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Foundations 1 > Meiosis and Chromosome Structure > Flashcards

Meiosis and Chromosome Structure Flashcards

1
Q

Cytogenetics

A

The study of chromosomes and cell division

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2
Q

What are the elements of chromosome structure (small -> big)?

A
  • Histones = proteins wrapped with 150 bp DNA; 50 bp linkers between histones
  • Nucleosomes = segments of DNA wrapped around 8 histone cores
  • Solenoid
  • Chromatin loops
  • Chromosomes = complete package
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3
Q

Metaphase spread

A

Method for viewing chromosomes in cytogenetics:

  • spindle fiber inhibitor inhibits anaphase, arresting cells in metaphase
  • hypotonic solution causes cell expansion
  • fixation hardens the membrane to stabilize
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4
Q

What are the different regions of a chromosome?

A
  • Telomere = TTAAGGG repeats on the end
  • Short (p) arm = “top” arm
  • Centromere = spindle fiber binding site in middle
  • Long (q) arm = “bottom” arm
  • Telomere
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5
Q

Metacentric chromosome

A

Centromere is in the center; p and q arms of similar length

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6
Q

Submetacentric chromosome

A

Centromere towards one end; p arm much shorter than q

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7
Q

Acrocentric chromosome

A
  • 13, 14, 15, 21, 22
  • Very small p arm (stalks and satellites)
  • All 5 chromosomes have the same stalk DNA => duplications and deletions w/o clinical consequence means little selective pressure to maintain => polymorphism
  • Stalks = tandem arrays of rRNA genes
  • Satellites = highly repetitive “junk” DNA
  • Associate in interphase to form the nucleolus
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8
Q

Ideograms

A
  • Banding pattern from enzyme digest of chromosomes
  • Identical pattern for all people
  • Numbering: 24.3 = region 2, band 4, sub-band 3. Numbers out from centromere
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9
Q

Euploid

A
  • Chromosome number is an exact multiple of the haploid set (23, 69, 92)
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10
Q

Aneuploid

A
  • Loss or gain of whole chromosomes (45, 47, 49)
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11
Q

What are the types of structural chromosome abnormalities?

A
  • Terminal deletion
  • Interstitial deletion
  • Duplication
  • Ring (telomere deletion => circularization to maintain integrity)
  • Isochromosome (2 copies of 1 arm)
  • Paracentric inversion (inversion of region, not including centromere)
  • Pericentric inversion (inversion of region including centromere)
  • Translocation (swapping DNA between chromosomes)
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12
Q

Lyon hypothesis of X-inactivation

A
  • One X chromosome is “active”, meaning genes are transcribed and translated
  • One X is “inactive”, remaining condensed and staining darkly as a Barr body in interphase cells
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13
Q

When does X-inactivation occur?

A

Early in embryonic life (2 wks post-fertilization)

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14
Q

Is there a pattern to X-inactivation?

A
  • Random (either paternal or maternal)

- Clonal: all of a cells descendants will have the same inactive X

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15
Q

How is X-inactivation mediated genetically>

A
  • XIST (X-inactivation specific transcript) gene located in the X-inactivation center of Xq13
  • Transcribed only from inactive X and never translated
  • Transcript remains in the nucleus and coats the inactive X affecting replication and condensation
  • Methylation: inactive X is hypermethylated; active X is mainly unmethylated
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16
Q

What are the effects of the incompleteness of X inactivation?

A
  • For genes that are incompletely inactivated, females (XX) will have 2x the [protein] as males (XY)
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17
Q

What is meiosis?

A
  • Specialized cell division that occurs during gametogenesis

- Shuffles genetic material through recombination and divides genetic material in half

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18
Q

What is the purpose of meiosis I?

A
  • Reduction division (46 -> 23, 2n -> 1n, diploid -> haploid)
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19
Q

What are the stages of prophase I?

A
  1. leptotene = chromosome condensation after interphase
  2. zygotene = 2 homologs (maternal and paternal) align forming a synapse and are held together by synaptonemal complexes
  3. pachytene = each homolog pair (bivalent) coils tightly and crossing over occurs
  4. diplotene = homologs begin to separate but remain attached at chiasmata (crossing-over points)
  5. diakinesis = separation of homolog pairs; chromosomes maximally condensed
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20
Q

What are some characteristics of recombination?

