Cytogenetics 3n

CYTOGENETICS

BY AHMED BAHIELDIN HUSSEIN SABIT

Chromosome Deletions

Backgroun d Four different classes of structural chromosome changes are: deletions, duplications, inversions, and translocations

• In deletions and inversions the chromosome breaks are confined to one pair of chromosomes only, whereas in duplications and translocations more than one chromosome pair can be involved

Deletion is the loss of genetic material. Any number of nucleotides can be deleted, from a single base to an entire piece of chromosome. Deletions can be caused by errors in chromosomal crossover during meiosis. This causes several serious genetic diseases.

• Loss of segment of DNA • Intragenic deletion: small deletion within gene – inactivates gene; non-revertible mutation • Multigene deletion – many genes deleted – often severe consequences

• gene imbalance • expression of deleterious recessive mutation (pseudodominance)

• Visible as deletion loop

Deletions on one chromosome can unmask recessive alleles on the other chromosome called pseudodominance

Deletion loop

Causes • Losses from translocation • Chromosomal crossovers within a chromosomal inversion • Unequal crossing over • Breaking without rejoining

Types • Types of deletion include the following: • Terminal Deletion - a deletion that occurs towards the end of a chromosome. • Intercalary Deletion - a deletion that occurs from the interior of a chromosome.

Effects • Small deletions are less likely to be fatal; large deletions are usually fatal - there are always variations based on which genes are lost. Some medium-sized deletions lead to recognizable human disorders. • Deletion of a number of base pairs that is not evenly divisible by three will lead to a frameshift mutation, causing all of the codons occurring after the deletion to be read incorrectly during translation, producing a severely altered and potentially nonfunctional protein.

.cont • Deletions are responsible for an array of genetic disorders, including some cases of male infertility and two thirds of cases of Duchenne muscular dystrophy. Deletion of part of the short arm of chromosome 5 results in a syndrome called Cri du chat. French for "cry of the cat" syndrome. It is found in approximately 1 in 50,000 live births. The surviving infants have a distinctive cry, severe mental retardation, and shortened life span.

Examples • Chromosome 1, 1p36 deletion syndrome is a medical condition caused by a rare chromosomal disorder where deletion of a portion of chromosome 1 causes various abnormalities such as • heart defects, mental retardation, developmental delay, and short stature • The symptoms are variable depending on the exact location of chromosomal deletion

Chromosome 1

?What is 22q11.2 deletion syndrome • 22q11.2 deletion syndrome is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2. • The features of this syndrome vary widely, even among affected members of the same family, and involve many parts of the body. • Characteristic signs and symptoms include heart defects that are often present from birth, an opening in the roof of the mouth (a cleft palate) or other palate defects, and mild differences in facial features.

.Cont • People with 22q11.2 deletion syndrome often experience recurrent infections caused by problems with the immune system, and some develop autoimmune disorders such as rheumatoid arthritis and Graves' disease. Affected individuals may also have kidney abnormalities, low levels of calcium in the blood (which can result in seizures), a decrease in blood platelets (thrombocytopenia), significant feeding difficulties, and hearing loss. Skeletal differences are possible, including mild short stature and, less frequently, abnormalities of the spinal bones.

Chromosome 6p deletion syndrome • A rare chromosomal disorder where part or all of the short arm (p) of chromosome 6 is deleted resulting in various abnormalities which are determined by the size of the deleted portion.

