MT6315 CHROMOSOMAL ALTERATIONS Flashcards
Chromosomal mutations are commonly known as?
chromosomal aberrations
Chromosomal mutations are variations from?
Wild type phenotype in chromosome structure or number
How do chromosomal mutations arise?
Spontaneously or induced by chemical or radiation mutagens.
Abnormal chromosomal number refers to?
Aneuploidy
Chromosomal alteration refers to?
Structural abnormality
Chromosomal abnormalities are influenced by?
Genomic imprinting
Mitochondrial inheritance
Expansion of trinucleotide repeats
Types of Chromosomal mutations based on Variation in Chromosome Structure
- Deletion
- Duplication
- Inversion
- Translocation
Types of Chromosomal mutations based on Variation in Chromosome Number
- Aneuploidy (Monosomics/Trisomics/Nullisomics/Tetrasomics)
- Polyploidy
3 broad categories of chromosome mutations?
Chromosome rearrangements
Aneuploidy
Polyploidy
one or more individual chromosome pair has its number altered
Aneuploidy
overall chromosome number is unaffected, but large pieces are moved
Chromosome rearrangement
one or more complete chromosome sets are added
Polyploidy
Chromosomal aberrations are most often caused by?
errors during cell division.
Aneuploidy may result in errors occurring in?
meiosis.
Most common aneuploidy error is?
nondisjunction, when a set of chromosomes do not properly separate, which leaves one or two sex cells with an extra chromosome or with one less chromosome.
chromosomes has failed to separate or segregate at
anaphase so that both chromosomes of the pair pass
to the same daughter cell.
Nondisjunction
Nondisjunction is common in?
commonly in meiosis, but it may occur in mitosis to produce a mosaic individual.
When is nondisjunction common in mitosis?
to produce a mosaic individual.
Structural chromosomal aberrations can result in?
Aneuploidy
Kinds of Structural chromosomal aberrations?
Deletion
Inversion
Duplication
Translocation
Chromosomal disorders are sometimes caused by?
Mosaicism
What is mosaicism?
Two or more different cell lines in one person.
Can occur after nondisjunction in meiosis during early embryonic development.
This results in one line of cells with a chromosomal aberration while other lines may stay unchanged.
Mutation that results in the doubling of a segment of a chromosome.
Duplication
Forms of duplication?
Tandem duplication
Reverse duplication
Terminal tandem duplication
Misplaced Duplication
The International System for Human Cytogenomic Nomenclature (ISCN) for duplication?
dup
dup(17p12)
Charcot–Marie–Tooth disease type 1A.
What type of duplication: one right after the other
Tandem
What type of duplication: duplicated region is inverted
Reverse duplication
T or F: Individuals can ONLY be homozygous for duplication
F, both hetero and homo
In heterozygous individuals for duplication, when do problems arise?
Prophase I of meiosis and synapsis
What does the duplicated chromosome need to do in order to let the synapsis occur?
Loop out
Duplications have an effect on an individual’s ____, due to ______.
Phenotype
Unbalanced Gene Dosage
Good side of duplication?
Contributed to evolution through new genes being “born” with novel functions
What is an example of evolution through duplication?
Fetal hemoglobin which allowed for in utero reproduction
loss of a segment of a chromosome.
Deletion
Where does deletion start?
breaks of chromosomes
What causes breaks of chromosomes?
agents (such as heat, ionizing radiation, viruses, transposable elements) or by errors in recombination.
What is pseudo dominance?
Dominant ‘A’ allele is deleted, causing the expression of the recessive ‘a’ allele
Types of deletions?
Terminal deletion
Intercalary/interstitial deletion
Microdeletion
a deletion that occurs from the interior of a chromosome.
Intercalary/interstitial deletion
a deletion that occurs towards the end of a chromosome.
Terminal deletion
a relatively small amount of deletion usually found in children with physical abnormalities
Microdeletion
Sizes of micro deletions?
up to 5Mb mutations that could include a dozen genes
Where is micro deletion usually found?
in children with physical abnormalities. A large amount of deletion would result in immediate abortion (miscarriage)
If a deletion is large enough it can be detected where?
