MBG: BLOCK 2: TOPIC 3: MITOSIS AND ERRORS IN CHROMOSOME SEGREGATION

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Questions and Answers

What is the primary consequence of mitotic nondisjunction?

Reduction in chromosome number

Increase in genetic diversity

Improved cellular function

Formation of mosaic organisms (correct)

Which type of chromosomal abnormality is characterized by the presence of an extra chromosome?

Aneuploidy (correct)

Monosomy

Mosaicism

Chimerism

In which trisomy syndrome is the individual most likely to have a risk of congenital heart defects and developmental delays?

Trisomy 18

Klinefelter syndrome

Trisomy 13

Trisomy 21 (correct)

What does the term 'uniparental disomy' refer to?

Both chromosomes of a pair are inherited from one parent Signup and view all the answers

Which of the following conditions is specifically linked to Turner syndrome?

Monosomy of the X chromosome Signup and view all the answers

What is a key difference between mitotic nondisjunction and meiotic nondisjunction?

Mitotic errors often affect specific tissues, while meiotic errors affect the entire organism. Signup and view all the answers

Which aneuploidy is most likely to result in spontaneous pregnancy loss?

Trisomy 16 Signup and view all the answers

What is the primary correlation found in studies regarding maternal age and aneuploidy?

Higher maternal age increases the risk of chromosomal nondisjunction. Signup and view all the answers

What defines chimerism in an individual?

Cells from two separate fertilized eggs. Signup and view all the answers

What is a characteristic of aneuploidy related to chromosome gene content?

Aneuploidies involving genes rich in structural functions are more severe. Signup and view all the answers

Which mechanism is primarily responsible for uniparental disomy?

Nondisjunction during cell division. Signup and view all the answers

What is the result of segmental uniparental disomy?

Mosaic expression affecting specific tissues. Signup and view all the answers

How do trisomies primarily differ from monosomies in terms of viability?

Trisomies can be more viable than monosomies due to the presence of additional genetic material. Signup and view all the answers

How can trisomic rescue contribute to the development of uniparental disomy?

By allowing one chromosome to be lost after fertilization. Signup and view all the answers

Which process is most responsible for the occurrence of chromosomal aneuploidies?

Inappropriate chromosome segregation Signup and view all the answers

What is the outcome associated with nondisjunction during maternal meiosis I?

It accounts for a majority of chromosomal aneuploidies. Signup and view all the answers

Which condition can uniparental disomy have significant implications for?

Differentially methylated regions. Signup and view all the answers

Which statement best describes Turner syndrome?

It is a sex chromosome monosomy that can result in adult viability. Signup and view all the answers

What is isodisomy?

Identical copies of a chromosome from one parent. Signup and view all the answers

Which of the following conditions is associated with uniparental disomy?

Beckwith-Wiedemann syndrome. Signup and view all the answers

Which type of mosaicism involves two lines of opposite imbalance?

Structural rearrangement mosaicism Signup and view all the answers

What might explain the presence of gonadal mosaicism in all women regarding chromosome 21?

It suggests a common mechanism of chromosome 21 aneuploidies. Signup and view all the answers

What primarily causes the absence of phenotypic consequences in most cases of uniparental disomy?

Equal expression of parental genes. Signup and view all the answers

What kind of mosaicism can lead to hermaphroditism in an individual?

Post-zygotic fusion chimerism. Signup and view all the answers

What does early mitotic error typically lead to regarding cell lines?

It results in a broader phenotypic impact. Signup and view all the answers

What does the production line hypothesis explain concerning oocytes?

Oocytes mature in the same order as fetal development. Signup and view all the answers

Which chromosomal abnormality is commonly observed in trisomy syndromes?

Three copies of a particular chromosome. Signup and view all the answers

What role does cohesin play in meiosis I nondisjunction?

Premature breakdown of cohesin can lead to nondisjunction. Signup and view all the answers

What is the chromosomal configuration in Turner syndrome?

45,X. Signup and view all the answers

Which risk factor is associated with increased chances of nondisjunction resulting in uniparental disomy?

Parental age, specifically maternal age. Signup and view all the answers

What is the most common example of aneuploidy observed in humans?

Trisomy 21. Signup and view all the answers

Study Notes

Mosaicism vs. Chimerism

Different cell types in a chimera are derived from two separate zygotes
Chimerism is a result of a post-zygotic fusion of dizygotic twin zygotes
Confined chimerism only involves specific tissues containing two different cell lines
Mosaicism originates from mitotic errors, whereas chimerism involves cellular fusion
Mosaicism explains the presence of two cell lines in a single individual without apparent errors
This can explain cases like 46,XY/46,XX hermaphroditism or a 45,X/69,XXY fetus

Uniparental Disomy (UPD)

UPD is the inheritance of two copies of a chromosome from a single parent
Despite the presence of two chromosome copies, the individual can still have developmental issues
Isodisomy occurs when both chromosomes are identical, while heterodisomy involves different chromosomes
UPD can result in homozygosity for autosomal recessive genes, leading to disease manifestation
UPD is often asymptomatic, but can have significant implications in differentially methylated regions
UPD is linked to conditions like Beckwith-Wiedemann syndrome, Prader-Willi syndrome, and Angelman syndrome

UPD Mechanisms: Whole Chromosomes

UPD arises from two separate abnormal events, usually caused by nondisjunction
Nondisjunction, a failure of chromosomes to separate properly during cell division, is a key factor in UPD development
The primary event is typically sporadic, with no increased risk of recurrence, unless parental chromosomes are affected
Advanced maternal age is a known risk factor for nondisjunction
UPD can occur through different mechanisms:
- Trisomic Rescue: A trisomic conceptus undergoes chromosome loss to become disomic.
- Monosomic Rescue: A monosomic conceptus duplicates the remaining chromosome to become disomic.
- Mitotic Error and Rescue: A trisomic embryo undergoes a mitotic error, losing one chromosome, resulting in a disomic conceptus.