Symptoms of Chromosome 6p deletion syndrome • • • • • • • • • • • • • • •

Low -set ears Malformed ears Widely spaced eyes Dental caries Cleft lip Short neck Umbilical hernia Short phalanges Single palmar creases Eczema Growth retardation Motor retardation Speech retardation Mental retardation Deafness

Breakage-Reunion and Exchange Hypotheses • Structural chromosome changes depend on breakage of chromosomes and on reunion of chromosome segments • Chromosome breakage results in sticky ends with the tendency for reunion with other such injured ends • According to this hypothesis, breaks occur spontaneously or as a result of mutagens and usually rejoin in the original order by repair process "restitution"

Breakage-Reunion and Exchange Hypotheses •

If restitution to the original structure does not take place, the chromosomes may undergo structural changes through the phenomenon of reunion, i.e., new arrangement

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An alternative to the breakage-reunion hypothesis, is the newer exchange hypothesis

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According to this hypothesis, the primary event that leads to chromosome aberrations is not breakage but the formation of so-called primary lesions

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Such lesions are regions of instability in the chromosomes or chromatids

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The visible evidence of such lesions are the gaps

Spontaneous and Induced Chromosome and Chromatid Aberrations • The timing of irradiation determines whether the aberration involves a chromatid or a chromosome • After the S period, only one chromatid will be involved in the lesion • Before the S period, both sister chromalids are affected • Spontaneous aberrations are the result of naturally occurring radiations, i.e., chromosomal anomalies can also be produced by viral infections !!! • i.e., measles, chicken pox and Simian tumor virus SV40, the sites of the chromosome breakage appear to be nonrandom

Spontaneous and Induced Chromosome and Chromatid Aberrations • Inducing chromosome aberrations include the application of various agents such as radiation, chemicals, viruses, temperature changes or drugs (caffeine, and 8-ethoxycaffeine) • Sister chromatid exchange (SCE): there is a close linkage between chromosome aberrations and sister chromatid exchanges • Powerful mutagens such as ionizing radiation (alpha, beta, gamma rays from radioactive sources, x-rays, protons, neutrons) cause only slight increases in SCE frequency

Spontaneous and Induced Chromosome and Chromatid Aberrations •

A small but significant rise in the number of SCE's was observed after the exposure of fresh human lymphocytes to 30 minute treatments with diagnostic ultrasound

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Chromatid-type damage, like triradial chromosomes and chromosome-type damage, like dicentrics, were observed in Louis-Bar syndrome lymphocytes, a defect of DNA repair in these patients- lack the full complement of functional polynucleotide ligases that are able to join breaks in one strand of a DNA double helix

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Postreplication repair is considered to be error-prone

Terminal Deficiencies •

A deficiency is a structural change of a chromosome resulting in the loss of a terminal acentric chromosome, chromatid, or subchromatid segment and in the loss of the genetic information which this chromatin segment contains followed by a healing of its broken end

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In contrast, a deletion involves an intercalary chromosome segment and requires two chromosome breaks. However, in practice, the term "deletion" frequently is used for both of these types of structural chromosome changes

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Generally, in both instances, a centric and an acentric chromosome segment are produced

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The centric segment will persist during cell division, while the acentric fragment will be lost

Terminal Deficiencies • Large deficiencies will lead to the death of the cell involved or will, at least, prohibit sexual reproduction • In plants, the treatment seems to make a difference • If maize was treated with ultraviolet radiation, terminal deficiencies mainly resulted. If x-rays were applied, only interstitial deletions were observed !!! • If the break occurs in the heterochromatic portion of the chromosome, it is more likely to heal than if it happens in the euchromatin, the frequency of recovered x-ray-induced breaks is highest in heterochromatin and lowest in euchromatin

Terminal Deficiencies • In Drosophila X chromosome, up to 11 bands are involved in terminal deficiency • If only 8 bands in this region are lost, this deficiency is lethal to the whole organism in the homozygous condition. A loss of 4 bands is viable in the homozygous. • On the other hand, loss of heterochromatic segments can occur almost unnoticed. Large pieces of the Y chromosome of Drosophila may be deficient without any lethal effect

Interstitial Deletions The loss of an intercalary or interstitial chromosome segment vary from the absence of a single nucleotide to large chromosome segments The genetic proof for a deletion is its failure to backmutate to the original form Bm1 gene in the short arm of chromosome 5 close to the centromere: • The recessive allele bm1 expresses brown midrib, producing a brown color in lignified cell walls. The absence of Bm1, as well as bm1, (interstitial deletion) also produces brown midrib

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