[MT 6315] Unit 5: Chromosome Aberrations

Chromosomal Mutations

Also known as **chromosomal** **aberrations** which refer to the **changes** in **chromosomal** **structure or number** which can lead to **chromosomal abnormalities** (deletion, duplication, rearrangement, and inversion of genes)

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Chromosomal Mutations

They are **relatively large** compared to gene mutations

Chromosomal Mutations

What is rare in live births but it is a common cause for **spontaneous abortions**?

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Chromosome Mutations

Refers to **variations from the** **wild-type condition** in either chromosome structure or chromosome number.

**…mutation in one or more of the** __**genes**__ on the chromosome

A person can have a normal chromosome in number and structure but **still have the disease** or condition caused by a mutation in one or more of the **____** on the chromosome

False. They **arise spontaneously or are induced by chemical or radiation mutagens.**

(True or False): Chromosome mutations do not arise spontaneously or are induced by chemical or radiation mutagens.

Wild type

Refers to what is **normally possessed** by the population at large and the **normal version** of your chromosome

**Gene**: Nucleotide sequence

**Chromosome**: Structure or number

### Gene vs Chromosome Mutation:

Alteration

1) Nucleotide sequence

2) Structure or number

**Gene**: DNA replication and mutagens

**Chromosome**: Crossing over during meiosis

### Gene vs Chromosome Mutation:

Errors

1) Crossing over during meiosis

2) DNA replication and mutagens

**Gene**: Nucleotide sequence

**Chromosome**: Segment

### Gene vs Chromosome Mutation:

Alteration Location

1) Segment

2) Nucleotide sequence

**Gene**: Single

**Chromosome**: Several

### Gene vs Chromosome Mutation:

Genes affected

1) Single

2) Several

**Gene**: Low

**Chromosome**: Lethal potential

### Gene vs Chromosome Mutation:

Influence

1) Low

2) Lethal potential

Deletion (del) / Deficiency

### Variation in Structure:

A **particular** or **portion** of a chromosome is **missing**; thus, it involves the **loss of a segment** of a chromosome

Duplication

### Variation in Structure:

**Extra copy** of chromosome or the **doubling of a segment of a chromosome**

Inversion

### Variation in Structure:

**Rotation** of sequence or **change in the orientation or sequence** of the chromosome

Translocation

### Variation in Structure:

**Transfer** of a portion of a chromosome to another

Monosomics

### Variation in Number:

**One** copy instead of a diploid chromosome

Nullisomics

### Variation in Number:

**A lack of both** **the normal chromosomes** or a pair of species

Aneuploidy

### Variation in Number:

Presence of the **abnormal number of chromosome** in a cell

Euploidy

### Variation in Number:

* Number of **complete** **set** of chromosome
* Organism or cell has one or exact multiple of complete set(s) of chromosomes
* A **somatic cell** with the normal number of chromosomes for that species

Polyploidy

### Variation in Number:

* **More than 2 complete sets** of chromosomes
* Common among plants

Deletion

* The segment may be **located anywhere along the chromosome**.
* Starts **in breaks of chromosomes**
* Caused by **agents or by errors in recombination**

The International System for Human Cytogenomic Nomenclature (ISCN)

It is an **international standard for human chromosome nomenclature**, which includes **band names**, **symbols** and **abbreviated terms** used in the description of human chromosome and chromosome abnormalities.

Minus sign (-)

What sign indicates the presence of deletion?

del

Abbreviation for deletions of parts

Terminal deletion

Type of deletion that occurs towards the **end** of a chromosome

Intercalary/interstitial deletion

Type of deletion that occurs from the **interior** of a chromosome

Microdeletion

Type of deletion that refers to a relatively **small amount** (up to **5Mb** that could include a dozen genes) of deletion. It is also found in **children** with physical abnormalities.

Cri-du-chat Syndrome

### Deletion

* **Chromosome:** 5p-
* **Phenotype**: Cat-like cry, facial anomalies (round small head and flattened bridge of the nose; eyes are spaced wide apart)
* Discovered by Jerome Lejeune (1963)

Wilm’s tumor

### Deletion

* **Chromosome:** 11q- \[Chromosome 11 (WT1)\]
* **Phenotype**: Kidney tumors, genital and urinary tract abnormalities

Retinoblastoma

### Deletion

* **Chromosome:** 13q-
* **Phenotype**: Cancer of the eye

Prader-Willi syndrome

### Deletion

* **Chromosome:** 15q- \[Chromosome 15q11-q13 (UPD)\]
* **Phenotype**: Weak slow growth (infant), obesity, compulsive eating (children and adults); poor sucking reflexes

Error in chromosome

## Deletion

### Cri-du-chat syndrome

Rare genetic disorder that is __not the result of anything that the parents had done__ but rather an ___

Pathognomonic cry of the cat

## Deletion

### Cri du chat syndrome

The abnormal anatomy of the throat

q11 and q13

## Deletion

### Prader-Willi syndrome

Bands included

Angelman syndrome

### Deletion

* Often smile and laugh frequently, and have happy, excitable personalities
* Tend to live close to a normal life span, but the disorder can't be cured

6 and 12 months of age

## Deletion

### Angelman syndrome

Developmental delays begin between about _____ and are considered to be the **first signs**

2 and 3 years old

## Deletion

### Angelman syndrome

Seizures begin between about __ and __ years old

OCA2

## Deletion

### Angelman syndrome

Which lost gene that is located on the segment of chromosome 15 is associated with light-colored hair and fair skin?