Karyotype
T or F: Deletions also have looping out in Prophase I to allow for the alignment of synapse
T
The effect of deletion depends on?
The genetic information deleted (some are lethal, some are asymptomatic)
If the deleted chromosome includes the centromere, the chromosome (will/will not) segregate during mitosis or meiosis.
will NOT, will be lost during cell division
When are deletions detrimental to an individual?
when HOMOZYGOUS due to the complete absence of that genetic information
What happens in a heterozygous individuals for deletion?
Gene imbalance
T or F: Recessive alleles appear more readily in deletions
T because there are no other alleles to mask
Human syndromes related to deletion are (common/rare).
Rare
The International System for Human Cytogenomic Nomenclature (ISCN) for deletion?
Abbreviations include a minus sign (-) for chromosome deletions, and del for deletions of parts of a chromosome.
Deletion of a number of pairs that is not evenly divisible by three will lead to?
frameshift mutation
Frameshift mutation causes?
Causing all of the codons occurring after the deletion to be read incorrectly during translation, producing a severely altered and potentially nonfunctional protein.
deletion that is evenly divisible by three is called?
in-frame deletion.
Deletions are responsible for an array of genetic disorders, including?
some cases of male infertility, 2/3 of cases of Duchenne muscular dystrophy, and 2/3 of cases of cystic fibrosis (those caused by ΔF508).
Deletions in the SMN-encoding gene cause?
spinal muscular atrophy, the most common genetic cause of infant death.
Microdeletions are associated with many different conditions, including?
Angelman Syndrome, Prader-Willi Syndrome, and DiGeorge Syndrome
Some syndromes are associated with both microdeletions and genomic imprinting such as?
Angelman syndrome and Prader-Willi syndrome
What is genomic imprinting?
Same microdeletion can cause two different syndromes depending on which parent the deletion came from.
5p-
Cri du chat syndrome
11q-
Wilms tumor
13q-
Retinoblastoma
15q-
Prader-Willi syndrome
Cancer of the eye, increased risk of other cancers
Retinoblastoma
Infants: weak slow growth; children and adults: obesity, compulsive eating
Prader-Willi syndrome
Infants have catlike cry, some facial anomalies, severe mental retardation
Cri du chat syndrome
This condition occurs in every 1 out of 100,000 births.
Mentally retarded, with defects on facial development, gastrointestinal malformations, and abnormal throat structures.
Cri du chat syndrome
del15q11 or q13
Prader-Willi Syndrome
Often smile and laugh frequently, and have happy, excitable personalities.
Developmental delays, which begin between about 6 and 12 months of age, are usually the first signs.
Seizures may begin between the ages of 2 and 3 years old.
Angelman Syndrome
The ____ gene is located on the segment of chromosome 15 that is often deleted in people with Angelman syndrome.
OCA2
Results when a segment of a chromosome is excised and then reintegrated in an orientation 180 degrees from the original orientation.
Inversion
Forms of Inversion?
Pericentric Inversion
Paracenric Inversion
The International System for Human Cytogenomic Nomenclature (ISCN) for inversion?
inv
Type of inversion: does not include the centromere
Paracentric
Type of inversion: includes the centromere
Pericentric
T or F: Inversions played a role in human evolution
T
Karyotypic differences between humans and chimpanzees include how many pericentric inversions?
9
What is a prerequisite for any assessment of the genetic consequences of these inversions?
Detailed analysis of the respective chromosomal breakpoints
The breakpoints of the inversion that distinguishes human chromosome 4 (HSA4) from its chimpanzee counterpart were identified by?
FISH
Comparative sequence analysis
These breakpoints, at _____ and ____, do not disrupt the protein coding region of a gene, although they occur in regions with an abundance of ____ and ____ elements
HSA4p14 and 4q21.3
LINE and LTR-elements.
When is a gene rendered inactive in inversion?
