Different Mutations Leading to Same Allele?

Different Mutations Leading to Same Allele?

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Can different mutations lead to the same allele? In my genetics books, I always see alleles referenced as, eg. Aa where A = dominant and a = recessive, but are these strictly binary phenotypes? Since there are an infinite number of mutations that could theoretically take place, wouldn't there be an infinite number of alleles? Eg (not an actual biological phenomenon but just as an example) A1C on chomosome 3 leads to allele a1, A1T leads to allele a2, etc.

You are looking at high school biology books. if that. I'd be shocked if a high school text didn't mention blood group genes, for instance.

The simple genetics that Mendel elucidated only applies to a very small number of situations.

In real life, very few situations are explained by the interactions of only two different alleles, one of which is classically dominant to the other, within a single gene.

So sure, you could have many alleles which break a gene, but where the presence of one working allele is enough to be functionally indistinguishable from having two working copies. You could also have slight sequence differences that are functionally identical.

Here's a random example; all the variants ensembl knows about for a random gene. Note that these are only variants which have been found, obviously private individuals and families might have their own variants that are not documented;g=ENSG00000280165;r=13:61409685-61415522;t=ENST00000409204

Most of these are in the 3' UnTranslated Region, and likely have no functional significance.

Step 3a: Mutations & Alleles

This brief video introduces mutation at the DNA level as the source of variation in genes. The next two activities will explore the mechanism and result of mutation in further detail.

Project video to the whole class.

Mutate a DNA Sequence (online)

This activity offers a closer look at the types of DNA mutations that can happen and their consequences. Make a small change to a DNA sequence of a gene and see the effect on the resulting protein product.

Have students explore individually or in pairs.

  • The arrangement of DNA building blocks in a gene specifies the order of amino acids in the protein it codes for.
  • During DNA replication, occasional errors change DNA sequences. This process is called mutation.
  • Changing the order of DNA building blocks in a gene can change the order of amino acids in the protein that it codes for, thereby changing the structure and function of the protein.

Computers with internet access.

To ensure your students understand frame shift mutations, you can review the content that's below the interactive.

Mutate a DNA Sequence (paper)

Using a paper model, students make a mutation of their choice (substitution, insertion, or deletion) in a gene during DNA replication. Then they transcribe and translate the mutated sequence to reveal the resulting amino acid sequence.

After completing the activity, students learn about the example gene and protein—Human Leukocyte Antigen (HLA-B)—including known variants.

You may wish to review the following:

  • DNA replication follows base-paring rules: A-T, C-G
  • Sometimes during DNA replication, a base is inserted, deleted, or substituted with a different one, changing the DNA sequence of a gene.
  • Changes in the DNA sequence of a gene can lead to changes in the protein it codes for.
  • Only mutations in germ cells (eggs or sperm) can be passed to offspring.

As in reality, the mutations students make are random. There will be variation in the resulting amino acid sequence.

Students may be tempted to skip using the “molecular machinery” (ribosome) in this model. Encourage them to use it as a visual reminder of where proteins are assembled.

  • During DNA replication, occasional errors change DNA sequences. This process is called mutation.
  • Changes in DNA sequences can lead to changes in proteins.

Using a paper model, students make a mutation and determine the effect on the resulting protein.

Students see the effect on a protein's structure caused by a change in a DNA sequence.

Make one copy per student or pair (copies may be re-used), or have students view on tables or computers:

Page 1 has two identical sets of strips. Give each student or pair a half-page:

Make one copy per student or pair (copies may be re-used), or project to the class:

What is an Allele?

This short interactive uses blue vs. brown eye color to introduce alleles, showing how different versions of a gene lead to differences in protein function and traits.

Same mutation, different phenotype?

Why is it that the same genetic mutation sometimes produces different disease phenotypes? We see this in a long list of inherited human diseases and in mouse models with specific mutations.

For some genetic diseases, a particular mutation does not always produce an aberrant phenotype in all individuals who carry it. This concept is referred to as the mutation&rsquos penetrance. In other cases, individuals that carry the same mutation show a range of phenotypes that vary in their severity. The relative consistency of the phenotype produced by a particular mutation is referred to the mutation&rsquos expressivity.

In many cases, both a mutation&rsquos phenotypic penetrance and expressivity vary due to the different combinations of modifying alleles that are present in one genetic background versus another. As an example, let&rsquos look at the impact of genetic background on the progressive neurodegenerative disease in popular mouse models of amyotrophic lateral sclerosis (ALS).

