It involves the duplication of DNA in large sections.

There are different types of mutations that occur in an organism they are chromosomal mutation and point mutation. If the mutation occurs as a result of crossing over in the meiosis is called a chromosomal mutation. When there is an alteration in the single base pair is known as a point mutation.

Point mutation, also known as substitution, is a type of genetic mutation where the nucleotide base is inserted, deleted, or changed in the DNA or RNA of the genome of an organism. These have a variety of effects on the products, where the consequences are predictable with the specific mutation.

In regard to the synthesis of protein, its function, and its composition the range of these consequences can be determined from no effect to deleterious effects. Point mutation examples include sickle-cell anaemia and cystic fibrosis.

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Types of Point Mutations

In the case of point mutations there are two different types of mutations these are further divided depending on the form they mutate

1. Substitution Mutations: If the mutation occurs by the substitution of a nucleotide in the genome of an organism then it is known as a substitution mutation. It is further subdivided into three types:

In the case of silent mutation, a nucleotide can be substituted that results in the formation of the same amino acid, and this situation can make the multiple codons code for the same amino acid. The effect on the protein will be less, for example, codons AAA and AAG codes for lysine, and in the case instead of ‘G’ if ‘A’ is produced then the same amino acid is formed thus the effect on the protein is not found.

In the case of non-sense mutation, the nucleotide is substituted resulting in the formation of a stop codon instead of the formation of the codon that codes for the amino acid. These stop codons are certain sequences of the base chain that have the capability to stop amino acid chain production. At the end of the mRNA sequence in the production of the protein, it is always found and when the substitution occurs it will terminate the sequence of amino acids and prevent the formation of the correct protein.

The missense mutation occurs when the nucleotide is substituted which results in the formation of the different codon. It is the same as that of the non-sense mutation but in this case, the difference is the newly produced codon is not a stop codon but it is a different amino acid in the sequence. For example, if AAG is substituted as AGG then this codon relates to arginine instead of lysine. This type of mutation is said to be conservative if the amino acid that has to be formed instead of that of the amino acid that is formed from the missense mutation shares similar properties. The mutation is said to be non-conservative if different properties are found in the amino acid that has to be formed instead of that of the amino acid that is formed from the missense mutation.

2. Insertion or Deletion Mutations: When an extra-base pair is added to the sequence of the amino acid then the insertion mutation occurs. If an extra-base pair is removed from the sequence of the amino acid then it is said to be a deletion mutation. These types of mutation are grouped together since they can affect the sequence of the amino acid drastically.

When one or two bases are deleted or added the change in all three base codons occurs that results in the mutation, it is also known as frameshift mutation. Suppose the sequence in the DNA is CCT ATG TTT if ‘A’ is added in between the cytosine and the change in the sequence will be as CAC TAT GTT T this changes the structure and functioning of the protein formed and sometimes can make this protein useless. The same effect can be found if a base is deleted.

Consequences of Point Mutation

In the non-coding sequences, most of the time the point mutation occurs without any consequences. If the mutated base pair is present in the promoter sequence then the gene expression will vary. If the splicing site of an intron the point mutation is involved then it interferes with the splicing site of the transcribed mRNA in the correct form.

By altering one amino acid the entire peptide chain will change this, in turn, changes the entire protein. Thus the newly formed protein is called a protein variant. If this original protein is involved in the functioning of the cellular reproduction then the single point mutation involves the change in the entire process of cellular reproduction.

The point germline mutations can be beneficial as well as can cause diseases. Depending on the environment where the organism lives the adaptations can happen. The scientific theory of evolution is completely based on the point mutation that happens in the cells. This theory explains the history and diversity of the organisms present on the Earth. The beneficial mutations can help the organism to reproduce where the positively affected genes are passed to the next generation. The harmful mutations can make the organism reduce the process of reproduction or it can make the organism die this happens through a phenomenon called natural selection.