If an inversion breaks a gene in half and that half moves to another part of the chromosome
How are genes regulated on the chromosome?
by their position
Changing a gene’s position will lead to?
Changes in regulation
Position effect
In inversion, do genes require looping?
Yes
Intense looping in inversion causes?
Chromosomal damage and loss
change in position of chromosome segments and the gene sequences they contain
Translocation
Is there a presence of gains or losses in genetic material for translocation?
No
Kinds of Translocation?
Intrachromosomal
Interchromosomal
change in position of a chromosome segment within the same chromosome.*
Intrachromosomal
Transfer of chromosome segment from one chromosome to a non homologous chromosome
Interchromosomal
T or F: Translocation is usually homologous
F; non homologous
broken piece attached to one end of chromosomes
Simple Translocation
broken segment inserted interstitially in a chromosome
Shift Translocation Translocation
Homozygotic & Heterozygotic translocation
Reciprocal
ISCN for translocation?
t(A;B)(p1;q2)
T or F: Crossing over and translocation are the same
F; crossing over is homologous translocation is non homologous
Effects of translocation?
Emergence of new genetic linkages
Result in position effects
Accompany deletions (Robertsonian deletions - common cause of Down syndrome)
Types of Interchromosomal translocation
Reciprocal
Non-Reciprocal (can also be intrachromosomal)
short arms and/or the long arms of the same chromosome join at the centromere
Isochromosomes / Isochromes
What kind of image is produced by isochromes?
mirror image appearance of banding patterns extending in both directions from centromere
special cases of joining at centromeres
Robertsonian Translocation
Robertsonian Translocation is common in what kind of chromosomes?
occur between chromosomes that have tiny short arms (acrocentrics)
Why is there no obvious loss in genetic information in Robertsonian translocation?
because the short arms contain repeated rRNA genes
What are the Human Tumors associated with Translocation?
CHRONIC MYELOGENOUS LEUKEMIA
BURKITT’S LYMPHOMA
In CML, leukemic cells have what type of chromosome?
Philadelphia chromosome
In CML, there is a transition of?
c-abl within the bcr
CML results in the?
It results to uncontrolled replication of myeloblasts.
Virus-induced tumor; malignant B cells secrete antibodies
Burkett’s Lymphoma
Burkett’s Lymphoma is a translocation between?
Chromosome 14 and 8
Burkett’s Lymphoma activates?
c-myc
Organism or cell has one or exact multiple of complete set(s) of chromosomes
EUPLOIDY
Chromosome mutations may occur which results in variations of?
the number of individual chromosomes or in variation in complete sets of chromosomes.
One or several chromosomes are lost from or added to the normal set of chromosomes.
ANEUPLOIDY
ANEUPLOIDY is a result of?
Nondisjunction
Loss or gain of single chromosome
Aneuploidy
When can aneuploidies happen?
when a chromosome is lost during mitosis and meiosis due to loss of a centromere
when translocation causes the shrinking of the chromosome reddening it informationless
nondisjunction when cohesion fails to degrade during mitosis or meiosis
4 types of aneuploidy?
- Nullisomy
- Monosomy
- Trisomy
- Tetrasomy
loss of one homologous pair; 2N-2
Nullisomy
involves a single extra chromosome; 2N+1
Trisomy
involves a loss of a single chromosome; 2N-1
Monosomy
involves an extra chromosome pair; 2N+2
Tetrasomy
T or F: AN individual can only harbor one aneuploidy
F; you can have multiple but still have the same number of chromosomes but not normal/healthy
T or F: There is a possibility of double trisomic individual
T
Why are aneuploidies lethal in most species?
Because of changes in dosage of multiple genes
Why is the X chromosome an exception of overdosage?
trisomy of X is well tolerated in females because of random inactivation (Barr bodies)
Miscarried babies are due to?
Chromosomal mutations (aneuploidies)
Why are most autosomal aneuploids spontaneously aborted?