Genetic background affects the onset of ALS phenotypes

Classic mouse models of familial ALS are transgenic mice that overexpress a mutant form of human superoxide dismutase 1 (Tg(SOD1*G93A)1Gur aka SOD1*G93A). Transgenic, hemizygote carriers manifest phenotypes that resemble ALS in humans: they become paralyzed in one or more limbs due to loss of motor neurons from the spinal cord. The genetic background of the original SOD1*G93A transgenic mice (002726) were on a non-uniform mixture of SJL/J and C57BL/6J. The transfer of this transgene on to different backgrounds has produced congenic strains with either early or late onset of symptoms:

ALS disease onset in SOD1*G93A transgenic mice varies depending on the genetic background

Early onset strains include ALR/LtJ and SJL/J congenic mice, which first show symptoms starting at 116 and 119 days of age (±10 days), respectively. Late onset strains include C57BL/6J and DBA/2J that don&rsquot develop overt ALS symptoms until 161 and 169 days of age (±10 days), respectively.

Genetic background affects the lifespan of ALS mouse model

Similarly, hemizygous SOD1*G93A transgenic carriers on the mixed B6SJL background also have a decreased lifespan compared to hemizygotes on the congenic C57BL/6J background: 50% survive to 128.9 (±9.1 days) versus 157.1 (±9.3 days), respectively.

Genetic background affects other ALS -related phenotypes

Mice with the G93A-SOD1 transgene on the mixed B6SJL background show abnormalities that are not evident on the B6 background. Some of these phenotypes are anomalous mitochondria morphology and cellular physiology, slow postnatal weight gain and atypical capillary morphology.

Table 1. Summary of the phenotypes observed in SOD1*G93A transgenic mice on the C57BL/6J (B6) congenic and B6SJL mixed background.

The Jackson Laboratory has excellent manuals and field guides to assist you if you are working with mouse models of ALS, Huntington&rsquos disease, and spinal muscular atrophy, where these and other issues are comprehensively addressed.

Whether you are working with models of ALS or other inherited diseases, be aware that genetic background-dependent variation in genetic modifiers may impact the phenotypes of your mice and your experimental results. If you are breeding and maintaining research colonies in your facility, it is particularly important that you avoid breeding errors that might compromise your strains&rsquo genetic backgrounds in order to minimize experimental variability and to ensure the reproducibility of your conclusions.

3.1 – Chromosomes, Genes, Alleles and Mutations

3.1.1 – State that eukaryote chromosomes are made of DNA and proteins

Chromosomes are composed of two daughter chromatids which are joined at the centromere. Chromosomes are mainly comprised of DNA and histone proteins

3.1.2 – Define gene, allele, and genome

Gene – A gene is a heritable factor that controls a specific characteristic Allele – An allele is a specific form of a gene,

Allele – An allele is a specific form of a gene, differing for other alleles by one or a few bases
only. They occupy the same gene locus as the other alleles on the gene Genome – The whole of the genetic information of an organism

Genome – The whole of the genetic information of an organism 4.1.3 – Define gene mutation

3.1.3 – Define gene mutation

A gene mutation is a change in the base sequence of an allele This may produce a different amino acid sequence in the protein translated, which may not

This may produce a different amino acid sequence in the protein translated, which may not be beneficial. A substance that causes mutation is called a mutagen, including radiation and chemicals.

Deletion is when one of the bases is removed, changing the whole gene. Insertion involves the addition of a base, which also changes the whole gene. Substitution is when a base is changed, altering only one amino acid. However, this will still affect the shape of the protein.

3.1.4 – Explain the consequence of a base substitution mutation in relation to the processes of transcription and translation, using the example of sickle-cell anaemia

Sickle cell anaemia is a genetic disease. It has a frequency of about 1 in 655 African Americans. The condition is inherited, and cannot be contracted by infectious routes. The affected gene is found on chromosome 11. The sequence that codes for the sixth amino acid normally has the base sequence GAG, which codes for glutamic acid. This amino acid carries a negative charge. However, the substitution produces a different sequence, GUG, which codes for the neutral amino acid valine. The result is that the beta chain changes shape.