In mutations, the long-term and short-term effects can arise. Where the long-term effects are permanent by changing the chromosome that leads to mutation, short-term effects are involved in the halting of the cell cycle at different stages. For example, a codon that codes for glycine is changed to form a stop codon makes the protein stop the tasks that are to be performed. Mutations can affect the DNA and prohibit the process of mitosis due to the absence of the complete chromosome. An example of the long-term effects is cancer.

The other effects of the point mutation involve the location where the mutation happens in the gene. If the mutation occurs in the gene that is responsible for the coding then the amino acid sequence of a protein can be altered. This alteration leads to protein localization, changes in the function, or protein complex. Many of the methods have been proposed in the determination of the effects of missense mutations. While these methods provide only the binary classification of the effects of the mutations if they are benign or damaging, another level is required to provide the explanation of why and how the mutations are capable of damaging the proteins.

If the mutation occurs in the region where the proteins are bound with the transcriptional machinery then the mutation can affect the factors of binding. Thus the rate of efficiency of the gene transcription can be affected. This in turn alters the levels of mRNA and proteins. The transcription mechanism of binding to a protein is through the recognition of the short nucleotide sequence. Depending on the region of the amino acid sequence of the protein the point mutation can affect the behaviour and the reproduction of the protein in several ways. If the mutation occurs in the region where the gene is responsible for the coding of the protein then the alteration in the amino acid can be found. This change can affect the protein activation that is how the protein is bound to the enzyme or the change in the function.

Diseases Caused by Point Mutations

1. Cystic Fibrosis: It is most commonly found in people of European descent, it is an inherited recessive disorder. There are many types of mutations that can cause CF, but the common one is the deletion of the three nucleotide bases in the CFTR gene that is abbreviated as cystic fibrosis transmembrane conductance regulator gene. This results in the loss of the phenylalanine amino acid and makes the protein folding incorrect. The symptoms are thick sticky mucus found in the lungs. Salty sweat, trouble while breathing, shortened life expectancy, and in some individuals it can cause infertility.

2. Sickle-Cell Anaemia: The single substitution in the gene of the haemoglobin that carries the oxygen in the blood causes sickle-cell anaemia. It is a recessive disorder. The valine is produced instead of the glutamic acid in the chain by the substitution. When there is the presence of two copies in the people this leads to the change of the blood cells from disc-shaped to sickle-shaped that lacks the supply of oxygen to the blood. Almost 80 percent of the people with this disease can protect against malaria. The symptoms are chest pain, obstruction of the blood vessels, and anaemia.

3. Tay-Sachs: It is another recessive disorder caused due to point mutation where the effects are found on the HEXA gene of chromosome 15. It can cause the nerve cells to deteriorate which results in the decline of the mental and physical functioning of the body.


The point mutations can be beneficial as well they can cause harmful effects. It is depending on the environment it is adapted to. The point mutations are sometimes caused by the replication of DNA. The rate of these mutations can increase when these are exposed to the mutagens such as extreme heat, X-rays, UV rays, or due to some of the chemicals such as benzene.

Changes at the DNA Level

Point mutations are classified in molecular terms in Table 7-1, which shows the main types of DNA changes and their functional effects at the protein level.

Table 7-1

Gene Mutations at the Molecular Level.

At the DNA level, there are two main types of point mutational changes: base substitutions and base additions or deletions. Base substitutions are those mutations in which one base pair is replaced by another. Base substitutions again can be divided into two subtypes: transitions and transversions. To describe these subtypes, we consider how a mutation alters the sequence on one DNA strand (the complementary change will take place on the other strand.) A transition is the replacement of a base by the other base of the same chemical category (purine replaced by purine: either A to G or G to A pyrimidine replaced by pyrimidine: either C to T or T to C). A transversion is the opposite—the replacement of a base of one chemical category by a base of the other (pyrimidine replaced by purine: C to A, C to G, T to A, T to G purine replaced by pyrimidine: A to C, A to T, G to C, G to T). In describing the same changes at the double-stranded level of DNA, we must state both members of a base pair: an example of a transition would be G୼ →𠂊·T that of a transversion would be G୼ → T୺.

