Cell division
Abnormalities of cell division and
fertilization
RNDr Z.Polívková
Lecture No 402 – course: Heredity
The Cell cycle
interphase, mitosis, cytokinesis
b
G0
c
M
a,b – G1,G2 checkpoints
c – spindle assembly
checkpoint
G1
G2
S
a
Cell cycle progression involves
sequentional activation of cyclin
dependent kinases by binding to
cyclins
Accuracy of the cell division is ensured by the system
of check-points
In check-points chromosomes are scanned for features as:
• DNA damage (in G1)
• incomplete replication (in G2)
• non-attachment to the spindle (between metaphase and
anaphase
• in meiosis - incomplete synapsis and recombination
(in pachytene)
The cell cannot proceed to the next stage until all
processes have been completed satisfactorily
Chromosomes during cell cycle
M
G1
G2
S
G1 –chromosomes with one chromatid
S – replication (initiation at many sites)
G2 – chromosomes with two chromatids
M - mitosis
Division of somatic cells = mitosis
from one diploid maternal cell – two diploid
daughter cells
Separation of sister chromatids
prophase
interphase
prometaphase
Mitosis
2n
2n
2n
metaphase
telophase
anaphase
Role of specific proteins in mitosis:
Topoisomerase II (TOPO II = scaffold protein I)
- role in chromosome condensation
- transient double strand breaks of DNA – role in decatenation, separation of
chromatids
Centrosome = microtubule organizing center – protein γ-tubulin,centrosomins
centrosome duplication in S phase (cyklin E/CDK2)
kinesin related motor protein Eg5 – separation of centrosomes (centrioles)
and moving to oposite poles
Separated centrosomes - reorganization of microtubules to mitotic spindle
Nuclear mitotic apparatus protein NuMA, motor protein dynein - assembly
of the spindle to poles
Kinetochore protein (kinesin family) = motor protein - chromosome movement
Cell division cycle (CDC) proteins – transition from metaphase to anaphase
Genes MAD,BUB, APC – responsible for proceeding through mitosis
protein PRC1- in cytokinesis
and many others
Meoisis = division of germ cells
reduction of diploid chromosomal number to haploid
Two divisions: MI, MII
n
M I = reduction 2n
= heterotypic
n
Prophase:
leptotene – spiralization of chromosomes
zygotene – pairing of homologous chromosomes (synapsis)
→ bivalents
synaptonemal complex = tripartite protein structure
pairing of X and Y by the ends (homologous sequences =
pseudoautosomal region) – sex vesicle
pachytene – each chromosome has two chromatids = tetrads of
two homologs
crossing-over = reciprocal exchange of
homologous parts of nonsister chromatids of
homologous chromosomes = recombination of
maternal and paternal genetic material
Chiasma formation = consequence of crossing-over
= prevention of premature disjunction
diplotene – separation of homologs
connection only in sites of chiasmata
diakinesis – maximal contraction of chromosomes
Crossing-over
A
B
a
b
A
B
a
b
A
B
a
b
A
B
a
b
A
cut
a
According Sumner 2003
double strand
break
digestion by
nucleases
→single-stranded
tails
strand invasion –single-stranded
tail pairs with complemetary
strand of double stranded DNA
molecule of homologous
chromosome
branch migration and
synthesis
(DNA polymerase fills
gaps)
B
cuts resolution of Holliday
junction - breaks
b
Crossing-over with
exchange of flanking markers
A
b
a
B
Difference between meiotic recombination and DSB repair:
• Meiotic recombination between non-sister homologues, which
are not identical – carry different alleles for many genes
• DSB repair in non-meiotic cells involves recombination between
sister DNA molecules
Metaphase – bivalents are in equatorial plane of the cell
without splitting of centromeres
Anaphase - migration of homologous chromosomes to the
opposite poles
randomly according parental origin !!
Telophase - chromosomes on the opposite poles - daughter nuclei
Cytokinesis – division of cytoplasm - equal in spermatogenesis,
unequal in oogenesis
Interkinesis – without replication
n
M II – homeotypic n
= mitotic division
n
splitting of centromeres in metaphase
separation of chromatids in anaphase
I. Meiotic divison
prophase
leptotene
zygotene
pachytene
crossing over
anaphase
diplotene
diakinesis
telophase
II.Meiotic division
anaphase
Another possibility of segregation
anaphase M I
telophase M I
Segregation of chromosomes – random according to parental origin
II.Meiotic division
anaphase
telophase
Gametogenesis – formation of gametes
migration of primordial germ cells to the gonads during early fetal development
number of mitotic division
Spermatogenesis
in the time of sexual maturity – continuous process
growth
spermatogonia
MI
primary spermatocyte
2 secondary spermatocytes
mitotic division
diferentiation
M II
1 cycle= about 9 weeks
4 spermatids
4 spermatozoa
Mitotic division
spermatogonia
growth
primary spermatocyte
MI
secondary spermatocyte
meiosis
M II
spermatids
maturation,
diferentiation
sperms
Spermatogenesis – in the time of sexual maturity
Oogenesis
MI till the end of prophase
diplotene=dictyotene
in the time of birth
3 month of fetal life
growth
Oogonia
primary oocyte
mitotic division
in the time of sexual maturity
M I continued
M II
secondary oocyte
+1st polar body
oocyte
+ 2nd polar body
ovulation in metaphase
anaphase + telophase
only after fertilization
prenatally
oogonia
Mitotic division
3rd months of fetal
life
primary oocyte dictyotene MI
at birth
growth
Sexual maturity
MI
1st polar body
meiosis
M II
secondary oocyte
Metaphase MII
- ovulation
2nd polar body
egg cell
Fertilization –
Ovum after MII-
pronucleus
pronucleus
Oogenesis
Anaphase,telophase
after fertilization
zygote
Degeneration of germ cells in ovary
5th month of fetal life
7 x 106 of cells
time of birth
2 x 106 of cells
puberty
ovulated
200 000 of cells
400 of cells
Long period between M I and ovulation = factor of nondisjunction
In older mothers increased risk of nondisjunctions !!!
