Structural abnormalities of chromosomes

Chromosomes

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CentromereCentromere

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Chromosome 5Chromosome 5

Classification of structural chromosomal anomalies

Structural (may be due to de novo error in meiosis or inherited)

Translocations - reciprocal - Robertsonian (centric fusion)

DeletionsDuplicationsInversions

Structural Abnormalities

1.Deletions: 1.A portion of the chromosome is missing or deleted.

2.The implications of this deletion depends on how big the deletion is, and what genes are now missing due to the deletion.

Deletions

Deletions

• Loss of chromosomal material

• Large-scale deletions are lethal

• Example: Cri du chat Syndrome– Deletion of short arm of chromosome 5– Affects motor and mental function– Infant cry resembles a meowing cat– Specific chromosomal break points are

associated with specific phenotypic changes

Cri du chat Syndrome

Fig. 6.26

Variation in phenotype associated with region deleted has been observed

Researchers have identified regions with genes involved in larynx and nervous system development

Cri-du chat syndromeDeletion in Chromosome 5

2. Duplications: • A portion of the chromosome is duplicated, resulting in

extra genetic material.

• The person with the duplication actually has 3 copies of a particular piece of DNA, rather than the normal 2.

• Sometimes the extra piece of genetic material is on the chromosome on which it's normally found, and other times it's on a different chromosome.

• In general, duplications are less harmful than deletions; however, the extra genetic material can cause birth defects and health problems.

Structural Abnormalities

3. Translocations: 1. When a portion of one chromosome is

transferred to another chromosome. 2. There are two main types of translocations. In

a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere.

Structural Abnormalities

• An example of reciprocal translocation. Breaks occur first in both chromosome 4 and chromosome 20. Then one fragment of chromosome 4 attaches to a fragment of chromosome 20 and another fragment of chromosome 4 attaches to another fragment of chromosome 20

Types of Translocations

Types of Translocations

• The Philadelphia chromosome results when a piece of chromosome #9 switches places with a piece of chromosome #22.

• The translocation forms an extra-long chromosome #9 and an extra-short chromosome #22, which is the Philadelphia chromosome that contains the abnormal, fused BCR-ABL gene.

• Chronic myelogenous leukemia (also known as chronic myeloid leukemia) or CML is a slowly progressing cancer of the blood and bone marrow.

• It is characterized by an overproduction of white blood cells which do not mature, ultimately cannot carry out their intended function and crowd out the healthy cells.

• CML is distinguished from the other types of leukemia by a genetic abnormality in the white blood cells called the Philadelphia chromosome which promotes the growth of leukemia cells and seems to be present in nearly 90% of CML cases.

• Named for the city where it was discovered, the Philadelphia chromosome is thought to be acquired after birth and is formed when two chromosomes (9 and 22) switch some of their gene material forming a new chromosome.

Types of Translocations

Burkitt’s lymphoma

Ig- myc

Robertsonian translocation

4. Inversions: 1. A portion of the chromosome has broken off,

turned upside down and reattached, therefore the genetic material is inverted.

Structural Abnormalities

Chromosomal abnormality resulting from

two breaks in a single chromosome. • Two breaks in a single

chromosome can cause  inversion, deletion or ring structure.

• Inversion: The segment between two breakpoints is inverted before resealing the breaks.

• Deletion: The breaks reseal without including the segment between breakpoints.

• Ring chromosome: Two ends of the segment between breakpoints are joined to form a circular structure.

• Ring chromosomes typically result in mental and/or physical abnormalities. This is most likely due to the loss of genetic material in the ends of the chromosome when a ring forms. Some examples of disorders caused by ring chromosomes include:

1. ring chromosome 20 syndrome - associated with epilepsy 2. ring chromosome 14 syndrome - associated with mental

retardation, skin pigment abnormalities, seizures and abnormal facial features

3. ring chromosome 13 syndrome - associated with mental retardation and abnormal facial features

4. ring chromosome 15 syndrome - associated with mental retardation, dwarfism and small head size (called microcephaly)

Structural Abnormalities

Structural Abnormalities

Structural Abnormalities

1. A marker chromosome is a very small, unidentified chromosome that can be seen on a karyotype. Individuals with marker chromosomes usually have this marker chromosome in addition to the normal 46 chromosomes.

Other Chromosomal Abnormalities

• Uniparental disomy– Both copies of a

chromosome are inherited from a single parent

– Due to error in cell division

– Examples • Females affected with

rare X-linked disorders• Prader-Willi and

Angelman syndromes

• How does UPD happen? Three possible mechanisms have been proposed for the origin of UPD:

• the loss of a chromosome from a trisomic zygote, "trisomic rescue"

• the duplication of a chromosome from a monosomic zygote, "monosomic rescue"

• the fertilization of a gamete with two copies of a chromosome by a gamete with no copies of the same chromosome, called gamete complementation.

• All of these mechanisms require two consecutive "mistakes".

Fragile Sites on the Human X Chromosome

• Fragile sites occur on various autosomal and sex chromosomes.

• One, on the tip of the X chromosome, results in fragile X syndrome.

• Fragile X results in apparently normal neurological development, with the effects of mental retardation becoming apparent during early learning (age 3-5).

• This disease is one of several CAG expansion diseases. In the general population we all carry a limited copy of this nuceotide sequence, it is only when the copy number increases that the encoded protein (FRP, Fragile X Protein) is decreased in neuronal expression.

Fig. 6.30

Total number of chromosomes,

Sex chromosome constitution,

Anormalies/variants.

46,XY47,XX,+2147,XXX69,XXY45,XX,der(13;14)(q10;q10)46,XY,t(2;4)(p12;q12)46,XX,del(5)(p25)46,XX,dup(2)(p13p22)46,XY,inv(11)(p15q14)46,XY,fra(X)(q27.3)46,XY/47,XXY

The Karyotype: an international description

Total number of chromosomes,

Sex chromosome constitution,

Anomalies/variants.46,XY47,XX,+21 Trisomy 21 (Down syndrome)47,XXX Triple X syndrome69,XXY Triploidy

45,XX,der(13;14)(p11;q11) Robertsonian translocation46,XY,t(2;4)(p12;q12) Reciprocal translocation

46,XX,del(5)(p25) Deletion tip of chromosome 546,XX,dup(2)(p13p22) Duplication of part of short arm

Chr 246,XY,inv(11)(p15q14) Pericentric inversion

chromosome 1146,XY,fra(X)(q27.3) Fragile X syndrome46,XY/47,XXY Mosaicism normal/Klinefelter syndrome

The Karyotype: an international description