Addition or deletion mutations are actually of nucleotide pairs nevertheless, the convention is to call them base-pair additions or deletions. The simplest of these mutations are single-base-pair additions or single-base-pair deletions. There are examples in which mutations arise through simultaneous addition or deletion of multiple base pairs at once. As we shall see later in this chapter, mechanisms that selectively produce certain kinds of multiple-base-pair additions or deletions are the cause of certain human genetic diseases.

What are the functional consequences of these different types of point mutations? First, consider what happens when a mutation arises in a polypeptidecoding part of a gene. For single-base substitutions, there are several possible outcomes, which are direct consequences of two aspects of the genetic code: degeneracy of the code and the existence of translation termination codons.

Silent substitutions: the mutation changes one codon for an amino acid into another codon for that same amino acid.

Missense mutations: the codon for one amino acid is replaced by a codon for another amino acid.

Nonsense mutations: the codon for one amino acid is replaced by a translation termination (stop) codon.

Silent substitutions never alter the amino acid sequence of the polypeptide chain. The severity of the effect of missense and nonsense mutations on the polypeptide will differ on a case-by-case basis. For example, if a missense mutation causes the substitution of a chemically similar amino acid, referred to as a synonymous substitution, then it is likely that the alteration will have a less-severe effect on the protein’s structure and function. Alternatively, chemically different amino acid substitutions, called nonsynonymous substitutions, are more likely to produce severe changes in protein structure and function. Nonsense mutations will lead to the premature termination of translation. Thus, they have a considerable effect on protein function. Typically, unless they occur very close to the 3′ end of the open reading frame, so that only a partly functional truncated polypeptide is produced, nonsense mutations will produce completely inactive protein products.

Like nonsense mutations, single-base additions or deletions have consequences on polypeptide sequence that extend far beyond the site of the mutation itself. Because the sequence of mRNA is “read” by the translational apparatus in groups of three base pairs (codons), the addition or deletion of a single base pair of DNA will change the reading frame starting from the location of the addition or deletion and extending through to the carboxy terminal of the protein. Hence, these lesions are called frameshift mutations. These mutations cause the entire amino acid sequence translationally downstream of the mutant site to bear no relation to the original amino acid sequence. Thus, frameshift mutations typically exhibit complete loss of normal protein structure and function.

Now let’s turn to those mutations that occur in regulatory and other noncoding sequences. Those parts of a gene that are not protein coding contain a variety of crucial functional sites. At the DNA level, there are sites to which specific transcription-regulating proteins must bind. At the RNA level, there are also important functional sequences such as the ribosome-binding sites of bacterial mRNAs and the self-ligating sites for intron excision in eukaryote mRNAs.

The ramifications of mutations in parts of a gene other that the polypeptide-coding segments are much harder to predict. In general, the functional consequences of any point mutation (substitution or addition or deletion) in such a region depend on its location and on whether it disrupts a functional site. Mutations that disrupt these sites have the potential to change the expression pattern of a gene in terms of the amount of product expressed at a certain time or in response to certain environmental cues or in certain tissues. We shall see numerous additional examples of such target sites as we explore mechanisms of gene regulation later on (Chapters 14�). It is important to realize that such regulatory mutations will affect the amount of the protein product of a gene, but they will not alter the structure of the protein. Alternatively, some mutations might completely inactivate function (such as polymerase binding or intron excision) and be lethal.

It appears that genes also contain noncoding sequences that cannot be “point mutated” to produce detectable phenotypes. These sequences are interspersed with the mutable sites. These sequences are either functionally irrelevant or protected from mutational damage in some way.

New mutations are categorized as induced or spontaneous. Induced mutations are defined as those that arise after purposeful treatment with mutagens, environmental agents that are known to increase the rate of mutations. Spontaneous mutations are those that arise in the absence of known mutagen treatment. They account for the �kground rate” of mutation and are presumably the ultimate source of natural genetic variation that is seen in populations.