Smaller chromosomes have fewer genes and less dosage problems, which tolerate aneuploidies better (causing trisomy 21)
three copies of chromosome 21
Down Syndrome: Trisomy-21
Down Syndrome used to be called?
mongolism
Three copies of chromosome 13
Patau Syndrome
cleft lip and palate; small eyes; polydactyly (extra fingers and toes); mental and developmental retardation; severe malformations of the brain and nervous system.
Patau Syndrome
have multiple congenital malformations affecting almost every organ system; clenched fists; elongated skull; low-set malformed ears; mental and developmental retardation.
Edward Syndrome
Trisomy 18
Edward Syndrome
What is the leading risk factor for Autosomal Trisomy?
Maternal age
Why is maternal age a risk factor for autosomal trisomy?
- The integrity of primary oocytes decreases as the woman age.
- Maternal selection becomes less effective.
T or F: Meiotic problems arise as female age rises.
T
Monosomy for the X chromosome
Turner Syndrome: (45, X)
T or F: Complete absence of X chromosome in the absence or presence of Y chromosome is always lethal.
T
Other forms are (48, XXYY), (48, XXXY) and (49, XXXXY)
Klinefelter Syndrome: (47,XXY)
Phenotypic features do not develop until puberty.
Klinefelter Syndrome: (47,XXY)
Phenotypic features – short and wide-chested; extra folds of skin on the neck, underdeveloped breasts and rudimentary ovaries, absence of Barr body, color blindness, narrowing of aorta
Turner Syndrome: (45, X)
Phenotypic features – above average height, suffered personality disorders, below normal intelligence
XYY Syndrome: (47, XYY)
Phenotypic features – poor sexual development; very
low fertility; with breast development
Klinefelter Syndrome: (47,XXY)
Early studies associate violent criminal behavior with the presence of extra Y chromosome.
XYY Syndrome: (47, XYY)
X or Y chromosome is essential for survival?
X
“getting 2 chromosomes from one parent”
UNIPARENTAL DISOMY
Abnormalities in the number of haploid chromosomal sets can arise in several ways which are?
- Errors in meiosis during gamete formation
- Events in fertilization
- Errors in mitosis following fertilization
variations from the normal state in the number of complete sets of chromosomes.
Polyploidy
when an entire set of chromosomes fail to separate during mitosis or meiosis
Polyploidy
Polyploidy is common in?
Plants for plant speciation
when all sets of chromosomes are from a single specie
Autopolyploidy
when polyploidy represents a hybridization between species
Allopolyploidy
Most allopolyploids are _____ in sense that they cannot ____ but since plants are often ____ they perpetuate themselves
sterile
cross-fertilize
self-fertilize
most common form of polyploidy
Triploidy
Forms of triploidy
(69,XXY), (69,XXX) and (69,XYY).
Regions with high transcriptional activity are loosely packed
Acetylation
Regions with low or no transcriptional activity are densely packed
Methylation
Chromosomal mutations: single or multiple genes are affected?
Single
T or F: Chromosomal mutation is due to errors in crossing over
F; errors in DNA replication and mutagens
Unbalanced set of chromosomes
Phenomenon when the relative gene dosage is upset
Aneuploidy
Chromosome with identical arms
Isochromosome
How do ring chromosomes form?
Due to deletions in the telomeres which cause ends to adhere
T or F: Duplications are deleterious
F; they are NOT deleterious
If inversions do not change the genetic content, what DO they change?
linear sequence of the genetic information
In an inversion heterozygote, chromosomes twist into?
a loop where the order is inverted
Paracentric crossing over results in?
one Acentric and one dicentric chromosomes
Pericentric crossing over results in?
duplications and deletions of genetic information
Why do Acentric chromatids fail to move to either pole?
Because they don’t have a centromere
In translocation in homozygotes, is there any cytological peculiarities?
No
In translocation of heterozygotes, where do breaks occur?
In one of the chromosomes of a homologous pair
Basic chromosome set from which all the other genomes are formed from is called?
