Numerical Chromosome Abnormalities Flashcards
2 key differences between mitosis and meiosis::
- Paternally and maternally derived homologous chromosomes pair at the onset of meiosis (prophase I) whereas the two homologs segregate independently in mitosis
- Recipricol recombination events between maternal and paternal sister chromatids generate chiasmata (physical linkages) between homologs. In contrast, recombination between homologs is rare during mitosis
Bivalents
Structures formed when maternal and paternal homologs of each chromosome become paired (or synapse) along their entire lengths during prophase I of meiosis
Maternal and Paternal pairing during prophase I to form bivalents requires formation of wht proteinaceous structure?
synaptonemal complex
The synaptonemal complex forms during which phase of meiosis and what does it promote?
prophase I
inter-homolog interactions
Reciprocal recombination events during the formation of bivalent in prophase I results in physical links between homologs, these attachments or crossovers are also known as_______
chiasmata
How many crossovers, on average, occur on each chromosome during chiasma formation?
2-3
What is the consquence of corssingover during prophase I of meiosis
Genetic reassortment between chromosomes
When does the synaptonemal complex disassemble?
Then end of prophase I
What is the important consequence of synaptonemal complex disassembly at the end of prophase I?
The bivalents are now only held together by chiasmata
In which phase of meiosis are homologs separated to opposite poles?
first meiotic division (anaphase I)
What is the most common error in meiosis?
Chromosome nondisjunction in meiosis I
3 Genetic consequences of meiosis?
reduction of chromosome number from diploid to haploid
random segregation give 2^23 combos
random shuffling due to crossover, increases genetic variability even more`
How many rounds of chromosome segregation occur in meiosis vs. mitosis
one in mitosis - yields daughter cell identical is chromosomal content to parental cell
two in meiosis - yield 4 cells with half the chromosomal content to parental cell
DNA replication proceeds each round of chromosome segregation in mitosis, what about meiosis?
Nope! two rounds of chromosome segregation occur without an intervening round of DNA replication
Is there pairing of homologous chromosomes in mitosis?
No
Is there pairing of homologous chromosomes in meiosis?
Yes! requires pairing of homologous chromosomes and recombination for its successful completion
Does recombination occur in mitosis
infrequently
When do the centromeres on paired sister chromatids segregate in mitosis
EACH anaphase
When do centromeres on paired sister chromatids divide in meiosis
ONLY anaphase II
What cells undergo mitosis?
somatic cells and germ line precursor cells prior to entry into meiosis
What cells undergo meiosis?
only germ line
Metacentric chromosomes
the centromere is located in the middle
submetacentric chromosomes
centromere is slightly removed from the center
acrocentric choromosomes
centromere is near one end of the chromosome
Treating chromosomes with Giemsa and DAPI results in what?
Unique banding patterns due to regions high in G+C and A+T –> banding pattern is unique to each human chromosome and allows for unequivocal identification
ISCN
International System for Human Cytogenetic Nomenclature - determines chromosome naming
Short arms =
Long arms =
p
q
When do we visualize chromosomes?
metaphase
1-22 human chromosomes are arranged by?
size
p and q are the short and long arm respectively, how do we subdivide
regions 1–> outward
then Bands 1—> outward
so p11 would be petite arm region 1 band 1 – right next to centromere
On the acrocentric chromosome there are little secondary constriction balls that are highly polymorphic, what are these called and what are they comprised of?
Satellites :)
Repetitive satellite and ribosomal DNA
Note that not all specimens are created equally, what does this mean?
peripheral blood chromosomes are different looking than bone marrow than amniotic fluid
Ploidy
Number of homologous chromosome sets present in a cell or organism -
so humans are diploid (2n)
Diploid
having two sets of chromosomes
haploid
having one set of chromosomes (gamete cells)
euploidy
“good ploidy” - full set(s) of chromosomes (46)
polyploidy
“many ploidy” having a chromosome number that is more than double the basic or haploid number - 69, etc.
triploid - 3 set (69)
tetrapolid - 4 set (92)
Aneuploidy
“not good ploidy” - incomplete set
trisomy - 47
monosomy - 45
When can aneuploidy occur?
meiosis I (maternal/paternal)
meiosis II (maternal/paternal)
post-zygotic
aneuploidy occuring in meiosis I
Discovery?
sponatneous abortions
Meiosis II aneuploidy discovery?
Stillbirths
Post-zygotic aneuploidy discovery?