The frequency at which spontaneous mutations occur is low, generally in the range of one cell in 10 5 to 10 8 . Therefore, if a large number of mutants is required for genetic analysis, mutations must be induced. The induction of mutations is accomplished by treating cells with mutagens. The mutagens most commonly used are high-energy radiation or specific chemicals examples of these mutagens and their efficacy are given in Table 7-2 on the following page. The greater the dose of mutagen, the greater the number of mutations induced, as shown in Figure 7-1. Note that Figure 7-1 shows a linear dose response, which is often observed in the induction of point mutations. The molecular mechanisms whereby mutagens act will be covered in subsequent sections.

Table 7-2

Forward Mutation Frequencies Obtained with Various Mutagens in Neurospora.

Figure 7-1

Linear relation between X-ray dose to which Drosophila melanogaster were exposed and the percentage of mutations (mainly sex-linked recessive lethals).

Recognize that the distinction between induced and spontaneous is purely operational. If we are aware that an organism was mutagenized, then we infer that any mutations that arise after this mutagenesis were induced. However, this is not true in an absolute sense. The mechanisms that give rise to spontaneous mutations also are in action in this mutagenized organism. In reality, there will always be a subset of mutations recovered after mutagenesis that are independent of the action of the mutagen. The proportion of mutations that fall into this subset depends on how potent a mutagen is. The higher the rate of induced mutations, the lower the proportion of recovered mutations that are actually “spontaneous” in origin.

Induced and spontaneous mutations arise by generally different mechanisms, so they will be covered separately. After considering these mechanisms, we shall explore the subject of biological mutation repair. Without these repair mechanisms, the rate of mutation would be so high that cells would accumulate too many mutations to remain viable and capable of reproduction. Thus, the mutational events that do occur are those rare events that have somehow been overlooked or bypassed by the repair processes.

A little clarification:

The standard contains this clarification statement:

Emphasis is on using data to support arguments for the way variation occurs.

Let’s look at this clarification a little closer to understand what is not included:

Supporting Arguments for Origins of Variation

The original arguments supporting the methods of variation came from Gregor Mendel and his famous “Pea Plant” experiments. During the experiments, Mendel showed empirically that offspring inherit different combinations of traits than their parents expressed. This lead to the Law of Segregation and the Law of Independent Assortment, which together explain why offspring exhibit variation in characteristics not seen in the parental generation.

Other simple arguments can include easily observable human traits, such as eye and hair color. In a class of 30, it should be possible to locate at least 1 (if not more) student that has a different eye color / hair color combination compared to either of their parents. This shows that traits can be distributed across maternal and paternal lines and explores the same basic mechanisms Mendel was looking at in pea plants.

3.2: Consequences of mutations - Biology

Since all cells in our body contain DNA, there are lots of places for mutations to occur however, some mutations cannot be passed on to offspring and do not matter for evolution. Somatic mutations occur in non-reproductive cells and won't be passed onto offspring. For example, the golden color on half of this Red Delicious apple was caused by a somatic mutation. Its seeds will not carry the mutation.

The only mutations that matter to large-scale evolution are those that can be passed on to offspring. These occur in reproductive cells like eggs and sperm and are called germ line mutations.

Effects of germ line mutations
A single germ line mutation can have a range of effects:

    No change occurs in phenotype.
    Some mutations don't have any noticeable effect on the phenotype of an organism. This can happen in many situations: perhaps the mutation occurs in a stretch of DNA with no function, or perhaps the mutation occurs in a protein-coding region, but ends up not affecting the amino acid sequence of the protein.

Little mutations with big effects: Mutations to control genes
Mutations are often the victims of bad press — unfairly stereotyped as unimportant or as a cause of genetic disease. While many mutations do indeed have small or negative effects, another sort of mutation gets less airtime. Mutations to control genes can have major (and sometimes positive) effects.