Haemoglobin is made up of four proteins, two of which can affected by the mutation. The usual shape of the red blood cells is a biconcave disc. However, when there is mutation, the cells become shaped like a sickle. As a result, the red blood cells cannot carry oxygen, causing anaemia. Furthermore, the irregular shape of the cells means that they do not move through the bloodstream properly, causing blockages in places such as the kidney tubules. This may damage the kidney and possibly lead to death.

In areas where malaria is common, those with the sickle cell anaemia trait are resistant to the infection. This is because normal blood cells are affected by the disease. As a result, those who do not have the mutation are more likely to die from malaria. In these regions, sickle cell anaemia has become more common since it gives carriers an advantage.

Different Mutations Leading to Same Allele? - Biology

Mendel implied that only two alleles, one dominant and one recessive, could exist for a given gene. We now know that this is an oversimplification. Although individual humans (and all diploid organisms) can only have two alleles for a given gene, multiple alleles may exist at the population level such that many combinations of two alleles are observed. Note that when many alleles exist for the same gene, the convention is to denote the most common phenotype or genotype among wild animals as the wild type (often abbreviated “+”) this is considered the standard or norm. All other phenotypes or genotypes are considered variants of this standard, meaning that they deviate from the wild type. The variant may be recessive or dominant to the wild-type allele.

An example of multiple alleles is coat color in rabbits (Figure 1). Here, four alleles exist for the c gene. The wild-type version, C + C + , is expressed as brown fur. The chinchilla phenotype, c ch c ch, is expressed as black-tipped white fur. The Himalayan phenotype, c h c h, has black fur on the extremities and white fur elsewhere. Finally, the albino, or “colorless” phenotype, cc, is expressed as white fur. In cases of multiple alleles, dominance hierarchies can exist. In this case, the wild-type allele is dominant over all the others, chinchilla is incompletely dominant over Himalayan and albino, and Himalayan is dominant over albino. This hierarchy, or allelic series, was revealed by observing the phenotypes of each possible heterozygote offspring.

Figure 1. Four different alleles exist for the rabbit coat color (C) gene.

Figure 2. As seen in comparing the wild-type Drosophila (left) and the Antennapedia mutant (right), the Antennapedia mutant has legs on its head in place of antennae.

The complete dominance of a wild-type phenotype over all other mutants often occurs as an effect of “dosage” of a specific gene product, such that the wild-type allele supplies the correct amount of gene product whereas the mutant alleles cannot. For the allelic series in rabbits, the wild-type allele may supply a given dosage of fur pigment, whereas the mutants supply a lesser dosage or none at all. Interestingly, the Himalayan phenotype is the result of an allele that produces a temperature-sensitive gene product that only produces pigment in the cooler extremities of the rabbit’s body.

Alternatively, one mutant allele can be dominant over all other phenotypes, including the wild type. This may occur when the mutant allele somehow interferes with the genetic message so that even a heterozygote with one wild-type allele copy expresses the mutant phenotype. One way in which the mutant allele can interfere is by enhancing the function of the wild-type gene product or changing its distribution in the body.

One example of this is the Antennapedia mutation in Drosophila (Figure 2). In this case, the mutant allele expands the distribution of the gene product, and as a result, the Antennapedia heterozygote develops legs on its head where its antennae should be.

Multiple Alleles Confer Drug Resistance in the Malaria Parasite

Malaria is a parasitic disease in humans that is transmitted by infected female mosquitoes, including Anopheles gambiae (Figure 3a), and is characterized by cyclic high fevers, chills, flu-like symptoms, and severe anemia. Plasmodium falciparum and P. vivax are the most common causative agents of malaria, and P. falciparum is the most deadly (Figure 3b). When promptly and correctly treated, P. falciparummalaria has a mortality rate of 0.1 percent. However, in some parts of the world, the parasite has evolved resistance to commonly used malaria treatments, so the most effective malarial treatments can vary by geographic region.

Figure 3. The (a) Anopheles gambiae, or African malaria mosquito, acts as a vector in the transmission to humans of the malaria-causing parasite (b) Plasmodium falciparum, here visualized using false-color transmission electron microscopy. (credit a: James D. Gathany credit b: Ute Frevert false color by Margaret Shear scale-bar data from Matt Russell)

In Southeast Asia, Africa, and South America, P. falciparum has developed resistance to the anti-malarial drugs chloroquine, mefloquine, and sulfadoxine-pyrimethamine. P. falciparum, which is haploid during the life stage in which it is infectious to humans, has evolved multiple drug-resistant mutant alleles of the dhps gene. Varying degrees of sulfadoxine resistance are associated with each of these alleles. Being haploid, P. falciparum needs only one drug-resistant allele to express this trait.

