Meiosis and Common Chromosomal Anomalies Flashcards
Fertilization of a female oocyte (gamete) by male spermatocyte (gamete) reconstitutes the 46 chromosome number in the
Zygote (diploid, N = 23)
How are autosomes and sex chromosomes characterized?
- ) Size
- ) Centromere index
- ) Chromosome G-bright
What is the centromere index?
Length of p arm / total chromosome length
Low AT/GC ratio, rich in SINE repeats and Alu sequences, early replicating, contain “housekeeping genes”, not tissue specific, and rich in transcribed genes give
Bright G bands
Diploid cells replicate and divide into two identical diploid cells
Meiosis I
DNA cells replicate and the replicated homologous chromosomes establish connections (synapsis)
Prophase I
Homologous chromosome pairs are ordered in the middle of the cell
Metaphase I
There is chiasmata at the chromosome ends, and the homologous pairs migrate to opposite poles of the cell
Anaphase I
The formation of nuclei and two daughter cells
Interkinesis I
Separates sister chromatids and is made up of Prophase without DNA synthesis, metaphase, and anaphase, and results in 4 haploid cells
Meiosis II
When there is no separation of homologues between metaphase and anaphase
Non-disjunction Meiosis I
Non-disjunction in meiosis I will lead to
2 Disomic gametes and 2 monosomic gametes
When there is no separation of sister chromatids between metaphase and anaphase
Non-disjunction Meiosis II
Non-disjunction Meiosis II results in two normal gametes and
One disomic gamete and one nullisomic gamete
In Males, we see meiosis I followed by Meiosis II starting at puberty. Male meiosis allows for the development of
4 spermatids
In females, meiosis I begins early in intrauterine development and stops before
Birth “diplotene”
Only 20% of the 6-7 million original oogonia survive as primary oocytes that are arrested in
“Dictyotene” until puberty
With folliculogenesis, meiosis-I is completed with the extrusion of the 1st polar body at the time of
Ovulation
Completion of meiosis-II with the extrusion of the 2nd polar body occurs at
Fertilization
Female meiosis ends with
1 Mature oocyte and 2 lost polar bodies
Can be used to determine parental origin of chromosomes
Polymorphic CA-repeats
Polymorphic markers at the beginning of the p-arm or q-arm of the chromosome permits the differentiation of whether non-disjunction occurred in
Meiosis I or Meiosis II
Non-disjunction in meiosis I will be indicated by markers that are
Heterozygous close to the centromere
Non-disjunction in meiosis II will be indicated by markers that are
Homozygous close to the centromere
Chromosomal synapsis is driven by DNA homology resulting in a quadri-radial arrangement with 16 possible segregations of which only
2 are balanced (12%)
Leads to acentric/dicentric chromatids with duplications/deficiencies or genetic information
Recombination in inversion loop during meiosis I
All female are mosaic. A few patients with
non-random inactivation of the X chromosome
that carry an X-linked disorders or that are
Homozygous for the X-chromosome could
manifest
X-linked conditions
The random and clonal X-inactivation in females at blastocyst stage for gene dosage compensation with a male
Mary Lyon Hypothesis
Refers to the situation in which 2 copies of a chromosome come from the same parent, instead of 1 copy coming from the mother, and 1 copy coming from the father
Uniparental Disomy
Fertilization with hyperhaploid (disomic) gamete with
subsequent loss of the normally inherited chromosome from the other gamete (trisomy rescue) during mitosis causes 1-2% chromosomal mosaicism detected in
Placental samples
Determined by:
1) Degree of mosaicism
2) Genomic imprinting mechanisms in affected chromosomes
3) The non-Mendelian expression of monogenic disorders that map to that chromosome
4) by the combination of all these
factors?
Fetal phenotype
Changes in gene expression in response to the environment
Epigenetics
Reversible condensed chromatin conformation represses
Transcription
This regulatory mechanism of gene expression is also clinically relevant for placenta differentiation and function causing Intrauterine fetal growth restriction
Imprinting
Imprinting has been reported on chromosomes
7, 11 (Beckwith Wiedemann), 15 (Prader WIlli/ Angleman), and X (inactivation)
Allow for genetically unique newborns across generations with a 46 chromosome complement.
Sexual reproduction and Meiosis
The consequence of random distribution of homologous chromosomes (8,388,608 possible combinations) together with the formation of Chiasmata among
non-sister chromatids during Meiosis with DNA crossing over events
Genetic Diversity
A meiotic non-disjunction even leads to numerical chromosomal abnormalities in the
Zygote
What are two sexual differentiation and sex-chromosome anomalies resulting from non-disjunction events?