Some regions of DNA control other genes, determining when and where other genes are turned "on". Mutations in these parts of the genome can substantially change the way the organism is built. The difference between a mutation to a control gene and a mutation to a less powerful gene is a bit like the difference between whispering an instruction to the trumpet player in an orchestra versus whispering it to the orchestra's conductor. The impact of changing the conductor's behavior is much bigger and more coordinated than changing the behavior of an individual orchestra member. Similarly, a mutation in a gene "conductor" can cause a cascade of effects in the behavior of genes under its control.

Many organisms have powerful control genes that determine how the body is laid out. For example, Hox genes are found in many animals (including flies and humans) and designate where the head goes and which regions of the body grow appendages. Such master control genes help direct the building of body "units," such as segments, limbs, and eyes. So evolving a major change in basic body layout may not be so unlikely it may simply require a change in a Hox gene and the favor of natural selection.

Causes of DNA Mutations (physical and chemical mutagens)

Causes of DNA mutation can be divided into two types:

Spontaneous mutations are a result of the molecular interactions which take place naturally within the cell.

Induced mutations are caused by agents outside the cell.

Some substances or events that increase the rate of mutation in an organism are called mutagens.

Two general categories of mutagens are physical mutagens and chemical mutagens:

Ionizing radiations (X-rays, gamma rays, and alpha particles cause DNA breakage)

Ultraviolet radiations (Wavelength above 260 nm can be absorbed by nitrogenous bases of DNA, producing pyrimidine dimers, which can cause replication errors.)

a molecule that can enter the cell nucleus and induce mutations:

Reactive oxygen species (ROS)

Aromatic amines and amides may cause carcinogenesis

Benzene increases the risk of cancer

Understanding the impact of stress

Why would Kishony and Leibler observe, in general, the amelioration of deleterious mutational effects by stress, whereas others found that stress tends to aggravate these effects? Kishony and Leibler discuss three possible explanations [1]. One is that particular stresses (for example, that caused by antibiotics) would confer an advantage on slowly growing cells. This possibility was immediately refuted by their data, as it would imply a positive correlation between fitness reduction and the level of mutation amelioration by the stress, but such a correlation was not observed. The second possible explanation is that the amelioration is an artifact caused by the mutagenic effect of certain stresses, which obscures the effect of the original mutation(s) under study. The third possibility is potentially the most interesting: that stress and mutation do not always affect the same cellular functions. When stress affects only a single function or pathway, as is true for certain antibiotics, and if growth rate is determined by the slowest of a number of parallel pathways, then a mutant cannot grow more slowly under stress than either the mutant growing under favorable conditions or the wild-type under stress. Hence, the mutational effect under stress would always be smaller than the effect under favorable conditions. While the distinction between stresses that target a specific pathway and those that have broad cellular effects is helpful, the 'parallel-pathway model' used to interpret this distinction is something of an oversimplification. For instance, it relies on the independence of the presumed parallel pathways, but the widespread occurrence of epistasis [17] is not consistent with this notion.

Alternative explanations for the discrepancy between Kishony and Leibler's results and those of others are possible as well. First, the stresses applied by Kishony and Leibler are unusual, from an evolutionary perspective, and different from the kinds of stresses applied in other studies, which instead relied on such stresses as starvation, intensified resource competition, population density or parasitism. Why stress caused by antibiotics, a reducing agent or low temperature might be essentially different from these other stresses is unclear, but this would be worth investigating in future studies. The authors' distinction between stresses with particular versus broad cellular effects may help to direct such studies. A second possible explanation for the discrepancy is that Kishony and Leibler used growth rate at low density as a measure of fitness, whereas others have measured fitness under more competitive conditions [2, 5, 6, 8, 9], or even in direct competition experiments [14, 16]. Competitive conditions may challenge more functions of an organism than non-competitive conditions, increasing the chance that stress and mutation interact in their effect on fitness. It is unclear why this interaction should be synergistic (such that stress amplifies mutational effects) under competitive conditions, but theoretical work [18] predicts that synergistic epistasis among deleterious mutations depends on competitive conditions.

