Chromosomal Aberrations Flashcards
What are chromosomal aberrations?
Abnormalities in the structure or number of chromosomes
What are the two types of cell division that occurs with chromosome?
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
What are numerical aberrations or aneuploidies?
Caused by nondisjunction or anaphase lag in meiosis producing gametes with missing or surplus chromosomes
What occurs during meiosis?
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
What is a normal diploid karyotype?
46,XX and 46,XY
What are some examples of autosomal aneuploidies?
47,+21 - Trisomy 21 (Down Syndrome)
47,+18 - Trisomy 18 (Edwards Syndrome)
47,+13 - Trisomy 13 (Patau Syndrome)
What are examples of aneuploidies of sex chromosomes?
45,X (45,XO) - Turner Syndrome, female
47,XXY - Klinefelter Syndrome, male
47,XYY - male
47,XXX - female
Are abnormalities of sex chromosomes or autosomal chromosomes more severe?
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
What are structural aberrations?
Rearrangements, loss and duplications of parts of a chromosome
Less frequent than numerical aberrations
What are the two processes that generate structural chromosomal aberrations?
- Nonhomologous end joining during emergency repair of DNA double strand breaks
- Unequal crossing over between non-homologous regions (illegitimate recombination)
What occurs during nonhomologous end joining?
Used to repair DNA double strand breaks
Attaches a loose chromosome fragment to another chromosome regardless of sequence homology
Can create chimeric chromosomes
What occurs during unequal crossover?
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
What are structural chromosomal abnormalities divided into?
Balanced and unbalanced alterations
What is an unbalanced alteration?
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
What are deletions and duplications in regards to structural aberrations?
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
What is a balanced alteration?
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
What is one example of an unbalanced Chromosomal alteration?
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
What is Di George Syndrome?
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
When are insertions and translocation not asymptomatic?
When rearrangement creates a new reading frame
When heavily methylated fragment is translocated
What is the Philadelphia Chromosome?
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
What is the robertsonian translocation?
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
What is an inversion?
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
What are the two inversions and what occurs?
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
What is a feature of balanced chromosomal aberrations?
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
What do Robertsonian translocations create?
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
What can clinical cytogenetic analysis do?
Detect chromosomal aberrations
What circumstances would indicate chromosomal aberrations?
Stillbirth/neonatal death
Fertility problems
Pregnancy with advanced maternal age
Sometimes cancer and family history
What is the inheritance of chromosomal aberrations?
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
What is a hallmark of cancer?
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)