In Southeast Asia, different sulfadoxine-resistant alleles of the dhps gene are localized to different geographic regions. This is a common evolutionary phenomenon that occurs because drug-resistant mutants arise in a population and interbreed with other P. falciparum isolates in close proximity. Sulfadoxine-resistant parasites cause considerable human hardship in regions where this drug is widely used as an over-the-counter malaria remedy. As is common with pathogens that multiply to large numbers within an infection cycle, P. falciparum evolves relatively rapidly (over a decade or so) in response to the selective pressure of commonly used anti-malarial drugs. For this reason, scientists must constantly work to develop new drugs or drug combinations to combat the worldwide malaria burden. [1]

The Evolution of Inbred Social Systems in Spiders and Other Organisms

Leticia Avilés , Jessica Purcell , in Advances in the Study of Behavior , 2012

F Spider Mites

Inbreeding has also arisen multiple times in the Acari ( Norton et al., 1993 ), but for the most part not in association with group living, except in spider mites (Prostigmata, Tetranychidae) and perhaps some taxa in the Mesostigmata ( Mori et al., 1999 Saito, 1997, 2010 ). Some spider mite species, such as species in the Tetranychid genus Stigmaeopsis in Japan ( Saito, 2010 ), live in extended family groups (two or three overlapping generations) housed by cooperatively built webs that are thought to have an antipredator function ( Mori and Saito, 2005 ). Inbreeding seems to be common in these species, which, much like the social spiders, also exhibit highly female-biased sex ratios ( Norton et al., 1993 ). Individuals in these species may remain in their natal nest throughout their life, or females may disperse to establish new nests. Male dispersal is thought to be rare and females likely disperse fairly short distances ( Saito and Mori, 2005 ). Mitchell (1973) estimated that dispersal may be quite costly and showed that Tetranychus urticae females in uncrowded conditions will often forego dispersal. Females that do disperse will usually mate with a nest mate prior to leaving the natal nest ( Mitchell 1973 ). Inbreeding depression, on the other hand, has been measured in the subsocial spider mite Stigmaeopsis miscanthi, which exhibits intermediate levels of inbreeding in nature. Saito et al. (2000) found no effect of inbreeding on the early survival of brood even after four generations of inbreeding, but they found that female fecundity decreased by at least 50% with increasing levels of inbreeding. They suggest that inbreeding depression due to recessive deleterious alleles may still be present even in species, such as are mites, with male haploidy. At the moment, there is no enough information to speculate on the balance between costs of inbreeding and of inbreeding avoidance or on the factors responsible for the inbred nature of these spider mite systems.

Different Mutations Leading to Same Allele? - Biology

Mutation is the ultimate source of variation. Without variation there could be no evolution, so mutations are of great importance to evolution. Important to point out that existing variation can be reshuffled by a variety of mechanisms that we don't always consider as mutations leading to increases or decreases in variation and thus altering the potential for evolution.

Mutation = a heritable change . This is often followed by the qualifier "in the DNA" or "in the genetic material". This is redundant with the term "heritable" but points out an important genetic issue: The mutations which are of primary concern are those in the germ line as these are the one that will be passed on. August Weismann was the first to point out the distinction between germ and soma . Mutations in your arm or knee cap are not going to get passed on because the germline is sequestered relatively early in development:

GERM / -----> GERM / -----> GERM / -----> GERM / ----->

Weismann's doctrine was a serious blow to Lamarkian inheritance of acquired characteristics. However, in plants and some animals (clonal ones in particular) the germline is not sequestered into a single part of the part of the organism so somatic mutations can be inherited (a mutation during the differentiation of a branch on which a flower will develop: all pollen and ovules made by that flower will have a genotype different from the rest of the plant. Think about corals, too).

Probably one of the most important things to understand about evolution is that mutation is random , i.e., is not directed towards the problems presented by the environment (although some recent evidence has been published on bacteria that challenges this assumption: Lenski, R. E. Are some mutations directed? Trends in Ecology and Evolution vol. 4, pp. 148-150.).

Mutation is an ongoing process. There are measurable mutation rates and that there can be a genetic variation for mutation rates "mutator strains" of bacteria exist. Mutations in the replication or repair machinery of DNA can alter mutation rates.