As an extrapolation from their findings, Kishony and Leibler [1] interpret the amelioration of single mutational effects by certain stresses as evidence for epistasis between multiple deleterious mutations, an issue of broad relevance for evolutionary theory [17]. The authors base their argument on the observed lower decrease in fitness of mutants under stressful conditions than under favorable conditions. If this tendency is extrapolated to mutants carrying multiple mutations, the multiple mutants would have higher fitness under stress than under favorable conditions. The authors found this idea unrealistic and invoked epistasis to avoid the potential for this situation to occur and to preclude the crossing of lines on the graph of fitness reaction norms. Conditionally beneficial mutations have in fact been observed previously [14–16], so the scenario may not be as unrealistic as the authors suggest support for epistasis from these data is therefore weak.

In conclusion, the classic view that deleterious mutational effects are magnified under environmental stress turns out to be somewhat naïve. As the number of precise studies of this issue increases, a new and more complex picture arises. Some mutations with deleterious effects across most environments appear to have beneficial effects in other environments [14–16]. In addition, stressful environments appear to sometimes alleviate rather than aggravate the deleterious effects of unconditionally deleterious mutations [1]. Although the reasons for these discrepancies are not known at present, some interesting suggestions have been made that should stimulate further studies. In particular, experiments in which the number of introduced mutations is controlled, the evolutionary history of the strain used is known, and fitness is measured in direct competition with the unmutated progenitor, are needed to improve our understanding of the qualitative and quantitative details of genotype-environment interactions. We believe that microbes are well suited for such studies [19].

A Appendix

Here, we present the details of our analytic derivations.

A.1 Probability of fixation

According to [26], the probability of fixation u(s) of a single allele with selection coefficient s is given by

For s ≳ 1/N, this expression simplifies to

whereas for Ns ≫ 1, this expression simplifies to

u(s) ≈ 1 - e -2s .

A.2 A single allele drifting to fixation or loss

We first consider a single allele with selective advantage s drifting to fixation or extinction, and ask how many mutations this allele generates until it is either fixed or lost. We will treat these two cases separately. Let nfix(s) be the expected number of mutations generated while the allele drifts to fixation, and let nloss(s) be the expected number of mutations generated while the allele drifts to extinction. We calculate these two quantities using diffusion theory, by integrating the sojourn times of the allele over all frequencies.

For an allele with selective coefficient s and starting at frequency p = 1/N, [50] calculated its mean sojourn time τ(y) between frequencies y and y + dy as

τ(y) = 2[V(y)G(y)] -1 [uloss(1/N)g(0, y)θ(1/N - y) + ufix(1/N)g(y, 1)θ(y - 1/N)].

and θ(z) is the Heaviside step function. We want to integrate expressions involving τ(y) from y = 0 to y = 1. Since y = 1/N corresponds to a single copy of the allele that drifts to fixation, values of y less than 1/N are not relevant for our analysis. Therefore, we discard the term proportional to θ(1/N - y) in Eq. (A4), and use in what follows

τ(y) = 2ufix(1/N)g(y, 1)/[V(y)G(y)] for y > 1/N.

A.3 Number of mutations conditional on fixation

For the sojourn time conditional on fixation, τfix(y), [50] finds

τfix(y) = τ(y)ufix(y)/ufix(p).

Using this expression, we have

Plugging the expressions for V(y)G(y), g(a, b), ufix(p), and τ(y) into τfix(y), we arrive at

This expression corresponds to the one by [51]. Note that fix(y) → 0 for y → 0. Therefore, we can extend the lower limit of integration to 0 in Eq. (A11), and rewrite nfix(s) as

The integral I(a) can be rewritten as

I(a) = γ - Ei(-a) + ln(a) + e -a [γ - Ei(a) + ln(a)],

where γ ≈ 0.5772 is the Euler-Mascheroni constant and Ei(z) is the exponential integral,

For s ≲ 1/N, we find

For Ns ≫ 1, we obtain the asymptotic expansion

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A.4 Number of mutations conditional on extinction

For the sojourn time conditional on extinction, τloss(y), [50] finds

τloss(y) = τ(y)uloss(y)/uloss(p).