A
  • Number of chiasmata correlates with chromosome size
  • > 1 chiasmata/chromosome arm required for normal segregation
  • Only one sister chromatid involved in each cross-over event
  • Female recombination > male recombination
  • Recombination varies by location: less near centromeres and more near telomeres
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21
Q

Pseudoautosomal regions

A
  • Two regions of homology on the X and Y chromosomes that undergo very high levels of recombination
  • Same genes are on both X and Y so females and males have the same dosage of these proteins
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22
Q

What are the odds of 2 gametes from 1 individual having the same chromosomes?

A

Random segregation => 1 in 2^23 (1 in 8 million)

23
Q

Compare start of meiosis, duration or meiosis, number of mitoses before meiosis, gametes produced per meiosis, and total gamete production for males and females.

A

Start: puberty (M) and early embryonic life (F)
Duration: 60-65 days (M) and 10-50 years (F)
# mitoses: 30-500 (M) and 20-30 (F)
gametes per meiosis: 4 spermatids and 1 ovum + 2-3 polar bodies
gamete production: 100-200 mil per ejaculate and 1 ovum per cycle

24
Q

When do meiosis I and meiosis II occur in females?

A
  • First meiosis begins in utero and arrests partway at birth
  • With each menstrual cycle, 1 oocyte completes meiosis I and begins meiosis II
  • Meiosis II is completed after fertilization
25
Q

What are the clinical indications for prenatal constitutional cytogenetic testing?

A
  • Advanced maternal age
  • Family history of chromosome abnormality
  • Ultrasound or screening test anomalies
26
Q

What are the clinical indications for postnatal constitutional cytogenetic testing?

A

For babies born with:

  • congenital heart defect
  • multiple congenital anomalies
  • mental retardation of unknown origin or associated with malformations
  • ambiguous genitalia
  • primary amenorrhea
  • 3+ unexplained spontaneous miscarriages
27
Q

How frequent are chromosome abnormalities in live births?

A

0.6%; often not compatible with life

28
Q

What aneuploidy is associated with Turner syndrome?

A
  • Only one sex chromosome (X)
29
Q

Nondisjunction

A
  • Mechanism of aneuploidy
  • Failure of homologous chromosomes (MI) or sister chromatids (MII) to separate
  • If homologous don’t separate: fertilized cells either trisomy or monosomy
  • If sisters don’t separate: fertilized cells normal, trisomy, or monosomy
30
Q

How is amniocentesis connected to maternal age?

A
  • Amniocentesis = collection of amniotic fluid to screen for abnormalities; 0.5-1% risk of miscarriage
  • Risk of miscarriage due to chromosomal abnormalities increases with maternal age
  • At age > 35: risk of abnormality > risk of procedure
31
Q

Why is most aneuploidy of maternal origin?

A
  • NDJ sperm are less fit and thus less likely to fertilize an egg
  • Most aneuploidy is of maternal MI origin
  • Exceptions: +18 is parental MII; X is paternal
32
Q

Balanced chromosomal translocation

A
  • Swapping of genetic material between two chromosomes but no net gain or loss
  • Usually no phenotype in self as breaks are usually in a noncoding sequence (only 5% of de novo translocations disrupt a gene)
  • Increased risk of abnormal offspring and multiple miscarriages
33
Q

How is meiosis I abnormal when a balanced translocation is present?

A
  • Chromosome homologs don’t align perfectly and form a tetravalent (two chromosomes with the translocation + their original homologs)
34
Q

What are the ways in which homologs can separate after forming a tetravalent?

A
  • normal: normal and translocation carrier
  • likely abnormal: slight monosomy A/slight trisomy B and slight monosomy B/slight trisomyA
  • likely nonviable: almost monosomy A/almost trisomy B and almost monosomy B/almost trisomy A
35
Q

Which trisomies are viable?

