MGB block 2 lecture 3-2.pdf

1.Define the following terms: nondisjunction, aneuploidy, euploidy, trisomy, monosomy, chimerism/chimera, mosaicism/mosaic, uniparental disomy, isodisomy, and heterodisomy Nondisjunction - Summarize the mechanisms of maternal meiotic nondisjunction and mitotic nondisjunction Nondisjunction...

1.Define the following terms: nondisjunction, aneuploidy, euploidy, trisomy, monosomy, chimerism/chimera, mosaicism/mosaic, uniparental disomy, isodisomy, and heterodisomy Nondisjunction - Summarize the mechanisms of maternal meiotic nondisjunction and mitotic nondisjunction Nondisjunction effects in Mitosis: normal cell division, effects cell populations after error, tissue specificity (can be nearly all tissues if it occurs early enough in development) Nondisjunction effects in Meiosis: gametogenesis, effects gametes, full organism/create errors in offspring unless corrections occur during embryogenesis mitoses - Compare and contrast consequences of mitotic and meiotic nondisjunction in terms of organismal structures, function, and mechanisms of action Aneuploidy: inappropriate chromosome numbers and unbalanced chromosome content Euploidy: abnormal chromosome content with balanced gene dosage Aneuploidy effect at a chromosomal level: severity of a particular autosomal aneuploidy correlates with the gene content of the chromosome, correlated to content not size Aneuploidies in gene rich chromosomes: more catastrophic, usually structural genes, embryonic lethal or prevent implantation Where are chromosomal aneuploidys most commonly derived from? inappropriate chromosome segregation, nondisjunction of maternal meiosis I What chromosomes are the exception from maternal meiotic nondisjuction? Chromosome 7,13, 18 What chromosome shows an equal number of maternal meiosis I and II errors in nondisjuction? Chromosome 13 What do studies show increases chances of nondisjuction events of maternal meiosis I? Advanced maternal age Mechanisms for Meiosis I nondisjunction: 1. Both homologous chromosomes to one pole 2. Premature separation of one of the homologous chromosomes What causes premature separation of one of the homologous chromosomes in meiosis I? Separase breaking down cohesion prematurely Two hypotheses of Maternal age correlating to nondisjunction: Production Line Hypothesis and Limited oocyte pool model Production Line Hypothesis: Maturation of oocytes occurs in the same order as original development in fetal life Limited oocyte pool model: The number of follicles in antral state decreases with increasing age, fewer number of follicles equals an increase in the probability that a lower quality one will be chosen Mechanism of Mitotic Nondisjunction: failure to split sister chromosomes Mechanism of Meiotic Nondisjunction: failure to separate homologous chromosomes (mostly meiosis I) Which mitoses are more vulnerable to nondisjunction? Early divisions, like Morula formation, are very quick, shorter G1, more prone to error, have greater effect What is the relationship between timing of nondisjunction event and fraction of cells exhibiting aneuploidy in mitosis? Early events impact more tissues and broader impact phenotypically, Direct relationship between severity of abnormality and probability that cell line will undergo cell death  - Explain the role of mosaicism in perpetuation of chromosomal abnormalities and aneuploidies and compare and contrast the different types of mosaicism (CPM and fetal with and without placental involvement) Mosaicism origin: the presence of two or more populations of cells with different genetic makeups within a single organism, resulting from mutations or chromosomal abnormalities that occur after fertilization during early embryonic development confined placental mosaicism: ​arises from a post-zygotic mutation affecting placental cells during development. since the fetus is unaffected, CPM may not result in any clinical abnormalities, May lead to complications in pregnancy (miscarraige) Fetal Mosaicism with Placental Involvement: presence of mosaicism in both fetus and placenta, May affect fetal growth, development, and pregnancy outcome Fetal Mosaicism without Placental Involvement: presence of mosaicism in only the fetus, May lead to fetal abnormalities depending on which fetal tissues are affected, without placental issues impact of mosaicism depends on: 1. Proportion of affected cells: The larger the population of aneuploid cells, the more likely an individual will present with clinical symptoms. 2. Tissue specificity: Mosaicism may affect certain tissues while sparing others, influencing the severity and type of symptoms. 3. Timing of mutation: Earlier mutations during embryonic development lead to more widespread mosaicism, while later mutations lead to more localized effects Cutaneous Mosaicism: Dermalogical pattern depending when error took place, how cells migrate, and what population was altered - Explain the difference between chimerism and mosaicism Chimerism origin: Different cell types are derived from two separate and external sources (originally separate conceptuses), cells from two separate fertilized eggs, Post-zygotic fusion of dizygotic twin zygotes, Not derived from mitotic error but rather a fusion or absorption event Confined Chimerism: Only specific tissue possesses the two unique cell lines/populations, explains the presence of two cell lines in a single individual where no apparent error is observed Mosaicism: results from mutations occurring in a single individual after fertilization, leading to genetically distinct cells within the same organism, all derived from one zygote. Chimerism: involves the presence of two or more genetically distinct cell populations originating from different zygotes, leading to an individual with mixed genetic material from separate fertilized eggs or from a donor. What conditions can Chimerism mechanism result in? 46,XY/46,XX hermaphroditism, 45,X/69,XXY fetus, diploid and triploid mosaics Mitosis and Errors in Chromosome Segregation - Explain how chromosome segregation can result in chromosome abnormalities during