Newborns
When does the synaptonemal complex form?
When we enter meiosis I
Nomenclature for numerical abnormalities
triploidy?
69,XXX
69,XXY
69,XYY
Nomenclature for numerical abnormalities?
trisomy
47,XX,+21
Nomenclature for numerical abnormalities?
Monosomy
45,X
Nomenclature for chromosomal abnormalities?
Mosaicism
45,X/46,XX
Aneuploidy (cells contain abnormal chromosome #) frequently results from
nondisjunction - the missegregation of chromosomes at metaphase in either mitosis or meiosis, such that daughter cells receive extra or fewer than the normal number of chromosomes
Monosomy
cell lacks one copy of a chromosome
trisomy
extra copy of chromosome
autosomal monosomies? viable?
no - result in early embryonic lethality
x monosomy?
Yes - 45,X = Turner syndrome
Autosomal trisomies? viable?
More so than monosomies, most trisomies are compatible with at least some fetal development, but often result in spontaneous abortion
What is the predominate cause of most trisomies?
maternal errors in the first meiotic division - increasing proximity to menopause is thought to increase risk
What is the most common human chromosomal disorder ascertained in liveborn infants?
Trisomy 21 (1/800)
More than 95% of trisomy 21 cases are due to ?
additional chromosome 21 of maternal origin
of the additional chromosome 21 from maternal origin, which nondisjunction event is responsible for the vast majority?
maternal meiosis I
What is essential for tethering homologous chromosomes during the first meiotic division?
meiotic recombination events (Crossovers)
Nondisjunction events can be related to (2)
- positioning of the chiasmata
2. frequency of crossover events
In what way is nondisjunction related to the positioning of chiasmata?
crossover events that occur too near or far from the centromere increase the odds of nondisjunction -
distal exchanges are less effective in ensuring spindle attachment
proximal exchanges can entangle paired homologs - that then undergo reduction division leading to what appears to be MII errors
In what way is nondisjunction related to the frequency of crossover?
reduction of crossover (Recombination) increases the likelihood of nondisjunction
How many cross over events normally take place / pair of homologous chromosomes?
2-3
cross-over event generates what?
chiasma - physical link between homologues which is critical for normal disjunction
in addition to being important for segregation, recombination is also important for
genetic diversity
2 key causes of genetic variability arising from meiosis
independent assortment of maternal and paternal chromosomes
recombination during prophase I
Consequence of nondisjunction in meiosis I
4 gametes what do they have?
N+1 (2) N+1 (2) N-1 (0) N-1 (0) Thus, 100% abnormal...The N+! have one maternal and one paternal from normal meiosis II following nondisjunction in meiosis I
Consequence of nondisjunction in meiosis II
N
N
N+1
N-1
If we have normal meiosis I then maternal and paternal will separate appropriately
Then if one of the second rounds (meiosis II) undergoes nondisjunction we will have one with double maternal (or paternal) and one with none
The other cell should have undergone normal to give rise to one each of normal maternal (or paternal)
*see slide 18
Incidence of aneuploidy (varies depending on age)
spontaneous abortions?
stillbirth?
newborns?
Spontaneous abortions -50-60%
stillbirth - 4-6%
newborns 0.6%
When does aneuploidy primarily take place?
first trimester?
Tolerated aneuploidies
Conceptions
many 45,x, trisomy16 trisomy21 trisomy22
Tolerated anueploidies
Live Births
trisomy 13, 18, or 21
Sex chromosome anueploidy
- gains of x and y
- loss of sex chromosome, e.g, monosomy x
Maternal age effect - on aneuploidy?
Two hit theory
- Diminished recombination
2. Diminished ability to complete segregation if unfavorable recombination
Maternal age effect - cohesin theory?
Postulates the degradation of cohesin complex over span of extended meiosis I arrest results in precocious homolog separation
What kind of cells must cytogenetic studies use?
Viable - because we need them to be in the mitotic phase of the cell cycle
What would the ISCN be for trisomy 21?
47,XY,+21
47,XX,+21
Down Syndrome - Trisomy 21 Clinical features
Characteristic facies Short Stature Hypotonia Hearing loss Moderate intellectual impairment Early alzheimers Leukemia in perinatal period
What would the ISCN be for a Down’s child who acquired luekemia and peripheral blood cell contained extra acquired X
48,XX+X,+21c
c is for constitutional, to distinguish it from the acquired leukemic extra X
Extra acquire X is a common finding in what
Leukemia
What is the most common chromosomal abrnomality in live born? How common?
