Chromosomal Aberrations

Question 1

What are chromosomal aberrations?

Answer 1

Abnormalities in the structure or number of chromosomes

Question 2

What are the two types of cell division that occurs with chromosome?

Answer 2

Diploid cells have two homologs for each chromosome - 46 chromosomes total

At time of each division, each chromosome has 2 identical chromatids

Mitosis separates chromatids and results in two cells with 46 chromosomes, one chromatid each

Meiosis separates chromosomes - results in 2 cells with 23 chromosomes and 2 chromatids each

Question 3

What are numerical aberrations or aneuploidies?

Answer 3

Caused by nondisjunction or anaphase lag in meiosis producing gametes with missing or surplus chromosomes

Question 4

What occurs during meiosis?

Answer 4

Homologous chromosomes pair up in metaphase

Crossovers exchange fragments between homologous chromosomes

Reduction division produces haploid cells with 23 chromosomes

Equational division produces gametes

Meiosis is error prone - more often in eggs

Nondisjunction produces aneuploidies - uneven number of chromosomes

Question 5

What is a normal diploid karyotype?

Answer 5

46,XX and 46,XY

Question 6

What are some examples of autosomal aneuploidies?

Answer 6

47,+21 - Trisomy 21 (Down Syndrome)

47,+18 - Trisomy 18 (Edwards Syndrome)

47,+13 - Trisomy 13 (Patau Syndrome)

Question 7

What are examples of aneuploidies of sex chromosomes?

Answer 7

45,X (45,XO) - Turner Syndrome, female

47,XXY - Klinefelter Syndrome, male

47,XYY - male

47,XXX - female

Question 8

Are abnormalities of sex chromosomes or autosomal chromosomes more severe?

Answer 8

Abdnormalities of sex chromosomes are less severe

Pregnancies affected with sex chromosome abnormalities have better chance of live births

Reason for more mild effect is X chromosomes inactivation which prevents harmful gene dosage effects but shutting down all X-chromosome except for one

Question 9

What are structural aberrations?

Answer 9

Rearrangements, loss and duplications of parts of a chromosome

Less frequent than numerical aberrations

Question 10

What are the two processes that generate structural chromosomal aberrations?

Answer 10

1. Nonhomologous end joining during emergency repair of DNA double strand breaks
2. Unequal crossing over between non-homologous regions (illegitimate recombination)

Question 11

What occurs during nonhomologous end joining?

Answer 11

Used to repair DNA double strand breaks

Attaches a loose chromosome fragment to another chromosome regardless of sequence homology

Can create chimeric chromosomes

Question 12

What occurs during unequal crossover?

Answer 12

Normally, meiotic recombination happens between homologous regions and does not alter chromosome structure

Sometimes chromosomal regions that are not identical undergo recombination

Can cause chromosomal rearrangements like deletions, duplications, or translocations

Question 13

What are structural chromosomal abnormalities divided into?

Answer 13

Balanced and unbalanced alterations

Question 14

What is an unbalanced alteration?

Answer 14

A change that reduces or increases the amount of DNA per cell.

Include examples like deletions or duplications and are likely to impact the carrier since the dosage of many genes is changed

Often severe phenotype

Affects only one member of a chromosome pair

A balanced alteration in the carrier can become unbalanced during meiosis

Question 15

What are deletions and duplications in regards to structural aberrations?

Answer 15

Deletions and duplications are unbalanced - change amount of genetic material in nucleus

Deletions are usually more severe than duplications

A deletion creates a partial monosomy and a duplication creates a partial trisomy

Question 16

What is a balanced alteration?

Answer 16

Chromosomal rearrangement that does not change the amount of DNA in the affected cell

Insertions and translocations - insertion moves fragment into the middle of another chromosome whereas translocation attaches it to the end

A carrier is often unaffected and unaware of the alteration. Often has no phenotype

Commonly a reciprocal translocation

Balanced alterations can become unbalanced through meiosis and this produces unbalanced gametes and greatly reduces the success of pregnancy

Question 17

What is one example of an unbalanced Chromosomal alteration?