Segmental UPD

Only a portion of the chromosome, instead of the whole chromosome, experiences UPD
Segmental UPD is often observed in chromosomes subject to imprinting, potentially impacting specific tissues and exhibiting mosaicism
Segmental UPD can develop due to:
- Postzygotic somatic recombination between maternal and paternal homologs
- Nondisjunction creating a disomic gamete, leading to trisomic conception, followed by crossing-over and chromosome loss
- Repair of double-strand breaks via break-induced replication

Aneuploidies: Introduction

Aneuploidy refers to an abnormal number of chromosomes, whereas euploidy denotes balanced chromosomal content
The severity of autosomal aneuploidies corresponds to the gene content of the affected chromosome, not its size
Severe phenotypes are associated with chromosomes rich in genes, particularly structural genes
Autosomal aneuploidies involving chromosomes with significant genetic content are often lethal before birth or even implantation

Trisomy and Monosomy

Trisomy involves three copies of a chromosome, while monosomy involves only one copy
All autosomal trisomies have been reported in spontaneous miscarriages, but the frequency varies
Trisomy 16 accounts for ~30% of spontaneous miscarriages
In live births, only trisomies 13, 18, and 21 are commonly observed, with other trisomies being rare and primarily found in mosaics
Monosomies are exceptionally rare in both miscarriages and live births, likely due to lethality before detection

Mechanisms of Aneuploidy: Nondisjunction

Nondisjunction, the failure of chromosomes to separate correctly during cell division, is the most common cause of aneuploidy
Nondisjunction primarily occurs in maternal meiosis I, accounting for the majority of cases, with exceptions for chromosomes 7, 13, and 18
Advanced maternal age is directly correlated with an increased risk of nondisjunction
Meiosis I nondisjunction can occur through:
- Both homologous chromosomes migrating to the same pole
- Premature separation of one homologous chromosome

Maternal Age and Nondisjunction

The "Production Line Hypothesis" suggests that oocytes mature in the same order as fetal development
The "Limited Oocyte Pool Model" implies that the number of follicles decreases with age, increasing the chance of selecting lower-quality oocytes
Despite extensive research, our comprehension of nondisjunction's processes and causes remains incomplete

Mitotic Nondisjunction

During mitosis, sister chromatids should separate evenly, ensuring each daughter cell receives an equal amount of genetic material.
Mitotic nondisjunction occurs when the chromatids fail to split properly, leading to unequal distribution.
Several outcomes are possible, including:
- One daughter cell receiving an extra chromosome
- One daughter cell lacking a chromosome
- Both daughter cells gaining or losing a chromosome
The consequences depend on the timing and severity of the error.
- Early errors can affect a broader range of tissues, resulting in more severe phenotypes.
- Late errors tend to have a more localized impact, with fewer cells affected.
- The severity of the abnormality also plays a role; severe abnormalities are more likely to result in cell death, reducing the impact.

Mosaicism: Mitotic Nondisjunction

Mosaicism is characterized by the presence of two or more cell lines with different genetic compositions within a single individual.
Detection often requires analyzing multiple tissues or cell types.
The first few mitotic divisions are particularly vulnerable to errors during development, potentially leading to more than one aneuploid cell line.
Structural rearrangement mosaicism is rare and involves cell lines with opposing chromosomal imbalances.
Gonadal mosaicism, while potentially common, is challenging to assess, leading to less accurate data.
The timing of the mitotic error directly impacts the prevalence of the aneuploid cell line:
- Earlier events result in a greater number of affected cells, leading to broader and potentially more severe phenotypic consequences.
The severity of the abnormality plays a role: more severe abnormalities increase the likelihood of cell death and removal of the affected cell line.

Mosaicism Types

Multiple types of mosaicism exist, including confined placental mosaicism, fetal mosaicism (with and without a normal placenta)
Mosaicism does not need to be organized or symmetrical, with different tissues potentially exhibiting varying degrees of aneuploidy.
Gonadal mosaicism is often a concern as it can lead to genetic abnormalities in offspring.
The types of mosaicism are distinguished based on the tissues where the aneuploidy is present.
Confined placental mosaicism indicates the presence of aneuploidy only in the placenta.
Fetal mosaicism indicates the presence of aneuploidy in the fetus, with or without placental involvement.

Chimerism vs. Mosaicism

Chimerism and mosaicism are often confused, but there are key differences:
- Origin: Chimerism originates from the fusion of two distinct zygotes, while mosaicism results from errors during cell division.
- Cell Lines: Chimerism involves two genetically distinct cell lines from different zygotes, while mosaicism involves two cell lines that originated from the same zygote.
- Timing: Chimerism occurs before or during early embryonic development, while mosaicism occurs later during development from mitotic errors.

Summary of Key Concepts:

Nondisjunction, the failure of chromosomes to separate properly during cell division, is a major cause of aneuploidy.
Advanced maternal age is a significant risk factor for nondisjunction.
Mosaicism is the presence of two or more cell lines with different genetic compositions within an individual, often resulting from mitotic errors.
Chimerism is the presence of two or more cell lines from different zygotes, which are genetically distinct.
Understanding the mechanisms of nondisjunction, mosaicism, and chimerism is crucial for diagnosing and managing genetic disorders.

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