Using this expression, we have

Plugging the expressions for V(y)G(y), g(a, b), uloss(p), and τ(y) into τloss(y), we find

We rewrite nloss as

The integral can be rewritten as

J(N, s) = -2e -2Ns (γ - Chi[2(N - 1)s] + ln [2(N - 1)s]),

where Chi(z) is the hyperbolic cosine integral,

For s ≲ 1/N, we find

For Ns ≫ 1, we obtain the asymptotic expansion

[This expansion follows directly from the definitions of Chi(z), cosh(z), and Ei(z).]

A.5 Number of mutations within a given time interval

We now extend the derivations in Section A.3 to calculate the number of mutations to allele 2 generated within a certain time interval T, conditional on fixation of allele 1. We assume that T is sufficiently large so that allele 1 has time to reach fixation within this interval. We only consider the case conditional on fixation because no new mutations are generated once allele 1 has gone extinct.

We calculate n(s) = nfix(s) + nT(s), where nT(s) is the total number of mutations generated once the first mutation has reached fixation. We have

nT(s) = NU[T - tfix(s)],

where tfix(s) is the time to fixation of a mutation with selective advantage s. This time is given by the integral over all sojourn times,

A partial fraction decomposition of the integrand reveals that I2(a) = 2I(a), and thus we have

Combining this result with Eqs. (A13) and (A30), we find

Note that n(s) = nfix(s) for T = tfix(s).

For s ≲ 1/N, we find

For Ns ≫ 1, using Eqs. (A15) and (A19), we obtain the asymptotic expansion

A.6 ξ for sβ ≪ 1

From Eq. (4), using Eqs. (A27), (A35), and (A2), we obtain to first order in

If further NU(T - N)u(s) ≪ 1, we obtain

A.7 ξ for Nsβ ≫ 1

For Nsβ ≫ 1, only the first term contributes to Eq. (2), and we obtain from Eqs. (A36) and (A3)

Likewise, in this limit we can simplify Eq. (3) to

Furthermore, for T → ∞, this expression simplifies to

If NU ≪ 1, then ξN in the limit s → ∞.

1- Point mutation (single base substitution)

  • Transition: In which one purine is replaced by another purine or one pyrimidine is replaced by another pyrimidine. (e.g. A⇔G or C⇔T)
  • Transversion: In which a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine. (e.g. T⇔A T⇔G, C⇔A C⇔G)

Changing a single nucleotide base on the mRNA can lead to any of the three results:

  1. Silent mutation:The codon containing the changed base may code for the same amino acid, for example, if the serine codon UCA is given a different third base (to become, say, UCU), it still codes for serine, therefore, this termed a silent mutation without any effect on the protein structure.
  2. Missense mutation:The codon containing the changed base may code for a different amino acid, the substitution of an incorrect amino acid may result in three variable effects on protein structure (e.g. hemoglobin β-chain).
    a- Acceptable missense mutation
    AAAAAU (codons)
    LysineAsparagine (amino acid) 61 (apparently normal functional hemoglobin)
    b- Partially acceptable missense mutation
    GAAGUA (codons)
    Glutamic acidValine (amino acid) 6 (Hb S it can bind and release O2 although abnormal).
    c- Unacceptable missense mutation
    UAU (codons)
    Tyrosine (amino acid) 58 (Hb M it cannot transport O2).
  3. Non-sense mutation:The codon containing the changed base may become a termination codon, for example, if the serine codon UCA is given a different second base (to become, say, UAA), the new codon causes the termination of translation at that point, this results in protein which is shorter than normal and is usually non-functional.

2- Frameshift mutation

It results from deletion (removal) or insertion (addition) of one or more nucleotides in DNA that generates altered mRNAs with different effects on protein structure.