Types of mutation: point mutation now generally refers to a change at a single nucleotide site. These can be transitions (purine to purine [A to G or G to A], or pyrimidine to pyrimidine [C to T or T to C]) or transversions (from a purine to a pyrimidine or vice versa). Synonymous and non-synonymous substitutions with respect to the effect on the amino acid coded for by the DNA. Deletions and insertion will cause frameshift mutations .

Transposable elements are mobile genetic elements that can move from one part of the genome to another. Generally they have repeated sequences at their ends and code for protein(s) in the middle. In moving from one location to another they can cause mutations. If the element landed in the middle of the coding sequence of a gene, it most likely would lead to a frameshift mutation or introduce a stop codon , and knock out the function of that gene.

Gene duplications can occur by unequal crossing over where gene families exist on the chromosome, homologous chromosomes may misalign and cross over (recombine). The daughter chromosomes include one with an extra copy and one with one fewer copies. Chromosome rearrangements can also be viewed as mutations. Classic cases: inversions were a section of the chromosome is inverted with respect to the "normal" chromosome. Drosophila polytene chromosomes show characteristic banding patterns and allow for easy recognition of inversions. A paradigm of natural selection (more later).

Several important consequences: Inversions can act as suppressors of crossing over in the heterokaryotype (= heterozygote for two different chromosomal types). An inversion does not prevent crossing over per se but the recombination products that result from a crossover within the inversion either have two centromeres and are pulled apart in division, or lack a centromere and are not transmitted. Only the unrecombined parental chromosomes are transmitted.

How will the frequency of an inverted chromosome in a population affect it role as a suppressor of recombination? The more frequent the inverted type gets, it will be present in a "homokaryotypic" state and recombination will not be suppressed. If the "inverted" chromosome were fixed in the population (=100%) then we would no longer consider it "inverted".

Translocations are instances where part of a chromosome is "translocated" = moved to another chromosome. When entire chromosome arms are translocated or fused this can lead to changes in chromosome number. Can also lead to genetic incompatibilities that may lead to reproductive isolation (more in lectures on speciation)


Gene loci on the same chromosomes are generally considered to be in the same linkage group because the alleles on each chromosome can be inherited as a "linked set" (like beads on the same string). But a chromosome can be long enough that the probability of a crossover (=recombination) event some where along the chromosome is very high. Thus genes at different ends of same chromosomes can be effectively unlinked . Conversely genes close to each other on the chromosome are usually tightly linked because the probability of a recombination event between them is very low.

Consider a pair of chromosomes, and think about the gene loci at each ends. Each locus carries two alleles and we will consider the case where the two alleles are different (each locus is heterozygous):

When this "individual" makes gametes, we can say that recombination occurs with a frequency (or probability) " r ". Thus recombination does not occur with a probability (1-r) . When recombination does not occur the gametes produced will be A B and a b (note only one letter is used at each locus because gametes are haploid) when recombination does occur the gametes will be A b and a B . (see figure 2.7, pg. 34).

If the loci were on separate chromosomes (unlinked) and we were "given" a gamete with the "A" allele, 1/2 of the gametes would be AB and 1/2 would be Ab (the under score is omitted as a shorthand notation). If we were "given" a gamete with the "a" allele, 1/2 the gametes would be ab and 1/2 would be aB. These four gametes would be in the relative proportions 1:1:1:1.

Now consider linkage. If the A and B loci were on the same chromosome, to determine the proportions of the four gametes we would have to know the probability of recombination between the two loci. This probability is r , so "given" an A allele, (1-r) of the gametes would be AB, and r of the gametes would be Ab (i.e., recombinants). Similarly, given the a allele, (1-r) of the gametes would be ab, and r of the gametes would be aB (recombinants). Since there are two kinds of recombinant gametes resulting from crossover (e.g., reciprocals: Ab and aB), these two types are split evenly within the proportion r of recombinants (r/2 of each reciprocal). For example, if r = 0.02 (i.e., 2%), then the gametes produced by a "double heterozygote" such as the one three paragraphs above will result in the following proportions

(1-r/2)AB : (r/2)Ab : (r/2)aB : (1-r/2)ab, e.g., 49%:1%:1%:49% respectively. For comparison, if there was no linkage between A and B, then the proportions of the four possible gametes would be 25%:25%:25%:25%. By definition then, ulinked loci have an r = 0.5 . For loci at opposite ends of long chromosomes, r can be very close to 0.5 because a recombination event is likely to occur.

