CYTOGENETICSCYTOGENETICS

BYBYAHMED BAHIELDINAHMED BAHIELDIN

HUSSEIN SABITHUSSEIN SABIT

Chromosome DeletionsChromosome Deletions

Four different classes of structural Four different classes of structural chromosome changes are:chromosome changes are:

deletions,deletions,

duplications,duplications,

inversions, and inversions, and

translocationstranslocations

BackgroundBackgroundBackgroundBackground

• In deletions and inversions the In deletions and inversions the chromosome breaks are confined to chromosome breaks are confined to one pair of chromosomesone pair of chromosomes only, only, whereas in duplications and whereas in duplications and translocations translocations more than one more than one chromosomechromosome pairpair can be involved 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 DNALoss of segment of DNA• Intragenic deletion: small deletion within Intragenic deletion: small deletion within

gene – inactivates gene; non-revertible gene – inactivates gene; non-revertible mutationmutation

• Multigene deletionMultigene deletion– many genes deletedmany genes deleted– often severe consequencesoften severe consequences

• gene imbalancegene imbalance• expression of deleterious recessive mutation expression of deleterious recessive mutation

(pseudodominance)(pseudodominance)

• Visible as deletion loopVisible as deletion loop

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

Deletion loopDeletion 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.

• 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

Symptoms of Chromosome 6p deletion syndrome

Structural chromosome changes depend Structural chromosome changes depend on on breakagebreakage of chromosomes and on of chromosomes and on reunionreunion of chromosome segments of chromosome segments

Chromosome breakage results in Chromosome breakage results in sticky sticky endsends with the with the tendency for reuniontendency for reunion with with other such injured endsother such injured ends

According to this hypothesis, breaks occur According to this hypothesis, breaks occur spontaneously or as a result of mutagens spontaneously or as a result of mutagens and usually rejoin in the original order by and usually rejoin in the original order by repair process "repair process "restitutionrestitution""

Breakage-Reunion and Exchange Breakage-Reunion and Exchange HypothesesHypotheses

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

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

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

Such lesions are regions of instability in the chromosomes or Such lesions are regions of instability in the chromosomes or chromatidschromatids

The visible evidence of such lesions are the The visible evidence of such lesions are the gapsgaps

Breakage-Reunion and Exchange Breakage-Reunion and Exchange Hypotheses Hypotheses

Spontaneous and Induced Chromosome and Spontaneous and Induced Chromosome and Chromatid Aberrations Chromatid Aberrations

The timing of irradiation determines whether the The timing of irradiation determines whether the aberration involves a chromatid or a chromosomeaberration involves a chromatid or a chromosome

After the S periodAfter the S period, only one chromatid will be involved in , only one chromatid will be involved in the lesionthe lesion

Before the S periodBefore the S period, both sister chromalids are affected, both sister chromalids are affected

Spontaneous aberrations are the result of naturally Spontaneous aberrations are the result of naturally occurring radiations, i.e., chromosomal anomalies can occurring radiations, i.e., chromosomal anomalies can also be produced by also be produced by viral infections viral infections !!!!!!

i.e., measles, chicken pox and Simian tumor virus SV40i.e., measles, chicken pox and Simian tumor virus SV40, , the sites of the chromosome breakage appear to be the sites of the chromosome breakage appear to be nonrandomnonrandom

Inducing chromosome aberrations include the Inducing chromosome aberrations include the application of various agents such as application of various agents such as radiation, radiation, chemicals, viruses, temperature changes or drugs chemicals, viruses, temperature changes or drugs (caffeine, and 8-ethoxycaffeine)(caffeine, and 8-ethoxycaffeine)

Sister chromatid exchange (SCE):Sister chromatid exchange (SCE): there is a close there is a close linkage between chromosome aberrations and sister linkage between chromosome aberrations and sister chromatid exchangeschromatid exchanges

Powerful mutagens such as Powerful mutagens such as ionizing radiationionizing radiation (alpha, (alpha, beta, gamma rays from radioactive sources, x-rays, beta, gamma rays from radioactive sources, x-rays, protons, neutrons) cause only slight increases in protons, neutrons) cause only slight increases in SCE frequencySCE frequency

Spontaneous and Induced Chromosome and Spontaneous and Induced Chromosome and Chromatid Aberrations Chromatid Aberrations

Spontaneous and Induced Chromosome and Spontaneous and Induced Chromosome and Chromatid AberrationsChromatid Aberrations

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

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

Postreplication repair is considered to be error-pronePostreplication repair is considered to be error-prone

Terminal Deficiencies Terminal Deficiencies

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

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

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

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

Large deficiencies will lead to the death of the cell Large deficiencies will lead to the death of the cell involved or will, at least, prohibit sexual reproductioninvolved or will, at least, prohibit sexual reproduction

In plants, the treatment seems to make a differenceIn plants, the treatment seems to make a difference

If maize was treated with ultraviolet radiation, terminal If maize was treated with ultraviolet radiation, terminal deficiencies mainly resulted. deficiencies mainly resulted. If x-rays were applied, If x-rays were applied, only interstitial deletions were observed only interstitial deletions were observed !!!!!!

If the break occurs in the If the break occurs in the heterochromatic portionheterochromatic portion of of the chromosome, it is more the chromosome, it is more likely to heallikely to heal than if it than if it happens in the happens in the euchromatineuchromatin, the frequency of , the frequency of recovered x-ray-induced breaksrecovered x-ray-induced breaks is highest in is highest in heterochromatin and lowest in euchromatinheterochromatin and lowest in euchromatin

Terminal Deficiencies Terminal Deficiencies

Terminal DeficienciesTerminal Deficiencies

In Drosophila X chromosome, up to 11 bands In Drosophila X chromosome, up to 11 bands are involved in terminal deficiencyare involved in terminal deficiency

If only 8 bands in this region are lost, this If only 8 bands in this region are lost, this deficiency is deficiency is lethallethal to the whole organism in to the whole organism in the homozygous condition. A loss of 4 bands the homozygous condition. A loss of 4 bands is is viableviable in the homozygous. in the homozygous.

On the other hand, loss of heterochromatic On the other hand, loss of heterochromatic segments can occur almost segments can occur almost unnoticedunnoticed. Large . Large pieces of the Y chromosome of Drosophila pieces of the Y chromosome of Drosophila may be deficient without any lethal effectmay be deficient without any lethal effect

Interstitial DeletionsInterstitial Deletions

The loss of an intercalary or interstitial chromosome segmentThe loss of an intercalary or interstitial chromosome segment

vary from the absence of a single nucleotide to large vary from the absence of a single nucleotide to large chromosome segmentschromosome segments

The genetic proof for a deletion is its failure to back-mutate to The genetic proof for a deletion is its failure to back-mutate to the original formthe original form

Bm1 gene in the short arm of chromosome 5 close to the Bm1 gene in the short arm of chromosome 5 close to the centromere:centromere:

The recessive allele bm1 expresses The recessive allele bm1 expresses brown midribbrown midrib, producing , producing a brown color in lignified cell walls. The absence of Bm1, as a brown color in lignified cell walls. The absence of Bm1, as well as bm1, (well as bm1, (interstitial deletioninterstitial deletion) also produces brown midrib) also produces brown midrib

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