Differences in male and female gametogenesis
Male
Female
Initiation
puberty
early embryonal life
Duration
60 - 65 days
10-50 years
Numbers of mitoses
30 - 500
20-30
Gamete production
4 spermatids
1 ovum+3 polar bodies
per meiosis
Gamete production
100-200 millions
per ejaculate
1 ovum per menstrual
cycle
 Fertilization
In metaphase M II
Male pronucleus (22 autosomes + 1 gonosome X or Y)
Female pronucleus completes M II (22 autosomes + 1 gonosome X)
Fusion of haploid nuclei = zygote – replication –
mitotic divisions
Spermatogenesis
MI
2n
spermatogonium
M II
n
primary
secondary
spermatocyte
n
spermatid
sperm
Oogenesis + fertilization
oogonium
I. meiotic division
primary
poar body
secondary
oocyte
2n
n
Fertilized ovum
fertilization and meiosis II
http://www.spacesciencegroup.nsula.edu/sotw/newlessons/defaultie.asp?Theme=humanbody&PageName=embryo
Consequences of meiosis
1. reduction of diploid chromosomal number to haploid
2. segregation of alleles in M I, M II (Mendel´s law)
(alelles segregate with homologous chromosomes)
3. random assortment of homologs – random
combination maternal and paternal chromosomes in
gametes (Mendel´s law) – genetic variability
4. increase of genetic variability by crossing-over
(chromatids with segments of maternal and paternal origin)
Errors of meiosis
 Nondisjunction in M I = failure of homologs to disjoin
 Nondisjunction in M II = failure of chromatids to disjoin
consequences for 1 chomosomal pair:
disomic + nullisomic gametes
after fertilization: trisomic or monosomic zygote
consequence for all chromosomal set: diploid gamete
after fertilization: triploid zygote
 Anaphase lag of 1 chromosome
consequence: nullisomic gamete
after fertilization: monosomic zygote
error in meiosis
46
46
MI
23
24
23
22
M II
23
23
23
23
24
24
22
22
Nondisjunction in M I
Normal meiosis
Consequences: trisomy/monosomy
after fertilization
46
46
MI
23
22
23
23
(X chrom.)
M II
24
22
23
23
22
22
23
22
Nondisjunction in M II
Anaphase lag in M I or M II
Consequences: trisomy/monosomy
after fertilization
Consequence: monosomy after
fertilization
Errors in meiosis
46
46
MI
46
23
23
M II
46
46
23
23
46
Errors in meiosis– nondisjunction of all chromosomes (M I or M II)
Consequence: nonreduced gamete, triploidy after fertilization
Errors of mitosis
• Nondisjunction or anaphase lag – mosaic of two (or more) cell
lines with different karyotype
• Endoreduplication – division of chromosomes without division of
cell - tetraploidy
46
46
46
46
46
46
46
46
47
46
47
45
47
Nondisjunction in mitosis → mosaic - trisomic and normal cell lines
(monosomy of autosomes is lethal !!!)
46
46
-X
MI
47
46
45
45
M II
47
47
45
45
Nondisjunction
Consequence: trisomy/monosomy (X)
mosaic
46
46
45
45
anaphase lag
monosomy (X) in mosaic with
normal cell line
Origin of mosaic from trisomic zygote
24
23
47
47
47
47
47
47
46
47
47
47
chromosome loss
47
47
47
46
46
Endoreduplication – division of chromosomes without
division of cell
46
92
tetraploidy
Errors of crossing-over
Unequal crossing-over → interstitial duplication and deletions
Crossing-over involving structurally abnormal chromosome (with
balanced aberration) and normal homologue → unbalanced
abnormality
Error in centromere splitting
Transverse splitting - izochromosome of one arm
Errors in fertilization
• Dispermy = fertilization of ovum by two sperms →
triploidy (69,XXX or XXY)- partial mole (abnormal pregnancy
= abundant trophoblast, poor embryonic development – in case of
additional paternal chromosomal set !!)
• Fertilization of ovum and polar body, each of them by
sperm with different gonosome → chimaera (46,XX/46,XY)
Errors in
fertilization
23,X
46
XX
fertilization
23,X
69
XXY
triploidy
Dispermy-fertilization
of ovum by 2 sperms
23,X
23,X
46XX/46,XY
fertilization of ovum and polar
body – origin of chimaera
Parthenogenesis
Gynogenesis - ovarial teratoma (benign tumor) = division
of ovum without fertilization (duplication of chromosomes,
karyotype 46,XX)
Androgenesis - hydatiform mole - complete (= pathological
pregnancy = hypertrophy of trophoblast, fetal tissues are not
present)
origin: dispermy or duplication of sperm chromosomes in ovum
with completely destroyed female nucleus
x
Partial mole = triploid product with additional set of paternal chromosomes
(hypertrophy of trophoblast + reduced embryonal tissues)
enucleated egg
Duplication of
chromosomes
46
XX
dispermy
46
XY
Origin of complete mole - only paternal chromosomes absence of maternal contribution !
Thompson &Thompson: Genetics in medicine,7th ed.
Chapter 2: The human genome and chromosomal basis of
heredity: Cell cycle, Mitosis, Meiosis,, Human gametogenesis
and fertilization
Chapter 5 (part) Abnormalities of chromosome number (origin
of triploidy tetraploidy, aneuploidy, hydatiforme moles,ovarial
teratomas)
+ informations from presentation
http://dl1.cuni.cz/course/view.php?id=324