Meiosis - Duncan

Question 1

What is important about meiosis? (3 main points)

Answer 1

1. required for generating a haploid gamete and genetic diversity
2. necessary for male and female gamete formation
3. defects result in infertility (loss of gamete), aneuploidy and genomic disorders

Question 2

What is aneuploidy and how frequently does it occur?

Answer 2

aneuploidy is having an abnormal number of chromosomes (typically more); normally with chromosomes 21, 18 and 13.

it occurs in ~10-30% of fertilized human eggs, but can be as high as 60% in older women. it is the leading cause of pregnancy loss and genetic cause of developmental disabilities and mental retardation.

Question 3

What is the main point of Meiosis I?

Answer 3

To create a haploid cell; during this phase, homologous chromosomes separate but sister chromatids do not. So the end result is going from 4 to 2 chromatids and diploid to haploid.

Question 4

What is the main point of Meiosis II?

Answer 4

an equational division where sister chromatids are separated - cell remains haploid but now there is only one chromatid per cell; similar to mitosis

Question 5

What are the two main phases in Meiosis I and what occurs during each phase?

Answer 5

Prophase I: homologous chromosome pairing, synaptonemal complex formation (synapsis), and recombination/crossing over

Chromosome Segregation (metaphase I - anaphase I): specialized chromosome connections to mediate the separation of homologous chromosomes vs. sister chromatids

Question 6

What are the stages of prophase I and what happens in each?

Answer 6

Leptotene: 1. chromosomes condense, 2. bouquet formation/pairing (clustering of telomeres attach at nuclear envelope; associated with rapid chromosome movements), 3. axial elements and synaptonemal complex (molecular glue holding homologous chromosomes together) begins to assemble; 4. programmed DSBs occur at recombination nodules (homologous recombination)
Zyogtene: pairing extends; axial elements mature into lateral elements, synapsis begins (zipper)
Pachytene: synapsis completes, maturation of meiotic recombination sites into crossovers
Diplotene: chromosomes undergo desynapsis, homologues held together by crossovers (ie chiasmata), further condensation

Question 7

Describe the process homologous recombination.

Answer 7

1. programmed formation of DSBs at hot spots
2. exonucleolytic resection of 5’ ends at the breaks
3. strand invasion into a chromatid of homologous chromosome
4. repair of DSBs by homologous recombination: non-crossover results in chromosome pairing (gene conversion) and crossover results in chiasmata (physical linkage of homologues)

failure of a chromosome pair to undergo at least 1 crossover event can lead to aneuploidy

generates genetic diversity among games (independent assortment of homologues and crossing over

Question 8

What holds chromatids together during meiosis and what is the process of removing them?

Answer 8

cohesion molecules hold sister chromatids together; allow exchange of genetic material between homologous chromosomes by the sister kinetochores acting as one functional unit. are removed during meiosis II

established during S phase at the centromere and along chromosome arms

helps to stabilize chiasmata and establishes proper geometry for kinetochore-microtubule interactions

separase is the enzyme that cleaves cohesion molecules - tightly regulated and mostly active in meiosis II

Question 9

What connects chromosomes together and what are the different ways this can malfunction?

Answer 9

chiasmata: physical manifestations of genetic recombination that tether homologous chromosomes

~1/2 chiasmata per homologous chromosome pair

abnormal crossovers (fewer #, too far or too close to centromere) are associated with non-disjunction

Question 10

What is the single most important thing to remember from this lecture?

Answer 10

failure of a chromosome pair to undergo at least 1 crossover event can lead to aneuploidy

Question 11

What are the most common autosomal trisomies and what type of aneuploidies are the most common?

Answer 11

trisomy 13: Patau syndrome
trisomy 18: Edward syndrome
trisomy 21: Down syndrome

sex chromosome aneuploidies are most common

Question 12

What is sexual dimorphism and what causes it? Give examples.

Answer 12

any morphological feature, biological process or phenotype that varies between males and females

1. onset, timing and duration (windows of susceptibility)…males: meiosis begins at puberty, is sequential, synchronous and continuous; females: meiosis begins at 11-12 weeks of gestation and by birth all oocytes are arrested at diplotene stage of meiosis I, meiosis I is completed at ovulation (years to decades), Meiosis II is completed at fertilization (hours)
2. gamete production outcome…males: 4 haploid cells produced; females: 1 haploid cell + 2 polar bodies
3. efficacy…most meiotic errors are maternal in origin and occur during Meiosis I (oogenesis is more robust but has more errors)
4. genetic mutation phenotypes…checkpoint mecahnisms appear to be more regulated in males and mutations in both male and female gametes may have different clinical effects

Question 13

What are predisposing risk factors for meiotic errors (specifically with aneuploidy)?

Answer 13

advanced maternal age (relationship is chromosome dependent and is due to the deterioration of the function of chromosome cohesion - requires multiple hits or contributing factors) and environmental chemical exposure (BPA…really bad for meiosis because is weakly estrogenic)

Question 14

How doe cohesin loss lead to chromosome segregation errors?

Answer 14

with cohesin loss, kinetochore geometry favors bivalent bi-orientation vs. mono-orientation and erroneous kinetochore-spindle microtubule attachments at Meiosis I

the problem: chromosome segregation in the oocyte depends on proteins formed in utero