A

13, 18, 21

36
Q

Robertsonian Translocation

A
  • Translocation between two acrocentric chromosomes, resulting in the loss of both short arms but doesn’t affect the DNA content of the long arms
  • Either occurs by centromere fusion (stalk and satellite DNA lost) or by translocation (stalk and satellite chromosome lost)
37
Q

Nucleolus organizer regions

A

Acrocentric chromosomes; associate during interphase to form the nucleolus

38
Q

How frequent are Robertsonian translocations

A

der(13;14) = 1 in 1500

39
Q

How do chromosomes associate in meiosis after Robertsonian translocation?

A

Trivalent forms: two normal chromosomes + translocated combo chromosome

40
Q

What are the possibilities for fertilized gametes with a Robertsonian translocation der(14;21)(q10;q10)?

A
  1. normal + balanced translocation (normal, balanced)
  2. unbalanced translocation + monosomy (unbalanced, unviable)
  3. trisomy + monosomy (both unviable)

Theoretical risk of Down’s is 33% but in reality: 10-15% for female carriers and 0-2% for male carriers

41
Q

Paracentric inversion

A

Break and inversion on one chromosome arm

42
Q

Pericentric inversion

A

Break on both chromosome arms and inversion (includes centromere)

43
Q

What are the clinical consequences of inversion?

A
  • Usually no clinical consequence for carrier because no gain/loss and breaks usually occur in noncoding regions
  • Abnormal meiosis
44
Q

Paracentric inversions and meiosis

A
  • Inverted chromosome will stretch to align with normal homolog, forming an inversion loop
  • If recombination occurs within the loop => acentric and dicentric products => miscarriage
  • If recombination does not occur within the loop => normal
45
Q

What are acentric and dicentric chromosomes?

A
  • Products of meiosis after paracentric inversion
  • Acentric = no centromere; dicentric = 2 centromeres
  • Not stable/non-viable
46
Q

Pericentric inversions and meiosis

A
  • Inverted chromosome will stretch to align with normal homolog, forming an inversion loop
  • If recombination occurs within loop => both homologs will have a centromere, but each will have a deletion and a duplication => viable or nonviable gametes depending
  • If recombination doesn’t occur within loop => normal
47
Q

Microdeletion syndromes

A
  • phenotypically and genetically characterized
  • usually not inherited but can be inherited in a dominant fashion
  • deletion of < 5Mb (10-100) genes; not visible by cytogenetics
  • low incidence: each individual syndrome is rare but all together, same frequency as Down’s
48
Q

How do microdeletions occur during recombination?

A
  • Misalignment between direct repeats => duplication and deletion
  • Alignment between inverted repeats => non homologous end joining or U-type exchange => deletion of region between repeats
49
Q

How does karyotype resolution vary?

A
  • Depends on exact stage of condensation in metaphase
  • Band level = level of condensation (400-850)
  • More bands = less condensed = greater sensitivity
50
Q

What is Fluorescent In-Situ Hybridization (FISH)?

A
  • Fluorescently labeled probes target 100kb-1Mb regions of interest
  • Probes added in excess to sample DNA
  • Sample DNA is heat denatured and then probes allowed to anneal to targets on ss sample
51
Q

What are the clinical uses of FISH?

A
  • detect numerical abnormalities using dividing or nondividing cells (interphase)
  • detect abnormalities that are not visible via karyotype (microdeletions)
  • detect trisomies prenatally
52
Q

Array based comparative genomic hybridization (aCGH)

A
  • FISH clones (probes) arrayed on a chip
  • fluorescently labelled patient and control DNA added
  • patient and control DNA should compete equally for probe binding (color ratio of 1:1 or 0.8-1.2)
  • look for gain or loss in color ratio
53
Q

What can aCGH detect and with what sensitivity?

A
  • can detect: copy number imbalances at a genome wide level (not all CNVs are pathogenic; 2-15 per patient)
  • cannot detect: mechanism of abnormality (trisomy, translocation)
  • microarray analysis more sensitive than chromosome analysis
  • 108,000+ probes at ~10-50kb intervals along the genome

Foundations 1 (26 decks)

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