Recombination can shuffle existing variation and lead to new variants. Consider two diploid "individuals": ABcd/abCD and AbCd/aBcD and a cross between them:

can produce ABCD/ABCD and abcd/abcd individuals assuming recombination along the chromosome: new types previously not present in either population that may have different phenotypes from either parent. Note recombination will produce variation faster than mutation alone (assuming "normal" mutation and recombination rates). Above, assuming no recombination we might get: ABcd/aBcD and we would have to wait for:

one a --> A, two c --> C and one d --> D mutations to get the homozygous "capital" phenotype. We can thus think of extensive "latent" variation in chromosomes: there is the potential to generate extremes of variation given certain chance recombination and mating events.

Mimicry patterns controlled by tightly linked loci controlling several different factors, wing pattern, body color, "tails", etc. favorable combinations of alleles with all coordinate phenotypes will tend to become linked. This is an example of a supergene were many loci are tightly linked and certain alleles become associated such that they behave as single "locus".

Important to note that just as recombination can generate favorable combinations of alleles, recombination can just as easily break up these favorable combinations.

Recombination does not always take place between genes but can take place within a gene ( =intragenic recombination ). At a monomorphic locus (=no variation), intragenic recombination will have no effect. At a polymorphic locus, intragenic recombination will generate more types: variation breeds more variation .

Mutation: Different Types.

Any permanent alteration in the DNA sequence is termed as mutation. Mutation is derived from the Latin word ‘mutacio’ which means “change”.

Mutations in DNA are of two types depending on the magnitude: Gene mutation and chromosome mutation. Mutations affecting only one or few base pairs are known gene mutations, while those affecting a large segment of the DNA molecules including multiple genes, almost at the chromosome level, are known as chromosome mutations. This post in more about the different types of gene mutations.

(Just for info:Read about a mutation that makes people need less sleep has been found)

The mutations can be categorised into different types based on various factors like effect on phenotype, effect on protein sequence and so on. We have listed a few in this and next coming post. So read on:

1. Based on Changes in Sequence:

The different type of mutation based on the type of changes that occur in the sequence of DNA are:

a. Insertion:

Insertion is a type of mutation, in which a base gets added into the DNA molecule. As a base pair is added, the total number of base pairs increases.

For eg: As shown in fig. 1, if the original sequence is ACCGATTCCGGAT (total bases: 13) and a C gets inserted into the sequence between the two T’s, it becomes ACCGATCTCCGGAT (total bases: 14).

Fig 1: Insertion mutation.

The insertion of additional base pairs may lead to frameshifts (see fig 2), depending on whether multiples of three base pairs are inserted.

Fig 2: The frameshift occurring in the codons due to the insertion of a base (C). (N: any other base).

This leads to change in the sequence of amino acids, and may in turn result into a non- functional or abnormal protein.

A deletion is opposite of the insertion. It involves removal of a DNA base from the DNA molecule. Due to the loss of a base, the total number of DNA bases change (fig 3). Small deletions may remove one or a few base pairs, while larger deletions can remove an entire gene or several neighbouring genes. Like insertion, deletion, too, may cause a frameshift and alter the function of the resulting protein.

For eg: if the original sequence is ACCGATTCCGGAT (13) and a T located between T and C gets deleted, the sequence changes and becomes ACCGATCGGAT (12).

Fig 3. Deletion mutation.

This leads to changing of the sequence of codons coding for the amino acid , and may result into a non- functional or abnormal protein, similar to insertion.

Fig 4: Frameshift due to deletion.

c. Duplication:

A duplication is the type of mutation wherein a region of DNA is abnormally copied one or more time. Gene duplication arises as the result of errors in DNA replication and repair. The duplicated region can be located adjacent to the original location or any other location in the genome.

This may result in the frameshift of the codons (depending on whether multiples of three are added) coding for the amino acids, which in turn causes alteration in the function of the resultant protein.

d. Substitution:

A substitution mutation is a type of mutation in which a single base is replaced by an incorrect one. This may occur due to error during DNA replication or repair or carcinogens or mutagens.

Fig 5: Substitution mutation.

