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Article under construction by undergraduate students for a Introduction to BioEngineering Class at the University of Maryland. Please only add constructive material with citations. Thank You.

Overview

Point mutation is a random mutation in the deoxyribonucleic acid (DNA) that occurs at one point. This mutation may be a deletion, translation, insertion, or transversion. Point mutations usually take place during DNA replication. DNA replication occurs when one double-stranded DNA molecule creates two single strands of DNA that is a template for the creation of the coinciding strand. A single point mutation can change the whole DNA sequence. Changing one purine or pyrimidine may change the amino acid that the nucleotides code for. By altering just one amino acid, the entire peptide may change, therefore changing the entire protein. If the protein functions in cellular reproduction then this single point mutation can change the entire process of cellular reproduction for this organism. Point mutations can lead to beneficial as well as harmful traits or diseases. This leads to adaptations based on the environment where the organism lives. An advantageous mutation can create an advantage for that organism and lead to the trait being passed down from generation to generation, improving and benefiting the entire population.

History

The Cellular Reproduction process of Meiosis was discovered by Oscar Hertwig in 1876. Mitosis was discovered several years later in 1882 by Walther Flemming.

Hertwig studied sea urchins, and noticed that each egg contained one nucleus prior to fertilization and two nuclei after. This discovery proved that one spermatozoon could fertilize an egg, and therefore proved the process of meiosis. Hermann Fol continued Hertwig’s research by testing the effects of injecting several spermatozoa into an egg, and found that the process did not work with more than one spermatozoa.

Flemming began his research of cell division starting in 1868. The study of cells was an increasingly popular topic in this time period. By 1873, Schneider had already begun to describe the steps of cell division. Flemming furthered this description in 1874 and 1875 as he explained the steps in more detail. He also argued with Schneider’s findings that the nucleus separated into rod-like structures by suggesting that the nucleus actually separated into threads that in turn separated. Flemming concluded that cells replicated through cell division and more specifically mitosis.

Matthew Meselson and Franklin Stahl are credited with the discovery of DNA replication. Watson and Crick acknowledged that the structure of DNA did indicate that there was some form of replicating process. However, there was not a lot of research done on this aspect of DNA until after Watson and Crick. People considered all possible methods of determining the replication process of DNA, but none were successful until Meselson and Stahl. Meselson and Stahl introduced a heavy isotope into some DNA and traced its distribution. Through this experiment Meselson and Stahl were able to prove that DNA reproduced semi-conservatively.

Reasons and Causes

There are multiple ways for point mutations to occur. First, ultraviolet(UV) light and higher frequency light are capable ionizing electrons and in turn impacting DNA. Also, one of the cell metabolic byproducts, reactive oxygen molecules with free radicals, can also be very harmful to DNA. These reactants can lead to both single stranded DNA breaks and double stranded DNA breaks. Thirdly, bonds in DNA eventually degrade which creates another problem to keep the integrity of DNA to a high standard. There can also be replication errors in which lead to substitution, insertion, or deletion mutations.

There are different short term and long term effects that can arise from mutations. Smaller ones would be a halting of the cell cycle at numerous points. This means that a codon coding for the amino acid glycine may be changed to a stop codon, causing the proteins that should have been produced to be deformed and unable to complete their intended tasks. Because the mutations can affect the DNA and thus the chromatin, it can prohibit mitosis from occurring due to the lack of a complete chromosome. Problems can also arise during the processes of transcription and replication of DNA. These all prohibit the cell from reproduction and thus lead to the death of the cell. Long-term effects can be a permanent changing of a chromosome, which can lead to a mutation. These mutations can be either beneficial or detrimental. Cancer is an example of how they can be detrimental.

What is a Point Mutation

This shows a series of codons. Each codon consists of three nucleotides, usually representing a single amino acid. When one of these amino acid is changed by a point mutation, the corresponding codon is changed.

Point mutation is a genetic sequence change at a specific location. The change occurs on a locus of gene. Point mutations alter a genetic codon which changes the genetic information by switching the basic nucleotide sequence. This can lead to a change the protein that is being coded. Furthermore, the end result can creating an evolutionary gene which can either be beneficial or harmful based on environmental factors.