Answer 17

Cri-du-chat arising from deletion on chromosome 5

Deleted region on chromosome 5 contains genes required for developmental of multiple systems

Facies include microcephaly, hyperterlorism, micrognathia

Severe intellectual disability, heart defects

Characteristic cry

Question 18

What is Di George Syndrome?

Answer 18

Microdeletion on chromosome 22

Unbalanced alteration

Difficult to diagnose because has wide variety of phenotypes

Include congenital heart defect, immunodeficiency, hypoparathyroidism, mild intellectual disability, cleft palate, and deletion of TBX1 gene

Question 19

When are insertions and translocation not asymptomatic?

Answer 19

When rearrangement creates a new reading frame

When heavily methylated fragment is translocated

Question 20

What is the Philadelphia Chromosome?

Answer 20

Somatic translocation between chromosomes 9 and 22 creates an oncogene

Exception to rule that balanced alteration does not affect health of carrier

Translocation moves the ABL tyrosine kinase gene from chromosome 9 to the BCR region on chromosome 22

Bcr/Abl kinase functions as oncogenes and causes chronic myelogenous leukemia

Classified as dominant gain of function mutation

Can be treated with tyrosine kinase inhibitor (Gleevec) and is not inherited

Question 21

What is the robertsonian translocation?

Answer 21

Chromosomes exchange long and short arms

Two derivative chromosomes result - One has both long arms and one is composed of both short arms

Derivative with short arm often disappears if it does not have essential genetic information

Frequently occurs between chromosomes 13 and 14 and is the most common alteration

Question 22

What is an inversion?

Answer 22

Chromosome suffers two breaks and the broken off fragment is re-inserted in the wrong orientation

Balanced alteration that is often asymptomatic in carrier

Problems result for offspring and depends on whether the inverted region includes the centromere or not

Question 23

What are the two inversions and what occurs?

Answer 23

Inverted chromosomes form inversion loop during meiosis

Pericentric inversion - involving the centromere and recombination in inversion loop results in unbalanced gametes (deletes and duplications)

Paracentric inversion - outside of the centromeric region and recombination in inversion loop causes unbalances gametes and chromosomes with 0 or 2 centromeres

Usually leads to inviable zygotes

Question 24

What is a feature of balanced chromosomal aberrations?

Answer 24

They produce unbalanced gametes in meiosis

In individuals with balanced translocations, meiosis is separating chromosomes that are not entirely homologous.

Gamete might be loaded with normal chromosomes, balanced, and unbalanced outcomes

50% of cases will be abnormal

Question 25

What do Robertsonian translocations create?

Answer 25

Create derivative chromosomes from long and short arms of acrocentric chromosomes

Short derivatives then get lost - 45 chromosomes per cell

Loss of short derivative often inconsequential for carrier

In meiosis, cell aligns all 3 affected chromosomes when there should normally be 2 pairs of 2

Separation of chromosomes can occur in 3 different patterns: alternate segregation that is balanced and normal gamete

2 adjacent (unbalanced) segregations

Question 26

What can clinical cytogenetic analysis do?

Answer 26

Detect chromosomal aberrations

Question 27

What circumstances would indicate chromosomal aberrations?

Answer 27

Stillbirth/neonatal death

Fertility problems

Pregnancy with advanced maternal age

Sometimes cancer and family history

Question 28

What is the inheritance of chromosomal aberrations?

Answer 28

Dominant mode of inheritance since they cause disease in heterozygous state

Usually new mutations - low fitness of carriers

Multiple abnormalities in affected children, often with developmental delay

3 outcomes in a child: normal, unbalanced, and balanced

Cause spontaneous abortions and multiple miscarriages and infertility

Question 29

What is a hallmark of cancer?

Answer 29

Genome instability

Leads to multiple aneuploidies often with hyperdiploid karyotype

High mutation rate helps cancer cells evolve quickly

Cancer cells survive genomic damage - loss of cell cycle control over genomic integrity so no stopping for DNA repair or replication. Other way it causes cancer is cancer cells become resistant to apoptotic signals that normally terminate mutated cells (amplify oncogenes and delete tumor suppressor genes)