For eg: As seen in the fig. 5, if the original sequence is ACCGATTCCGGAT (13) and a T located between T and C is replaced by C, it becomes ACCGATCCCGGAT (13). This leads to change in a single codon. The resultant protein may be non-functional or abnormal. The number of bases remain the same, unlike as observed in the insertion and deletion mutations. Also there is no frameshift. Usually the substitution involving a single nucleotide is very common, which is a type of point mutation.

DNA substitution mutations are, further, of two types: Transition and Transversion.

Transitions involves the interchange among purines (A-G) or pyrimdines (C-T), which involve bases of similar shape. Transversions are the mutations which involve interchange between purine and pyrmidine bases.

Substitution can be caused by different mechanisms:

I. Depurination:

Depurination is the one process wherein the β-N-glycosidic bond between an adenine or guanine and the deoxyribose is hydrolyzed, releasing the purine bases. Depyrimidination of cytosine and thymine can also takes place at a comparatively slower rate than depurination. Depurination is repaired by the base excision repair (BER) machinery. However, few errors may be left unrepaired, resulting into substitution mutation.

II. Deamination:

Deamination is the loss of exocyclic amino group present in the structure of the bases. The four bases cytosine, adenine, guanine (see fig 4) and 5- methylcytosine are converted to uracil, hypoxanthine, xanthine and thymine, respectively on deamination.

Fig 6: The exocyclic amino groups in the bases of DNA (Ziad & Stypczynska, 2013).

As a result during replication, wrong base pairs are incorporated in the daughter strand leading to substitution mutation. When the DNA replicates, the new nucleotide becomes permanently integrated.

III. Carcinogens and mutagens:

These are chemicals that cause lots of mutations. Various physical factors like UV light and other ionising radiations can also cause substitution mutation (see induced mutation later in this post).

2. Based on their ability to express.

Depending on their ability to express in an individual, the mutation is either Dominant or Recessive.

As is known, the higher organisms are diploid and have homologous chromosomes. The different forms of gene are called as alleles. If an individual carry two identical alleles on both the chromosomes, they are called as homozygous. If an individual carry different alleles, they are said to be heterozygous for a gene. The genes can be either dominant or recessive based on the ability to express itself in presence of another allele.

Dominant gene is the one which is expressed in a heterogenous individual, while recessive is the one whose effect is suppressed or concealed. Recessive phenotype is observes in individuals homologous for the recessive allele. Similarly, the mutations are also of two types, i.e. Dominant or Recessive, based on their ability to effect the phenotype of an individual.

• Dominant mutation:

Dominant mutation is the one which exhibits its effect on the phenotype, even when a single copy of the mutant gene (p) is present alongwith the normal gene (P). That is the mutant phenotype is observed in the heterozygous individual (P/p) as shown in fig 7a.

Fig 7: The Dominant and Recessive mutations.

The dominant mutation may cause either inefficient amount of the gene product, abnormally functioning or interfering product or increased protein activity.

In cases where the mutation in one gene copy, leads to insufficient production of protein needed for the normal functioning, the genes are referred to as haplo-insufficient (that is one is insufficient). Hence for the normal phenotype, both the normal copies are required.

In some cases, mutation in one allele may result in production of an abnormally functioning protein, which may in turn interfere with function the wild type protein. These mutations are termed as dominant negative mutations.

Examples of disorders due to dominant mutation includes

– polycystic kidney disease (see the NIH page) and

– osteogenesis imperfecta (see the NIH page).

(Just for info:Read more on Dominant mutations.)

• Recessive mutation:

Recessive mutation is one in which both the copies of the gene must be mutant (p/p) in order for the mutant phenotype to be observed that is, the individual must be homozygous for the mutant allele to show the mutant phenotype (see fig 7b).

If the individual carries one copy of mutant allele and one normal allele (heterozygous), the phenotype will be normal (fig 7b). However the individual will be the carrier of the mutant allele. Recessive mutations causes a gene to get inactivated and leads to loss of function.

Examples of autosomal recessive disorders include

cystic fibrosis (see the NIH page) and

sickle cell anemia (see the NIH page).

3. Based on the cause of mutation:

Based on the cause of the mutation, they can be Spontaneous or Induced.

– Spontaneous mutations:

Few mutations arise spontaneously due to the chemical instability of purine and pyrimidine bases as well as due to the errors during DNA replication.