Types of Point Mutations

Deletion

A deletion mutation is where genetic material is removed from a codon. The amount of genetic material removed determines the proteins functionality.

Silent

A silent mutation has no effect on the functioning of the genome. A single nucleotide can change, but the new codon specifies the same amino acid resulting in an unmutated codon. This type of change is called synonymous change, since the old and new codon code for the same amino acid. This is possible because 64 codons specify only 20 amino acids.

Missense

A missense mutation changes a codon so that a different protein is created, a non-synonymous change. At times a change to one amino acid in the protein is not detrimental to the organism as a whole. Most proteins can withstand one or two point mutations before their functioning changes. Other times the protein will lose its function which can result in a disease in the organism.

Nonsense

A nonsense mutation converts an amino acid codon into a termination codon. This causes the protein to be shortened because of the stop codon interrupting it's normal code. Depending on how much of the protein is lost determines whether or not the protein is still functional.

Example of Translation (Substitution) Point Mutation

THE CAT IS IN THE BAG

THE HAT IS IN THE BAG

The change from C→H is an example of point mutation which later on will result in an altercation of a protein being coded.

Mainly point mutation is related to DNA and genetic substance. Any time a point mutation occurs, it occurs by the RNA strand miss copying the strand of DNA which it is trying to copy the sequence of the codon for replacement proteins.

Flow of genetic information occurs between offspring and parent. In humans each offspring has a set of genetic information, one coming from their mom, and one from their dad, this incoming information is combined to give the offspring its DNA. During the replication cells can copy DNA wrong, which leads to an every single cell having the same genetic error being passed down from parent to offspring giving them a genetic mutation.

Genetic mutation can either be harmful or beneficial. Through different mutations which result diseases, because of a change in codon. The beneficial aspect includes environmental benefits; being able to thrive in certain weather conditions by being a different race. For example living in hot weather makes you more acceptable to sunlight and alters your skin according to your surroundings, and vice versa living in harsh weather conditions like in Antarctica. Alberts, Bruce.

Examples

Hemoglobin is a protein found in red blood cells, and is responsible for the transportation of oxygen through the body. There are two subunits which make up the hemoglobin protein: beta-globins and alpha-globins. Beta-hemoglobin is created from the genetic information on the HBB, or “hemoglobin, beta” gene found on chromosome 11p15.5. A single point mutation in this polypeptide chain, which is 147 amino acids long, results in the disease known as Sickle Cell Anemia . Sickle Cell Anemia is an autosomal recessive disorder which affects 1 in 500 African Americans, and is one of the most common blood disorders in the United States. The single replacement of the sixth amino acid in the beta-globin, glutamic acid, with valine, results in deformed red blood cells. These sickle-shaped cells cannot carry nearly as much oxygen as normal red blood cells and they get caught more easily in the capillaries, cutting off blood supply to vital organs. The single nucleotide change in the beta-globin means that even the smallest of exertions on the part of the carrier results in severe pain and even heart attack. Below is a chart depicting the first thirteen amino acids in the normal and abnormal sickle cell polypeptide chain.

Sequence for Normal Hemoglobin

ATG

GTG

CAC

CTG

ACT

CCT

GAG

GAG

AAG

TCT

GCC

GTT

ACT

START

Val

His

Leu

Thr

Pro

Glu

Glu

Lys

Ser

Ala

Val

Thr

Sequence for Sickle Cell Hemoglobin

ATG

GTG

CAC

CTG

ACT

CCT

GTG

GAG

AAG

TCT

GCC

GTT

ACT

START

Val

His

Leu

Thr

Pro

Val

Glu

Lys

Ser

Ala

Val

Thr

Advantages of Point Mutation

The scientific theory of evolution is greatly dependent on point mutations in cells. The theory explains the diversity and history of living organisms on Earth. In relation to point mutations, it says that beneficial mutations allow the organism to thrive and reproduce, thereby passing its positively affected mutated genes on to the next generation. On the other hand, harmful mutations cause the organism to die or be less likely to reproduce in a phenomenon known as natural selection.