mitosis Chromosome segregation during mitosis is the process by which replicated chromosomes (sister chromatids) are equally divided into two daughter cells. Errors in this process can lead to chromosome abnormalities, such as aneuploidy (an abnormal number of chromosomes). These abnormalities can arise due to various issues during the key stages of mitosis: 1. Defective Spindle Assembly: The mitotic spindle, made of microtubules, is responsible for pulling sister chromatids apart during anaphase. If spindle fibers do not attach properly to the centromeres of chromosomes (via the kinetochores), unequal distribution of chromosomes may occur. This improper attachment can result in one daughter cell receiving too many chromosomes and the other too few. 2. Non-disjunction: This occurs when sister chromatids fail to separate during anaphase. As a result, both chromatids may be pulled to one pole of the cell, leading to one daughter cell with an extra chromosome (trisomy) and another cell with a missing chromosome (monosomy). Non-disjunction is a major cause of aneuploidy.  3. Lagging Chromosomes: Sometimes, a chromosome may not move to either pole during anaphase and instead get left behind in the middle of the cell (termed "lagging chromosomes"). These chromosomes may fail to be incorporated into the nuclei of the daughter cells, resulting in one or both daughter cells missing chromosomes. 4. Multipolar Spindle Formation: In some cases, instead of forming two spindle poles, the cell may form more than two (multipolar spindles). This can cause chromosomes to be distributed unevenly among more than two daughter cells, leading to severe aneuploidy or polyploidy. 5. Cohesin Dysregulation: Cohesins are proteins that hold sister chromatids together after DNA replication. If cohesin does not degrade properly during anaphase, the chromatids may not segregate as they should, causing unequal chromosome distribution and leading to abnormalities. Uniparental Disomy Uniparental disomy: when both copies are derived from a single parent (2 copies of the chromosome or region of chromosome from maternal source or paternal source exclusively) Isodisomy: Both chromosomes copies derived from one parent are identical Heterodisomy: Both chromosomes copies derived from one parent are different Whole chromosome UPD: trisomic rescue, mitotic error and rescue, gametic complementation Uniparental Disomy Mechanism: error occurs usually from nondisjunction that is meiotic or mitotic followed by an attempt to correct it Segmental Uniparental disomy: UPD of only parts of a chromosome instead of the entire chromosome, greatest consequences observed for chromosomes subject to imprinting, can impact specific tissues/exhibit mosaicism Mechanisms of segmental UPD: - Postzygotic somatic recombination between maternal and paternal homologs - Meiotic nondisjunction producing a disomic gamete followed by a trisomic conception with crossing-over between maternal and paternal homologs and chromosome loss - Repair of double strand break via break-induced replication Errors in meiosis (gametogenesis) - Monosomies - Trisomies - Sex chromosome aneuploidies Errors in mitosis leading to mosaicism - Can include “rescue” of a trisomic cell (with or without uniparental disomy) - Chimerism Errors in fertilization - Triploidy - All chromosomes from one parent - Partial and complete moral pregnancies Aneuploidy Examples - Compare and contrast trisomy 21, 18, 13, 16, Turner and Klinefelter syndromes in terms of causes, phenotypic consequences, and viability - Explain why there is variable viability across autosomal and sex chromosome aneuplodies Autosomal aneuploidies generally have more severe consequences because they disrupt the balanced expression of many essential genes, and autosomes lack compensatory mechanisms like X-inactivation. Therefore, most autosomal aneuploidies result in miscarriage or severe developmental disorders. Sex chromosome aneuploidies are more viable because of mechanisms like X-inactivation and the limited gene content of the Y chromosome, which allow for better compensation for gene dosage changes. Thus, individuals with sex chromosome aneuploidies can survive and often present with less severe phenotypes. Condition Cause Viability Trisomy 21 Extra copy of chromosome High viability; average life 21 expectancy ~60 years Trisomy 18 Extra copy of chromosome Low viability; most die 18 within first year Trisomy 13 Extra copy of chromosome Low viability; most die 13 within first weeks Trisomy 16 Extra copy of chromosome Nonviable (in full form); 16 mosaic form rare Turner syndrome Missing X chromosome High viability; normal life (45,X) expectancy with care Klinefelter syndrome Extra X chromosome High viability; normal life (47,XXY) expectancy Condition Phenotypic Consequences Trisomy 21 Intellectual disability, characteristic facial features, heart defects Trisomy 18 Severe intellectual disability, organ malformations, clenched fists Trisomy 13 Severe intellectual disability, polydactyly, CNS defects, cleft lip Trisomy 16 Incompatible with life (full), growth and developmental delays (mosaic) Turner syndrome Short stature, webbed neck, ovarian insufficiency, normal intelligence Klinefelter syndrome Tall stature, gynecomastia, reduced fertility, learning difficulties  1. Meiotic nondisjunction during the first half of meiosis differs from meiotic nondisjunction during the second half of meiosis in what way? (LO2 and LO3) a. Amount of content and most likely causes Nondisjunction in meiotic - More likely, multiple daughter cells - Sister chromatid separation eros Nondisjunction in second half of meiosis - Fewer daughter cells - Lack of centromeres, no spindle attachment 2. Maternal isodisomic UPD as a consequence of fertilization is most likely associated with what cause of UPD? (LO8) a. Nondisjunction and trisomic rescue Nondisjunction is always the first event in UPD - Where it takes place, what is the outcome Trisomic rescue is most common response 3. Mitotic segregation errors are more closely associated with errors in what? (LO2 and LO3) - Spindle attachment