**Prader-Willi:** q-arm, paternal deletion

**Angelman:** maternal origin

## Deletion

### Prader-Willi vs Angelman syndrome

What is missing in Chromosome # 15?

Duplication

Results in the **doubling of a segment** of a chromosome

Charcot–Marie–Tooth disease type 1A

### Duplication

dup(17p12) or “duplication involving P-arm chromosome #17 with band-1 and subband-2”

Tandem

### Duplication

* Duplicated but the sequence is maintained

Reverse

### Duplication

* Backwards duplication

Terminal

### Duplication

* Terminal site or towards the end of the chromosome

Normal

### Duplication: *Gene Dose*

* Wild Type, Female
* B+B+

Duplicated once

### Duplication: *Gene Dose*

* Heterozygous Bar Female
* B+B

Both strands are duplicated

### Duplication: *Gene Dose*

* Homozygous Bar
* BB

Double duplication in pair

### Duplication: *Gene Dose*

* Heterozygous Double Bar
* B+B0

Paracentric

### Inversion

The inverted segment **does not include the centromere**

Pericentric

### Inversion

The inverted segment **includes the centromere**

Translocation

Change in position of chromosome segments and the gene sequences they contai

Intrachromosomal

### Translocation

Change in position of a chromosome segment **within the same chromosome**

Interchromosomal

### Translocation

Transfer of a chromosome segment **from one chromosome into a non-homologous chromosome**

Reciprocal

### Translocation: Interchromosomal

Exchange of segments **between two chromosomes**

Non-reciprocal

### Translocation: Interchromosomal

* **Transfer** of segment in one direction from **one chromosome to another**
* One-way translocation

Isochromes

### Translocation

* Short arms and/or the long arms of the same chromosome **join at the centromere**
* Two copies of a **large genetic region**
* **Mirror image** appearance of banding patterns extending in both directions from the centromere

Robertsonian (rob)

### Translocation

* Most common form
* **Two chromosomes** make up the person's DNA, joined together in an abnormal way; joining at centromeres
* 1 in 1,000 people
* Tiny short arms

Chronic Myelogenous Leukemia

### Translocation

* **Philadelphia** chromosome
* Reciprocal translocation between chromosome 22 and 9
* Transition of *C-ABL within the BCR*
* causes the *CML* to grow and reproduce out of control
* Uncontrolled replication of **myeloblasts**

Burkitt’s Lymphoma

### Translocation

* Africa
* Virus-induced tumor
* Malignant B cells secrete antibodies
* Reciprocal translocation between chromosomes 8 and 14
* Activation of *C-MYC*
* Highly aggressive B-cell non-Hodgkin lymphoma

Nondisjunction (non separation)

### Translocation

* **Irregular distribution** of sister chromatids during mitosis or of homologous chromosomes during meiosis
* Phenomenon of **unequal separation**

Nullisomy

**Aneuploidy**

* Loss of **one homologous pair**; 2N-2

Monosomy

### Aneuploidy

* It involves a loss of a **single chromosome**; 2N-1

Trisomy

### Aneuploidy

* Involves a single extra chromosome; 2N+1
* Cell is still a diploid but with additional chromosome

Tetrasomy

### Aneuploidy

* Two extra chromosomes; 2N+2
* Four copies of a particular chromosome

Down Syndrome

### Aneuploidy

* Trisomy-21
* Mongolism
* Phenotypic features:
* Wide skull that is flat at the back
* Eyelids have an epicanthic fold
* Iris contains spots
* Tongue are furrowed & protruding
* Physical growth, behavior and mental development are retarded
* Some have congenital heart defects.