Monoploid set
Set of chromosomes present in a gamete, irrespective of the chromosome number in the species
Haploid set
Polyploids can arise from?
genome duplications occurring before or after fertilization
Formation of unreduced gametes that have double the normal complement of chromosomes or the abortive mitotic division
Endoreduplication
What indicates the chromosome number, sex chromosome structure, and the nature of the specific chromosomal abnormality?
Chromosomal shorthand
Male with a translocation between the short arm of chromosome 7 at band 21.1 and the long arm of chromosome 9 at band 34.1
46, XY t(7;9)(p21.1;q34.1)
Triplo-X Syndrome
47, XXX
Detects trisomies, monosomies and micro deletions
FISH
Detects copy number variations of genetic material
CGH
Illnesses that are exceptions to the lethality of spontaneous mutations?
Trisomy 21, 18, 13 and extra X or Y chromosomes (little/mild effect)
Examples of Aneuploidy illnesses?
Klinefelter, Turner, Down syndrome
Nondisjunction means that a pair of chromosomes has failed to separate or segregate at what stage of meiosis (or mitosis)?
Anaphase
A deleted segment of a chromosome may be located where?
Anywhere along the chromosome
A large amount of deletion would result in?
immediate abortion (miscarriage)
Prader-Willi syndrome is associated with maternal or paternal deletion?
Paternal
Is Angelman Syndrome associated with maternal or paternal deletion?
Maternal
For inversions to take place, the DNA must?
Have double stranded breaks (break in two places)
Chromosome inversions between humans and chimpanzees concerned what chromosomes? And what kind of inversion?
Human chromosome 4 and chimpanzee chromosome 4
Pericentric
More common type of translocation?
Interchromosomal
Type of translocation where DNA only moved in one direction?
Nonreciprocal
Type of translocation where DNA exchanged in both directions?
Reciprocal
What causes Burkitt’s lymphoma?
Epstein Barr Virus (EBV)
Most human aneuploid are found in which chromosomes?
X or Y
Having more than two sets of chromosomes
Polyploidy
Lifespan of triploidies?
Limited, most die within a month
Origin of tetraploidy?
DNA duplication but no cell division (endomitosis)
What causes nucleosomes to pack tightly together?
Methylation of DNA and histones
Does methylation of DNA and histones express the genes?
No
Results in loose packing of the nucleosomes, where genes are expressed
Acetylation of histones
High transcriptional activity and loosely packed
Acetylation
Low or no transcriptional activity and densely packed
Methylation
Chromosome that forms this shape due to deletion in telomeres which cause ends to adhere
Ring chromosomes
Are duplications deleterious?
No
Example of a useful duplication in the evolution of new genetic material?
Position effect in Drosophila
What do inversions alter in the genetic content?
Linear sequence of genetic information
In an inversion heterozygote, the chromosomes _______ which inverts the gene
Twist into a loop
Crossing over produces one acentric and one dicentric chromosome
Paracentric
Crossing over results in duplications and deletions of genetic information
Pericentric
The acentric chromosomes fault to move to either pole during paracentric inversion due to?
Lack of centromere
Basic chromosome set is called?
Monoploid
Set of chromosomes present in a gamete, irrespective of the chromosome number in the species
Haploid
Can arise from genome duplications occurring before or after fertilization
Polyploids
Abortive duplication that leads to the formation of unreduced gametes that have double normal complement of chromosomes
Endoreduplication
t(9;22)(q34;q11)
CML
inv(14)(q13q24)
Microcephaly
48, XXXX
X tetrasomy
47, XX +21
Down syndrome
46, XX, upd(15) mat
Prader-Willi syndrome
i, iso
Isochromosome
Abbreviation t
translocation
der
derivative chromosome
Indicates chromosome number, sex chromosome constitution, and nature of the specific abnormality
Chromosomal shorthand
47, XY +13
Male with Patau
Female with Edwards Syndrome
47, XX +18
Male with translocation between the short arm of the chromosome 7 at band 21.1 and long arm of chromosome 9 at band 34.1
46 XY t(7;9)(p21.1;q34.1)