Trisomy 21
1/800 - 1/900
What is the most common genetic cause of moderate intellectual disability
Trisomy 21
-4% of Trisomy 21 is associated with what?
balanced translocation in parent
What causes the majority of trisomy 21
maternal meiosis I nondisjunction errors
What percent of Trisomy 21 Conceptus survive to birth?
20-25%
Risk of Trisomy 21 Age 30 35 40
30 -1%
35 -2.8%
40 - 10.4%
Cause of maternal risk for trisomy with age?
Due to meiosis I suspension from pre-birth until sexual maturity
Trisomy 18 - Edwards syndrome
Clinical features
Small for gestational age Microcephaly Clenched fingers Rocker bottom feet Heart/brain abnormalities
Trisomy 18 - frequency
1/8000 live births
Trisomy 18 - perinatal lethality?
90%
Turner syndrome ISCN?
45,X
Most common chromosome abnormality in spontaneous abortions?
Turner Syndrome 45,X
What percent of Turner Syndrome fetuses survive to term?
1%
Thus 99% do not
Turner syndrome incidence
1/2,500 female live births
Turner syndrome clinical presentation
prenatal lymphedema Cystic hygroma (large cyst-like cavity containing lymph) Congenital heart disease Coarctation of the aorta Gonadal dysgenesis Short stature* Webbed neck*
Most classic phenotype of Turner
Webbed neck and short stature
Possible Turner syndrome karyotypes…
Don't need to know them all 45,X (50%) 46,X,i(Xq) mos45X,46XX mos45,X/46X,i(Xq) Other
The take home point is that only 50% are seen in peripheral blood as pure 45X
25% have known mosaic in the peripheral blood
What is hypothesized about the mosaicism seen in 25% of Turner peripheral blood?
Contributes to survival
Turner Syndrome variants should remind you to consider what?
To always consider mosaicism including tissue specific mosaicism
Which Turner variants have a more severe phenotype?
The 46X tiny ring (X)
Trisomy 13 =
Platau syndrome
Trisomy 13 (Platau) clinical features
characteristic facies severe intellectual deficits congenital malformations holoprosencephaly (failure to cerebrum to divide) facial clefts polydactyly renal anomalies
47, XXY =
Klinefelter Syndrome
Is Klinefelter Syndrome common?
Yes, 1/1000 liveborn males
Is Klinefelter lethal in utero?
no
Klinefelter phenotype
Tall
Hypogonadism
Underdevelopment 2nd sex
Learning disability and poor psychosocial development
Klinefelter parent of origin?
50% paternal meiosis I error
50% maternal meiotic errors (75% in Meiosis I)
Klinefelter mosaicism
Most common?
47,XXY/46,XY
Thought to be from postzygotic loss of one copy of the X chromosome
(15%)
Some have normal testicular development
Variants of Klinefelter?
48, XXYY
48, XXXY
49, XXXX7 etc
Significance of additional X variants in Klinefelter?
increasingly more severe phenotype and retardation
Mechanism of tetraploidy (3)
2 sperm (n) fertilize (n) egg
n sperm fertilize 2n egg
2n sperm fertilize n egg
tetraploidy mechanism?
Dna duplication but no cell division (endomitosis)
Triploid = 3n
How often do we see?
Survive to birth?
Most common cause
1-3% karyotypes
may survive to birth but not long after
most due to two sperm fertilizing one egg
How many chromosomes in triploid?
69, XXX
69, XXY
What is mosaicism?
Two or more different karyotypes from the same individual
What is the most common cause of mosaicism?
Nondisjunction early in embyronic develoment
Germ line mosaicism, result of?
nondisjuction in germ cell precursor
pseudomosaicism
occurs in lab / not patient
Broadly: polyploidy
Extra copies of all chromosomes e.g. 3n or 4n
Broadly: aneuploidy
loss or gain of certain chromosomes e.g. 21 or 45x
Broadly: mosaicism
A zygote containing two cell lines which differ in chromosome number
Chromosomal abnormalities make up __% spontaneous 1st trimester abortions
50
Chromosomal abnormalities make up ___% live born infants with congenital abnormalities
3
What % of sperm are abnormal?
1-3%
What percent of ova are abnormal?
> 3% with increasing abnormality with age
