College of Medical technologyCytogenetics:

MutationPrepared by: Mrs. C. A. Ignacio

MutationThese are changes to the base pair sequence of genetic material (either DNA or RNA).

It can be caused by copying errors in the genetic material during cell division and by exposure to ultraviolet or ionizing radiation, chemical mutagens, viruses, or can occur deliberately under cellular control during processes such as meiosis or hypermutation.

They may be cytologically visible in the nucleus as chromosome changes or cytologically invisible gene or point mutations

Both kinds have observable developmental effect on the phenotype of an organism

Changes in chromosome numberChanges in geneCaused by natureCaused by artificial method

Chromosome variation in numberEuploidy- refers to the changes involving the whole genome or the entire set of chromosome

Monoploid (1)- ABCDiploid (2) AABBCCPolyploid- tetraploid, pentaploid, hexaploid,heptaploid, octaploid

Identify the euploidy type:CCCCCCCC

~OCTAPLOID

Identify the euploidy type:LLLLLLLLLLMMMMMMMMMMNNNNNNNNNN

~DECAPLOID

PolyploidRefers to any organism in which the number of complete chromosomes sets exceeds that of a diploid.

Reasons for polyploidyFertilization of an egg by more than one sperm leading to a zygote nucleus with 3 or more sets of chromosomes.Failure of mitosis that multiplies the number of somatic chromosomes in a sex organ , thereby increasing the number of gametic chromosomes.Failure in meiosis that produces a diploid gamete instead of a haploid.

AneuploidyOccurs when one or more chromosomes of a normal set (genome) are lacking or are present in excess.

The nuclei will contain chromosomes whose numbers are not multiples of the genome.

Characterized by incomplete genomes.

Types:Disomic (2N)- AABBCCMonosomic- (2N-1)- AABBCNullisomic- (2N-2) AABB_ _Polysomic extra chromosomesTrisomic- AABBCCCDouble trisomic, tetrasomic,pentasomic,.

Identify the type of aneuploidy AABBCCCCC

AAAAAABBCC

AABBBBBBBCC

AABBBCCC

Trisomy in humans:The occurrence of aneuploidy for autosomal chromosomes in humans is often lethal since a change an autosomal dosage lacks the inactivation mechanism that seems to operate for additional chromosomes.Example- Down syndrome, trisomy 21

Down syndromeTriplo21 trisomic for autosome 21Translocation- extra 21 chromosome to another chromosome 14,15 or 21

Patau syndromealso known as trisomy 13, is a chromosomal abnormality, a syndrome in which a patient has an additional chromosome 13 due to a non-disjunction of chromosomes during meiosis. Some are caused by Robertsonian translocations. The extra chromosome 13 disrupts the normal course of development, causing the characteristic features of Patau syndrome. Like all non-disjunction diseases (Down syndrome, Edwards syndrome, etc.), the risk of disease in the offspring increases with maternal age at pregnancy, with about 31 years being the average.Patau syndrome affects approximately 1 in 12,000 live births.

Edward syndromeis a genetic disorder caused by the presence of all or part of an extra 18th chromosome. It is named after John H. Edwards, who first described the syndrome in 1960. It is the most common autosomal trisomy, after Down Syndrome, that carries to term.Trisomy 18 is caused by the presence of three as opposed to two copies of chromosome 18 in a fetus or infant's cells. The incidence of the syndrome is estimated as one in 3,000 pregnancies and approximately one in 6,000 live births. The incidence increases as the mother's age increases. The syndrome has a very low rate of survival, resulting from heart abnormalities, kidney malformations, and other internal organ disorders

Changes in chromosome structureChromosome usually remains the same, but their genetic material becomes altered through the loss, gain or rearrangement of particular sections.

Chromosomal rearrangementsDeficiencies or Deletions- loss in chromosomal material- Cri du chat syndrome (Chromo#5)- Philadelphia 22Kinds:Interstitial deficiencyTerminal

2. Duplication or repeats- is the presence of a section of a chromosome in excess of the normal amount.- the repeated section of chromosomal material may be present in one pair of homologous chromosomes may have been transposed to a nonhomologous on occasion; may even exist independently with its own centromere.

Types:a. Tandemb. reverse tandemc. displacedd. transpositione. extra chromosome

a b c d e dea b c d e eda de b c d e k l m n o 0 p q r de s td e

3. Inversion- It is the rotation of a chromosome segment to a full 180 degrees- It develops most likely when breaks occur at a place where a chromosome forms a tight loop during synapsis.

Types:a. Pericentric includes the centromereb. Paracentric does not include the centromere

4. Translocation- transfer of a section of one chromosome to a non-homologous chromosome

Types:a. Simple translocation involves a single breakb. Shifts involves 3 breaksc. reciprocal occurs when single breaks in 2 non-homologous chromosome produce an exchange of chromosome section

Gene MutationsAny kind of mutation is basically a change in the DNA which leads to a corresponding change in phenotype.Point mutations

Most common is the transition that exchanges a purine for a purine (A G) or a pyrimidine for a pyrimidine, (C T). A transition can be caused by nitrous acid, base mis-pairing, or mutagenic base analogs such as 5-bromo-2-deoxyuridine (BrdU).

Less common is a transversion, which exchanges a purine for a pyrimidine or a pyrimidine for a purine (C/T A/G).

A point mutation can be reversed by another point mutation, in which the nucleotide is changed back to its original state (true reversion) or by second-site reversion (a complementary mutation elsewhere that results in regained gene functionality). These changes are classified as transitions or transversions. An example of a transversion is adenine (A) being converted into a cytosine (C).