Regulation of Gene Expression

Gene mutations

Types of Gene expression

  1. Constitutive gene expression is the unvarying expression of a gene, it is responsible for the expression of House Keeping genes, these are genes for products that are required at all times, they are expressed at a more or less constant level in every cell of an organism, e.g. genes for the enzymes of central metabolic pathways, such as citric acid cycle.
  2. Regulated gene expression is the expression of genes in which the cellular level of their products varies in response to molecular signals, they are called inducible genes or repressible genes.

Inducible genes are the genes which their products increase in concentration under particular molecular circumstances. Repressible genes are the genes which their products decrease in concentration in response to molecular signals, the process of decreasing their expression is called repression, i.e. negative regulation.

Regulation of Gene Expression in Eukaryotic cells

I- Gene Loss

  • If the genes are completely or partially deleted from the cells, functional proteins can’t be produced
  • E.g: during the development of the red blood cells.
    Immature erythroblasts contain nuclei that produce mRNA for the globin chain of hemoglobin, as the cells maturate, the nuclei are extruded, so that the fully mature red blood cells have no genes, so they can no longer produce mRNA.

II- Transcriptional Regulation

DNA regulatory region

Each gene can be divided into coding and regulatory regions, as defined by the transcription start site. The coding region contains the DNA sequence that is transcribed into mRNA, which is translated into proteins. The regulatory regions consist of two classes of elements:

(A) Basal expression elements consist of the proximal element of the TATA box that direct RNA polymerase II to the correct start site (+1) and the upstream element e.g. CAAT box or GC box that specifies the frequency of initiation.

(B) Regulated expression elements: (Cis-acting elements): They are specific DNA sequences that are present on the same gene, so-termed Cis-elements, and are responsible for the regulation of expression, they can exert their effect on transcription even when separated by thousands of base pairs from a promoter, they include the following elements:

  • Enhancers are Cis DNA elements that facilitate or enhance initiation of transcription at the promoter, they interact with gene regulatory proteins or trans-factors (so termed because they are produced by other genes) and increase the rate of expression.
  • Silencers interact with gene regulatory proteins or trans-factors and decrease the rate of expression.
  • Other regulatory elements mediate response to various signals including hormones called hormone response elements (HRE), chemicals, and metals.

III- Post-Transcriptional Regulation:
Regulation can occur during the processing of the primary transcript (hnRNA) and during the transport of mRNA from the nucleus to the cytoplasm.

  1. Alternative splicing and polyadenylation sites:Processing of the primary transcript involves the addition of a cap to the 5´-end, removal of introns, and the addition of poly(A) tail to the 3´-end (polyadenylation) to produce mature mRNA. In certain cases, the use of alternative splicing and polyadenylation sites causes different proteins to be produced from the same gene, for example, in parafollicular cells of the thyroid gland, the calcitonin gene produces mRNA that codes for calcitonin.
  2. RNA editing:It is the processing of RNA in the nucleus by enzymes that change a single nucleotide either by insertion, deletion, or substitution, an example of RNA editing occurs in the production of β apoprotein (apoβ) that is synthesized in the liver and intestinal cells and serves as a component of the lipoproteins, although these apoproteins are encoded by the same gene, the version of the protein made in the liver (B-100) contains 4563 amino acid residues, while the (B-48) made in the intestinal cells has only 2152 amino acid.

IV- Regulation at the level of Translation:
Most eukaryotic translational controls affect the initiation of protein synthesis, the initiation factors for translation, particularly eukaryotic initiation factor 2(eIF2), are the focus of these regulatory mechanisms, the action of eIF2 can be inhibited by phosphorylation.

V- Post-Translational Regulation:
After proteins are synthesized, their lifespan is regulated by proteolytic degradation, proteins have different half-lives, some last for hours or days, others last for months or years, some proteins are degraded by lysosomal enzymes, other proteins are degraded by proteases in the cytoplasm. Some of these proteins appear to be marked for degradation by attachment to a protein known as ubiquitin, ubiquitin is a highly conserved protein, there is very little variation in its amino acid sequence between organisms.

Watch the video: The different types of mutations. Biomolecules. MCAT. Khan Academy (September 2022).


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