A common cause of spontaneous point mutations is the deamination especially of cytosine to uracil. As mentioned before, during replication Adenine is incorporated into the daughter strand instead on Guanine, leading to substitution mutation.

Another cause of spontaneous mutation is the mistakes in DNA replication. Usually an incorrect nucleotide is added by the replication machinery into the DNA daughter strands.

(Just for info:Read about the spontaneous mutations in more details.)

– Induced Mutation:

Exposure to some physical and chemical factors like UV light, ionising radiations and chemical carcinogens can cause mutations. The mutations arising due to such environmental factors are called induced mutations.

Ionising radiations include gamma or X-rays while chemical carcinogens include chemicals like alkyl or aryl epoxides, nitrosoureas, nitrosamides, polycyclic aromatic hydrocarbons, aromatic amines and aflatoxin B1. Generally, chemical mutagens induce point mutations, whereas ionizing radiation causes aberrations at chromosomal level.

(Just for info:Read our post on structure of Chromosome.)

For e.g.: Ethylmethane sulfonate (EMS), a mutagen causes alkylation of guanine in DNA to give O6-ethylguanine. O6-ethylguanine is paired with thymine (T), instead of the original cytosine (C), resulting in substitution of G·C by A·T base pair.

The mutation can also be categorised based on their origin (hereditary or induced) and on the basis of their effect on the structure a protein (missense mutation, nonsense mutation, etc). These types of mutation will be discussed in the next post.

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Read other posts by The Biotech Notes:

Lodish et al. (2000) Mutations: Types and Causes. Molecular Cell Biology. 4th edition. New York: W. H. Freeman.

Fay and Spencer (2005) Dominant mutations. Copyright © 2005, WormBook Research Community.

Ziad & Stypczynska (2013) Clustering algorithms in radiobiology and DNA damage quantification. Data Security, Data Mining and Data Management: Technologies and Challenges, Nova Science Pub Inc.

5. Genetic tests for dominance classes

To attempt to distinguish between various classes of dominant mutations, a number of genetic tests can be performed. For example, to determine if a mutant phenotype observed in a heterozygous animal is due to haploinsufficiency, one can directly examine animals that are heterozygous for a chromosomal deficiency that removes the entire gene (as well as a number of other genes presumably). Alternatively, if a deletion or null allele of the gene exists, placing this mutation over the wild-type chromosome could provide an even cleaner answer. In addition, to distinguish haploinsufficieny effects from hypermorphic mutations, one can further compare homozygous mutant animals ( dom-1/dom-1 ) with animals that are heterozygous for the mutation and the deficiency ( dom-1/Df ). If the homozygous mutants show a more severe phenotype than the mutant allele over the deficiency, then it is likely that the mutation is at least partially dominant, although one can have both dominance and haploinsufficient effects for the same allele.

In addition, a hypermorphic mutation would be expected to exert an effect even in the presence of two normal copies of the gene. Thus, a genetic test of this can be carried out using a free duplication that contains a wild-type copy of the gene, which is examined in the background of the heterozygous mutant (e.g., dom-1/+ Dp ). A further test is to examine dom-1/dom-1 Dp animals. In this case, if the mutant allele is not hypermorphic (only LOF associated with haploinsufficieny), the phenotype of this animal should be no more severe than dom-1/+ animals and may even be less severe if the dom-1 allele contains some residual activity.

Other questions may be more difficult to answer genetically, particularly in the absence of knowing or understanding the molecular functions of the gene. For example, distinguishing dominant negatives from dominant gain of function alleles may be difficult in a vacuum. The ability of RNAi to phenocopy or enhance a dominant mutation would suggest that the mutation is a dominant negative, although a negative result in this case is difficult to interpret. Also, if the gene is cloned, then attempts to overexpress the wild-type version of the gene product may be informative in this regard, as phenocopy would indicate a hypermorphic mutation. Also, a dominant negative might be expected to be less penetrant in a background that contains one or more copies of the wild-type gene (e.g., dom-1/dom-1 versus dom-1/dom-1 Dp ), although a number of hand-waving explanations can theoretically weaken these types of arguments.

In closing, we refer readers to a number of published papers dealing with various types of dominant mutations in C. elegans (see below). We hope you enjoyed this discussion of dominant alleles. Now get back to work, dammit (A. Spencer).

Watch the video: Punktmutationen: Stumme Mutation, Missense Mutation Fehlsinn, Nonsense Mutation - 2. Genetik (August 2022).