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Mutation- is a change of the nucleotide sequence of the genome of an organism, virus, or extra chromosomal genetic element.

Types of Mutation• Substitution• Insertion•Deletion• Frameshift

SubstitutionA substitution is a mutation

that exchanges one base for another (i.e., a change in a single "chemical letter" such as switching an A to a G).

InsertionInsertions are

mutations in which extra base pairs are inserted into a new place in the DNA.

Inversiona DNA sequence of

nucleotides is reversed. Inversions can occur among a few bases within a gene or among longer DNA sequences that contain several genes.

DeletionDeletions are

mutations in which a section of DNA is lost, or deleted.

Frameshift Since protein-coding DNA is

divided into codons three bases long, insertions and deletions can alter a gene so that its message is no longer correctly parsed.

Chromosomal Variation in

Number

Aneuploidy- the abnormal condition

were one or more chromosomes of a normal set of chromosomes are missing or present in more than their usual number of copies.

Nullisomy- the loss of both pairs of

homologous chromosomes- nullisomics - 2N-2

Monosomy-the loss of a single

chromosome-monosomics -2N-1

Trisomy- the gain of an extra copy of

a chromosome; - trisomics - 2N+1

Tetrasomic- the gain of an extra pair of

homologous chromosomes- Tetrasomics- 2N+2

Gene Mutationis a permanent change in the

DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.

Inherited• hereditary mutations or germline

mutations• This type of mutation is present

throughout a person’s life in virtually every cell in the body.

Acquired• or somatic mutations• occur in the DNA of individual cells

at some time during a person’s life. • caused by environmental factors • cannot be passed on to the next

generation.

How Causes Mutations To Occur?

Natural Cause• DNA fails to copy accurately –when a cell divides, it makes a

copy of its DNA and sometimes the copy is not quite perfect.

External Influences/Mutagens

In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level.

Effects of mutagens• can affect the transcription and

replication of the DNA, • can lead to cell death. • produces mutations that can result in

aberrant, impaired or loss of function for a particular gene,

• accumulation of mutations may lead to cancer.

• (chromosomal instability)chromosomal breakages and rearrangement of the chromosomes such as translocation, deletion, and inversion. (clastogens)• Some mutagens can cause

aneuploidy and change the number of chromosomes in the cell.

Types of Mutagens

Physical mutagens• Ionizing radiations such as X-rays,

gamma rays and alpha particles–may cause DNA breakage and other

damages. The most common sources include cobalt-60 and cesium-137.

• Radioactive decay

• Ultraviolet radiations with wavelength above 260 nm – are absorbed strongly by bases, producing

pyrimidine dimers, which can cause error in replication if left uncorrected.

• DNA reactive chemicals –A large number of chemicals may interact

directly with DNA. However, many are not necessarily mutagenic by themselves, but through metabolic processes in cells they produce mutagenic compounds.

• Reactive oxygen species (ROS)– These ROS may result in the production of many

base adducts, as well as DNA strand breaks and crosslinks.

• Deaminating agents– for example nitrous acid which can cause

transition mutations by converting cytosine to uracil.

• Aromatic amines and amides– have been associated with carcinogenesis, may

cause cancer of the bladder, liver, ear, intestine, thyroid and breast

Biological Agents• Virus –Virus DNA may be inserted into the genome and

disrupts genetic function. Infectious agents have been suggested to cause cancer.

• Bacteria – some bacteria such as Helicobacter pylori cause

inflammation during which oxidative species are produced, causing DNA damage and reducing efficiency of DNA repair systems, thereby increasing mutation.

Protection Against Mutagens

• Fruits and vegetables that are rich in antioxidants–Antioxidants are an important group of

anticarcinogenic compounds that may help remove ROS or potentially harmful chemicals.

• An effective precautionary measure an individual can undertake to protect themselves is by limiting exposure to mutagens such as UV radiations and tobacco smoke.

Mutation in Humans

Down Syndrome• also known as trisomy 21, is a genetic disorder

caused by the presence of all or part of a third copy of chromosome 21.

• It is typically associated with physical growth delays, characteristic facial features and mild to moderate intellectual disability.

• The average IQ of a young adult with Down syndrome is 50, equivalent to the mental age of an 8 or 9 year old child, but this varies widely.

Edward’s syndrome• (also known as Trisomy 18 [T18]) is a

chromosomal disorder caused by the presence of all or part of an extra 18th chromosome.

• This genetic condition almost always results from nondisjunction during meiosis.

• named after John Hilton Edwards, who first described the syndrome in 1960.

• It is the second most common autosomal trisomy, after Down syndrome, that carries to term.

• Characteristics: kidney malformations, structural heart defects at birth, intestines protruding outside the body (omphalocele), intellectual disability, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis.

Patau syndrome• is a syndrome caused by a chromosomal

abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13.

• The extra genetic material from chromosome 13 disrupts the normal course of development, causing multiple and complex organ defects.

Monosomy 7

• is typically characterized by early-childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML).

• Bone marrow failure/MDS/AML follows within a few months to years of identification of a monosomy 7 cell line in peripheral blood. Nearly all individuals reported with familial mosaic monosomy 7 have died of their disease.

Tetrasomy 18p• is a genetic condition that is caused by the

presence of an isochromosome, composed of two copies of the short arm of chromosome 18. It is characterized by multiple medical and developmental concerns.

• cryptorchidism among males• feeding difficulties, respiratory difficulty and

jaundice are also relatively frequent.

Pallister–Killian syndrome• Pallister–Killian syndrome (also

tetrasomy 12p mosaicism or Pallister mosaic aneuploidy syndrome) is an extremely rare genetic disorder occurring in humans.

• Pallister-Killian occurs due to the presence of the anomalous extra isochromosome 12p, the short arm of the twelfth chromosome.

• Characteristics include varying degrees of developmental disability, epilepsy, hypotonia, and both hypopigmentation and hyperpigmentation.

• Patients also exhibit a distinctive facial structure, characterized by high foreheads, sparse hair on the temple, a wide space between the eyes, epicanthal folds, and a flat nose.

• Vision and hearing impairments may occur. Patients may also exhibit congenital heart defects, gastroesophageal reflux, cataracts, and supernumerary nipples.

• Diaphragm problems seen in newborns can lead to death shortly after birth.

• As patients pass into adolescence, the syndrome is characterized by a coarse and flat face, macroglossia prognathia, inverted lower lip, and psychomotor retardation with muscular hypertonia and contractures.