There are also many other examples that can be found. Point mutations that occur within the protein coding region of a gene may be classified into three kinds, depending upon what the erroneous codon codes for: Silent mutations: which code for the same amino acid. Missense mutations: which code for a different amino acid. Nonsense mutations: which code for a stop and can truncate the protein.

Harmful and beneficial mutations

Harmful mutations

Changes in DNA caused by mutation can cause errors in protein sequence, creating partially or completely non-functional proteins. To function correctly, each cell depends on thousands of proteins to function in the right places at the right times. When a mutation alters a protein that plays a critical role in the body, a medical condition can result. A condition caused by mutations in one or more genes is called a genetic disorder.

However, only a small percentage of mutations cause genetic disorders; most have no impact on health. For example, some mutations alter a gene's DNA base sequence but dont change the function of the protein made by the gene.

If a mutation is present in a germ cell, it can give rise to offspring that carries the mutation in all of its cells. This is the case in hereditary diseases.

On the other hand, a mutation can occur in a somatic cell of an organism. Such mutations will be present in all descendants of this cell, and certain mutations can cause the cell to become malignant.

Often, gene mutations that could cause a genetic disorder are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, the process of DNA repair is an important way in which the body protects itself from disease

Beneficial mutations A very small percentage of all mutations actually have a positive effect.

These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment.

For example, a specific 32 base pair deletion in human CCR5 confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes.

The CCR5 mutation is more common in those of European descent. One theory for the etiology of the relatively high frequency of CCR5-32 in the European population is that it conferred resistance to the bubonic plague in mid-14th century Europe. People who had this mutation were able to survive infection thus its frequency in the population increased.

It could also explain why this mutation is not found in Africa where the bubonic plague never reached. Newer theory says the selective pressure on the CCR5 Delta 32 mutation has been caused by smallpox instead of bubonic plague.

A mutant is an individual, organism, or new genetic character arising or resulting from an instance of mutation, which is a sudden structural change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not found in the wildtype.

In an organism or individual, the new character or trait may or may not be trivial, may occasionally be beneficial, but will usually result in either a genetic disorder or have no phenotypic effect whatsoever. The natural occurrence of genetic mutations is integral to the process of evolution. A more general term for mutant is sport, which includes individuals who vary from type due to mutation, as well as those who vary from type due to other reasons.

In multicellular organisms, mutations can be subdivided into germ line mutations, which can be passed on to descendants, and somatic mutations. The somatic mutations cannot be transmitted to descendants in animals

Mutations create variations in the gene pool, and the less favorable (or deleterious) mutations are removed from the gene pool by natural selection, while more favorable (beneficial or advantageous) ones tend to accumulate, resulting in evolutionary change.

For example, a butterfly may develop offspring with a new mutation caused s by ultraviolet light from the sun. In most cases, this mutation is not good, since obviously there was no 'purpose' for such change at the molecular level. However, sometimes a mutation may change the butterfly's color, making it harder for predators to see it; this is an advantage and the chances of this butterfly surviving and producing its own offspring are a little better, and over time the number of butterflies with this mutation may form a large percentage of the species.

Neutral mutations are defined as mutations whose effects do not influence the fitness of either the species or the individuals who make up the species. The overwhelming majority of mutations have no significant effect, since DNA repair is able to mend most changes before they become permanent mutations, and many organisms have mechanisms for eliminating otherwise permanently mutated somatic cells.

Causes of mutation

Two classes of mutations are spontaneous mutations (molecular decay) and induced mutations caused by mutagens.

Spontaneous mutations on the molecular level include:Tautomerism - A base is changed by the repositioning of a hydrogen atom. Depurination - Loss of a purine base (A or G). Deamination - Changes a normal base to an atypical base; C U, (which can be corrected by DNA repair mechanisms), or spontaneous deamination of 5-methycytosine (irreparable), or A HX (hypoxanthine). Transition - A purine changes to another purine, or a pyrimidine to a pyrimidine. Transversion - A purine becomes a pyrimidine, or vice versa.

Induced mutations on the molecular level can be caused by:

Chemicals Nitrosoguanidine (NTG) Hydroxylamine NH3OH Base analogs (e.g. BrdU) Simple chemicals (e.g. acids) Alkylating agents (e.g. N-ethyl-N-nitrosourea (ENU)) These agents can mutate both replicating and non-replicating DNA. In contrast, a base analog can only mutate the DNA when the analog is incorporated in replicating the DNA. Each of these classes of chemical mutagens has certain effects that then lead to transitions, transversions, or deletions. Methylating agents (e.g. ethyl methanesulfonate(EMS)) Polycyclic hydrocarbons (e.g. benzopyrens found in internal combustion engine exhaust) DNA intercalating agents (e.g. ethidium bromide) DNA crosslinker (e.g. platinum) Oxidative damage caused by oxygen (O)] radicals

Radiation Ultraviolet radiation (nonionizing radiation) - excites electrons to a higher energy level. DNA absorbs one form, ultraviolet light. Two nucleotide bases in DNA - cytosine and thymine-are most vulnerable to excitation that can change base-pairing properties. UV light can induce adjacent thymine bases in a DNA strand to pair with each other, as a bulky dimer. Ionizing radiation

DNA has so-called hotspots, where mutations occur up to 100 times more frequently than the normal mutation rate A hotspot can be at an unusual base, e.g., 5-methylcytosine.

Mutation rates also vary across species. Evolutionary biologists have theorized that higher mutation rates are beneficial in some situations, because they allow organisms to evolve and therefore adapt more quickly to their environments. For example, repeated exposure of bacteria to antibiotics, and selection of resistant mutants, can result in the selection of bacteria that have a much higher mutation rate than the original population.

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