- ) Turner Syndrome (45, X)
2. ) Klinefelter Syndrome (47, XXY)
Affects 4% of all conceptus. Characterized by cystic hygroma, gonadal dysgenesis, and short stature
Turner Syndrome
Affects 1 in 1,000 males, tall, hypogonadism,
gynecomastia, social dysfunctions. Mental Retardation associated with increasing numbers of X chromosomes in males
Klinefelter syndrome
Affects 1 in 7,500 births with Heart/ CNS/ Renal
abnormalities, growth restriction, Micrognathia, Omphalocele, Equinovarus, Clenched hands
Edwards syndrome (47, XX, +18)
Affects 1 in 20,000 births with IUGR, CL/P, CNS, Renal,
Heart, Omphalocele, Equinovarus, Polydactyly
Patau Syndrome (47, XY, +13)
The most common genetic cause of mental retardation
Down Syndrome (47, XX, +21)
Overexpression and interactions of multiple genes from chromosome 21 cause
Down Syndrome (47, XX, +21)
A translocation resulting in an even exchange of genetic information with no genetic information extra or missing
Balanced translocation
In a newborn, almond-shaped eyes with up slanting palpebral fissures, epicanthal folds, small dysplastic
ears, depressed nasal bridge with mid face hypoplasia, strabismus, and brushfield spots suggests
Down syndrome
Brachycephaly, i.e. round head shape w/flattened occiput and excess nuchal skin, hypotonia,
atlantoaxial instability, joint laxity, shallow acetabular angle are also indicators of
Down Syndrome
Affects 1 in 15,000 liveborn with morbid obesity, short stature, hypogonadism, mental retardation, and hiyperphagia
-Due to a paternal deficiency (deletion) of the 15q11-13 and imprinting of the maternal chromosome
Prader-Willi Syndrome
The affected have severe mental retardation, absent speech jerky gait, protruding tongue, and inappropriate laughter
-Due to a maternal deficiency of the 15q11-13 loci (deletion) and imprinting of the paternal chromsome
Angleman Syndrome
No separation of sister chromatids; disjunction of homologues results in segregation of alleles
Meiosis I
There is no S phase in
Meiosis II
Nullisomic gametes yield
-Lethal except for X chromosome
Monosomic zygotes
Disomic gametes yield
-Lethal except for X, Y, and a few small autosomes (13, 18, 21)
Trisomic Zygotes
Create partial trisomy/monosomy syndromes
Balanced translocations
Imprinting will result in disease if the individual has
Uniparental Disomy (ex: Prader-Willi and Angleman syndromes)
Result from a uniparental disomy of chromosome 15
Prader-Willi and Angleman syndromes
Characterized by chromosomal synapse driven by DNA homology resulting in a quadrivalent arrangement with 16 possible segregations, of which only alternate segregation can lead to 2 balanced gametes (12%)
Balanced translocation
Phenotypically normal parents with pericentric inversion can have children with
deletions/duplications (5-10% risk)
Results in 4 chromosomes coming together in synapses in prophase I
Balanced translocation
All the cells in our body have 46 chromosomes, the purpose of meiosis is to create gametes that only have
23
In G-banding, the bright bands are the ones rich in
Genes
The most common mutations in humans
Chromosomal abnormalities
What percentage of 1st trimester spontaneous pregnancy losses have chromosomal abnormalities?
50%
If it occurs in the egg, nondisjunction is more common in
Meiosis I
If it occurs in the sperm, non-disjunction is more common in
Meiosis II
In females, meiosis-I begins early in intrauterine development and stops in the 4th stage of prophase I known as
Diplotene
Only 20% of the 6-7 million original oogonia survive as primary oocytes that are arrested in
Dictyotene (part of prophase I)
The polar body from meiosis I with 2 sister chromatids
1st Polar body
The polar body from meiosis II with 1 sister chromatid
2nd Polar body
When one cell line is normal and the other cell line is trisomic
Mosaic form
Phenotypically normal parents with pericentric inversions can have children with
Deletions/duplications
How many Barr bodies are there?
Barr bodies = # X-chromosomes - 1
A disorder that affects males because they do not have an extra X chromosome to compensate
Duchenne Muscular Distrophy
Duchenne muscular dystrophy should not appear in females unless there is a skewing of the
X inactivation centers
When 2 chromosomes are inherited from the same parent
-enables AR diseases to appear when only one parent is a carrier
Uniparental Disomy
3% of all down syndrome cases result from parents that have a
Balanced translocation
The robertsonian translocation 45, XX, der(21;21) has a recurrence risk of
100%
The rate of down syndrome identification after 20 weeks of gestation is
1 in 2000
How many americans have down syndrome?
400,000
Free fetal DNA in maternal circulation can also be used for
Aneuploidy screening
Integrates image of fetus with biochemical maternal age
Sequential Integrated Screening Test
Step 1 of the sequential integrated screening test occurs in trimester 1 and step 2 in trimester 2. How efficient is the test for detecting down syndrome?
98%
a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections. The fetal DNA is examined for genetic abnormalities.
-The most common reason to have this test is to determine whether a baby has certain genetic disorders or a chromosomal abnormality, such as Down syndrome.
Amniocentesis
A test made in early pregnancy to detect congenital abnormalities in the fetus.
-A tiny tissue sample is taken from the villi of the chorion, which forms the fetal part of the placenta.
Chorionic Villous Sampling
What is the frequency for chromosomal abnormalities for:
- ) Abnormal complement of sex chromosomes
- ) Autosomal trisomy
- ) Translocation (mostly balanced)
- ) Total
- ) 1/500
- ) 1/700
- ) 1/400
- ) 1/150
What is the procedure related risk for US-guided diagnostic amniocentesis?
1 in 300
A recombination of an inversion creates an
Acentric/dicentric chromosome
Balanced translocations create
Partial monosomy/trisomy syndromes