Patau Syndrome

### Aneuploidy

* Trisomy 13
* Phenotypic features:
* Cleft lip and palate
* Small eyes; cyclopia (single median eye)
* Polydactyly (extra fingers and toes)
* Mental and developmental retardation
* Severe malformations of the brain and nervous system
* Proboscis (elongated appendage from head)
* Polycystic kidney

Edward Syndrome

### Aneuploidy

* Trisomy 18
* Most affected infants are female
* Average survival time is **2-4 months**
* Phenotypic features:
* Multiple congenital malformations
* Clenched fists
* Elongated skull
* Low-set malformed ears
* **Club foot** (talipes) - twisted foot that turns in and points down

Turner Syndrome

### Aneuploidy

* 45, X
* Monosomy for the **X chromosome**
* Only affects **females**
* Absence of Barr body
* Absence of X chromosome
* Phenotypic features:
* Short and wide-chested
* Extra folds of skin on the neck
* Underdeveloped breasts and rudimentary ovaries
* Color blindness
* Narrowing of aorta

Klinefelter Syndrome

### Aneuploidy

* (47, XXY), (48, XXYY), (48, XXXY), and (49, XXXXY)
* Breast development because of the decrease in the production of testosterone
* Phenotypic features:
* Poor sexual development
* Very low fertility

Jacob Syndrome

### Aneuploidy

* (47, XYY)
* Criminal behavior with extra Y chromosome
* A more rare genetic condition compared to Klinefelter
* Phenotypic features:
* Above average height
* Suffered personality disorders
* Below normal intelligence

Triploidy

### Polyploidy

* Most common form
* Caused by fertilization of diploid gametes with haploid gametes
* 69 chromosomes
* 69, XXY (Klinefelter)
* 69, XXX
* 69, XYY (Jacob Syndrome)

False. Structural defect = missing 1 arm in chromosome; Numerical aberrations = > or < the number of total chromosomes

(True or False): Structural defect refers to the more than or less than the number of total chromosomes, while numerical aberrations refers to the missing one arm in chromosome.

Inversion

It results when a **segment of a chromosome is excised** and then reintegrated in an orientation **180°** from the original orientation.

True

(True or False): In translocation, the same genes would be present despite the change in the position.

False, it should be **nullisomy**

(True or False): In monosomy, humans with this condition will **typically** **not survive**.

Cri-du-chat Syndrome

Which syndrome?

dup

Abbreviation for duplication

Reciprocal

### Translocation: Interchromosomal

Type of translocation that occurs when the chromosomal segments are exchanged **between two non-homologous chromosomes**

False. Robertsonian forms a very **recognizable and long product** due to the merging happened in both **q arms**.

(True or False): In Robertsonian translocation, the product is short and unrecognizable due to the merging in both p arms.

Acrocentrics

The term for having both tiny short arms or p-arms

Tyrosine kinase

A type of protein that promotes proliferation in chronic myelogenous leukemia

C-myc

Linked to cell proliferation that causes metastasis or rapid growth of cancer cells

Aneuploidy

Phenotypic effects range from minor physical symptoms to devastating and lethal deficiencies in major organ systems.

Aneuploidy

There is **variation** in the amount of specific chromosomes inside a set

False, it is the **maternal age** since the integrity of primary oocytes decreases as the woman ages and maternal selection becomes less effective.

(True or False): Paternal age is the leading risk factor for autosomal trisomy.

False, it should be **Y chromosome**

(True or False): Early studies associate violent criminal behavior with the presence of extra X chromosome

True

(True or False): Addition of extra copies of either sex chromosome interferes with normal development and causes both physical and mental problems

* Errors in meiosis during **gamete** formation
* Events in **fertilization**
* Errors in **mitosis** following fertilization

**VARIATION IN COMPLETE SETS OF CHROMOSOMES**

Abnormalities in the number of haploid chromosomal sets can arise in several ways:

* Errors in meiosis during _______ formation
* Events in _______
* Errors in _______ following fertilization

Tetraploidy

There is a **DNA duplication but no cell division** (endomitosis), which results in **4n**.

Triploidy

There is a diploid cell that was fertilized by your chromosome, or diploid sperm cell that fertilized an egg

Chromosome aberration/mutation

Chromosomal disorders form a category of human genetic diseases, that are manifested by developmental and reproductive abnormalities, as well as playing an important role in the pathogenesis of malignancy

Inversion (inv)

Functional impacts include:

* Inhibit recombination in heterokaryotes, chromosomes displaying different orientation are expected to evolve independently and lead to distinct gene-expression patterns
* Have a role as disease-causing mutations by both directly affecting gene structure or regulation in different ways, and by predisposing to other secondary arrangements in the offspring of inversion carriers.

Burkitt Lymphoma

* **Overexpression** of the **proto-oncogene** leads to the disease
* A cancer with tumor that **grows in the jaw**
* Can be detected through FISH

Robertsonian Translocation (rob)

* Only occur in (Human) Chromosome 13, 14 15, 21 and 22
* The ends of their short arms have similar repetitive DNA sequences that predispose their fusion

Philadelphia Chromosome

* Chromosome 9 (ABL) and 22 (BCR)
* Not found in any nonleukemic WBC

Deletion (del) / Deficiency

* Lethal on Homozygous
* Zero (0) copy of the genes
* Usually Lethal (Heterozygotes)
* Results in zygotic loss, still birth, or infant death

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Deletion (del) / Deficiency

* Critical for tumor suppressor gene