Cell cycle, mitosis, meiosis

Question 1

DNA basics

Answer 1

• Complex arrays of linear DNA and associated proteins
• DNA coils around histones to make nucleosomes
• Chains of nucleosomes fold to form chromatin fibers
• Chromatin fibers hypercoil to form chromosomes
• Total of 46 in each somatic cell (not egg or sperm)
  o Arranged into 23 pairs
   22 autosomes
   1 pair of sex chromosomes

Question 2

Abnormal chromosome number

Answer 2

• Abnormal chromosome number: - in generally = aneuploidy
  o Extra chromosome = trisomy
  o Complete duplication of set of chromosomes = tripoidy, tetraploidy
  o Abnormal chromosome rearrangement = translocation (balanced or unbalanced)

Question 3

Normal mitosis

Answer 3

Mitosis – typical cell division
- Enables consistent duplication of the complete chromosome complement with every cell division
o Preceded by chromosome duplication
o Spindle fibers attach to centromeres and retract
o New nuclear and cell membranes are assembled during cytokinessis
o Prophase = condenation
o Metaphase: align
o Anaphase: split
o Telophase
o Meiosis = division of gametes

Question 4

Normal meiosis

Answer 4

• Meiosis: reduction cell division
  o Process isolated to germ cells to generate egg and sperm with 23 chromosomes
  o 2 part process
   Meiosis I; reduction division – reduces the chromosome number from diploid to haploid
   Meiosis 2: equational division – begins with haploid number but proceses like mitosis with that number
  o Unique meiosis events:
   Homologous chromosomes, after duplicating themselves into 2 chromatids held together by a single chromosomes are matched by homologue alignment
• Referred to as “pairing”
• Formation of a synaptonemal complex of protein which holds the pair together in synapsis (metaphase)
   Homologue pairs are locked together through recombination of chromosomes
• Also called crossing over or exchange or chiasmata formation
   Orientation of centromeres of each pair align to the opposite poles of developing spindle apparatus
• Enables separation of pairs at meiosis I
   Critical event of meiosis:
• Crossing over or chiasmata formation:
  o Preceded by ds DNA breaks, many more of which occur than cross over
  o Followed by adherence of the arm from one homologous pair to the site of break on the other
   Crossing over: exchange events are not random
• Only occur in euchromatin (stretched out chromatin material)
• Not in heterochromatin (condensed chromatin material)
• Exchanges are lowest near the telomere; highest in medial regions of the arms
• Usually 1 exchange per chromosome arm
   Misalignments of chromosome in meiosis
• If pairing occurs between nonhomologous chromosomes
• These are called translocations
  o Usually not a problem if there is no loss of material (balanced)
  o If material is lost, then it is an unbalanced translocation – usually severe

Question 5

Gamete formation

Answer 5

• Gamete formation: major differences in meiosis 1 in egg and sperm production
  o Sperm meiosis: process initiates at puberty
   Progress through meiosis 1 to meisosis 2 in 64-70 days
• Yields 50% 23X and 50% 23Y sperm; minimal cytoplasm and mitochondria maintained
  o Egg meiosis: process initiates in embryonic life
   Undergo mitosis to create 7 million oogonia by 20 weeks; cells then lose ability to undergo mitosis and enter meiosis 1
   By birth only 2 milliion remain, by puberty – 400,000.
   Approx 400 are ovulate din a lifetime
   Arrest of meiosis:
• Initial arrest in egg development at meiosis 1 prior to metaphase – dictyotene
• May last from 12-50 years
• Complete meiosis 1 triggered by LH surge in menstrual cycle
• Arrest occurs at beginning of meiosis 2; not completed until fertilization after penetration of sperm into oocyte
• With fertilization, nucleus completes meiosis 2
  o Results in one large ovum and 3 polar bodies

Question 6

Abnormalities of meiosis

Answer 6

Abnormalities of meiosis
- Multiple checks and balances (more common in male meiosis); no similar process in female meiosis
- Abnormalities in female meiosis 1:
o Greater potential for errors related to length of time egg spends in Meiosis 1; spindle apparatus has aged related impairment of protein assembly
o Overall reduction in number of exchanges
o Position of exchanges alters towards the telomeres
o With reduced number of exchanges, chromatids are less likely to separate
- End result of Meiosis 1: the longer the egg remain in meosis 1, the older the mother; the greater the likelihood it will divide unevenly
o Abnormal: 20% of all eggs may be aneuploidy (1 in 5 pregnancies miscarry)
o 50-75% of all early SABs are aneuploidy
 Most common is trisomy (tri 16)
 Most common single specific abnormality = monosomy X
o 3-5% of stillborns are aneuploidy; 0.3%j of liveborns are aneuploidy
o Most common liveborn aneuploidy: DS (1/700 livebirths)
 93% of time straight extra chromosome 21
* 95% of time related to maternal meiosis 1 abnormalities
 5% may how chromosomal rearrangement
 Rarely mosaic
- Down: 1/700 – chromosome 21 is small; small amount of genetic material is duplicated
- T 18: 1/3000 – nail hypoplasia; micrognathia
- T13: 1/5000
- Turner: 1/5000

Question 7

Causes of deletion, missing chromosome segments

Answer 7

• May occur de novo or as result of parent with balanced chromosomal rearrangement which cannot separate properly at meiosis
  o 4p deletion: Wolf-Hirshhorn syndrome: shielded forehead
  o 5p deletion : Cri du chat; larynx affected
  o 7q deletion: Williams syndrome: need to to microarray; down turned mouth; CHD, supravalvular aortic stenosis
  o 15q11 (mat) deletion: Angelman syndrome
  o 15q11 (pat) deletion: Prader Willi Syndrome – hypotonia; eating disorder; obesity; thin upper lip
  o Del 22q11: velocardiofacial syndrome (DiGeorge) – long nose
  o Del 17p11.2: Smith magenis syndrome: square jaw; behavior issues