It was previously believed that these mutations happened completely by chance, with no regard for their effects on the organisms. Recently, there have been studies suggesting that these mutations occur in response to environmental challenges. That is to say, they are more likely to occur when they are advantageous to the organism, rather than when they are neutral or disadvantageous. When cells were deprived of a certain amino acid, tryptophan, for prolonged periods of time, point mutations in trp operon reverted to tryptophan, leading to an advantageous result, more frequently than under normal conditions when the mutations were neutral. Additionally, the tryptophan mutation rate was unaffected when the cells were deprived of another amino acid, cysteine, further suggesting that the mutation rate was specific to situations in which the mutation was advantageous.

Single Nucleotide Polymorphisms

Other effects of point mutations, or single nucleotide polymorphisms in DNA, depend on the location of the mutation within the gene. For example, if the mutation occurs in the region of the gene responsible for coding, the amino acid sequence of the encoded protein may be altered causing a change in the function, activation, localization or stability of the protein. Moreover, if the mutation occurs in the region of the gene where transcriptional machinery binds to the protein, the mutation can affect the binding of the transcription factors because the short nucleotide sequences recognized by the transcription factors will be altered. Mutations in this region can affect rate of efficiency of gene transcription, which in turn can alter levels of mRNA and thus, protein levels in general. Point mutations can have several effects on the behavior and reproduction of a protein depending on where the mutation occurs in the amino acid sequence of the protein. If the mutation occurs in the region of the gene that is responsible for coding for the protein, the amino acid may be altered. This slight change in the sequence of amino acids can cause a change in the function, activation of the protein meaning how it binds with a given enzyme, where the protein will be located within the cell, or the amount of free energy stored within the protein. If the mutation occurs in the region of the gene where transcriptional machinery binds to the protein, the mutation can affect the way in which transcription factors bind to the protein. The mechanisms of transcription bind to a protein through recognition of short nucleotide sequences. A mutation in this region may alter these sequences and thus, change the way the transcription factors bind to the protein. Mutations in this region can affect the efficiency of gene transcription which controls both the levels of mRNA and overall protein levels.

Diseases Caused by Point Mutation

Cystic Fibrosis

A defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene causes cystic fibrosis (CF). A protein made by this gene controls the movement of the water and salt in and out of your body's cells. Genes in people with CF incorrectly code proteins. This causes thick, sticky mucus and very salty sweat.

Sickle Cell Anemia

Sickle-cell anemia is caused by a point mutation in the β-globin chain of haemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position.

The β-globin gene is found on the short arm of chromosome 11. The association of two wild-type α-globin subunits with two mutant β-globin subunits forms haemoglobin S (HbS). Under low-oxygen conditions (being at high altitude, for example), the absence of a polar amino acid at position six of the β-globin chain promotes the non-covalent polymerisation (aggregation) of haemoglobin, which distorts red blood cells into a sickle shape and decreases their elasticity.

Tay-Sachs Disease

The cause of Tay-Sachs disease is a genetic defect that is passed from parent to child. This genetic defect is located in the HEXA gene, which is found on chromosome 15.

The HEXA gene makes part of an enzyme called beta-hexosaminidase A, which plays a critical role in the nervous system. This enzyme helps break down a fatty substance called GM2 ganglioside in nerve cells. Mutations in the HEXA gene disrupt the activity of beta-hexosaminidase A, preventing the breakdown of the fatty substances. As a result, the fatty substances accumulate to deadly levels in the brain and spinal cord. The buildup of GM2 ganglioside causes progressive damage to the nerve cells. This is the cause of the signs and symptoms of Tay-Sachs disease.

Color Blindness

People who are colorblind have mutations in their genes that cause a loss of either red or green cones, and they therefore have a hard time distinguishing between colors. There are three kinds of cones in the human eye: red, green, and blue. Now researchers have discovered that some people with the gene mutation that causes colorblindness lose an entire set of “color” cones with no change to the clearness of their vision overall.