Transmission of genetic information Genetics and genomics for 3 rd year Dentistry students...
-
Upload
kory-morris -
Category
Documents
-
view
218 -
download
0
Transcript of Transmission of genetic information Genetics and genomics for 3 rd year Dentistry students...
Transmission of genetic information
Genetics and genomics for 3rd year Dentistry students 13.02.2015.
Genetic informations (DNA) is passed
- within cells of an organism
- from one generation to next
generation
Multicellular cell cycle
GoG2
G1
S
M-phase
Restriction point
G2
M
- Growth factors- anchorange
mitosis cytokinesis
Interphase
Checkpoints:
Restriction pointG2M (spindle)
Regulators of cell cycle
cyclin dependent kinases (Cdk-s) cyclins phosphatases
other kinase regulatory proteins: activating and inhibitory kinases, kinase inhibitors, Aurora and polo like kinases (Plk) ubiquitin ligases
universal and conservative
Due to the activity of cell cycle and checkpoint machinary
DNA and centrosome are duplicated (interphase – S-phase)
and halved in M-phase (mitosis) with high fidelity
Genetically identical cells
Intact DNA is replicated in then is precisely halvedsemiconservative way (for this centrosome is(only once), needed)
G1 S meta-anaphase
Structure of centrioles and
centrosome (MTOC)
PCM = pericentriolar matrixTuRCs = tubulin ring
Distal appendages
Subdistal appendages
Different kinases regulate the duplication and separation of centrosome
M phase (events and
regulation)
Dramatic changes in M-phase (initiated by MPF)
DNA microtubules nuclear envelope marker
Interphase metaphase
telophase
anaphase
Initiation of M-phase: activation of MPF (M-phase promoting complex=Cdk1-B
cyclin)
Cdk1
B cyclin
Activating kinase
Inhibitory kinase
MPFiMPFi
phosphatase
MPFa
Main substrates of MPF
• lamins of nuclear lamina nuclear envelope breaks down
• condensin complex chromosome condensation
• MAP-s (microtubule associating proteins) mitotic spindle formation
• phosphatase (+ feedback) activation
• GM130 (Golgi matrix protein) disruption of Golgi
• myosin II
• activation (indirectly) of APC (anaphase promoting complex)There are much more substrates of MPF
from DNA to chromosome
Phosphorylation of condensin
induces the condensation of DNA
Cohesin Condensin
Cornelia de Lange syndrome (SMC = structural maintance of chromosomes = ATP-ases + other proteins)
Cohesin Condensin
Cornelia de Lange syndrome (SMC = structural maintance of chromosomes = ATP-ases + other proteins)
Centromere and kinetochore are not the same structures
telomere Chromosomal passenger complex
Kinetochore
Scleroderma
Autoimmune disease – autoantibodies produced againts kinetochore proteins
Mitotic phases
Mitotic spindle in metaphase
polar
Types of kinetochore–microtubule attachments
Normal in mitosis
not normal in mitosis
Kinetochors are
Bioriented
Monooriented
Monooriented
bioriented
Mitotic phases
If kinetochor MT-s are attached to all kinetochors ensuring precise segregation of duplicated DNA, checkpoint machinary allows the cell to step over M checkpoint and it enters anaphase and M-phase is completed.
In anaphase sister chromatids separate.
Anaphase
(Kinetochore MT depolymerisation)
(Polar MT polymeriation)
Anaphase is promoted by Anaphase Promoting Complex (APC)
MPF indirectly activates APC (needed to complete mitosis and to start cytokinesis) APC is a ubiquitin ligase induction of protein degradation in proteasome
(Securin and B cyclin, protein binding the centrioles)
Different kinases regulate the duplication and separation of centrosome
APC
Cohesin Condensin
(SMC = structural maintance of chromosomes = ATP-ases + other proteins)
Separase (activated by APC) and Plk are needed for the separation of
cohesin
Nature Reviews Molecular Cell Biology
Kinetochores are bioriented Amphitelic attachment
1.
2.
Activity of APC
Separation of cohesin
Activation of phosphatases (completion of mitosis an d cytokinesis)
APC ubiqutination of B cyclin
degradation of B cyclin
MPFi activation of phosphatase dephosphorylation of lamins reformation of nuclear envelope condensin chromosome decondensation MAP-s disappearance of mitotic spindle (MPF effects are reversed) cytokinesis
Activity of APC
M-(spindle) checkpoint
APCAPC
APCAPC
Cdc20
Van szabad kinetochor
Cdh1
APCAPC
Cdc20
No free kinetochors
APC, stops in metaphaseAPC, stops in metaphase
M-(spindle) checkpoint
Free kinetochore
Types of kinetochore–microtubule attachments
Normal in mitosis
not normal in mitosis
Kinetochors are
Bioriented
Monooriented
Monooriented
bioriented
Activated M (spindle) checkpoint
Aurora B activates M-checkpoint machinary
Inactive M (spindle) checkpoint, enters anaphase
Cytokinesis is usually symmetric
(actin és myosin II)
Contractile ring
Asymmetric cytokinesis
Ontogenesis, gametogenesis (couse – asymmetric mitotic spindle)
There are several forms of atypical mitosis (M-phase)
• Have been listed and shown in practice
• They result genetically different cell populations
in an organism mosaicism
which can be the cause of genetic diseases (see later)
Type Description Consequence
Typical Genetically identical cells.
Atypical Genetically not identical cells
(In the organism: mosaicism)
Endomitosis (Endoreduplication)
DNA is duplicated, but during M-phase the nuclear envelope remains intact. - No separation of chromatids- Separation of chromatids
Giant cell, giant nucleus
Polythene chromosomesMore chromosome (polyploid cell)
No cytokinesis Mitosis is not followed by cytokinesis.
Multinucleated (giant ) cells.
Multipolar division Due to atypical duplication and division of centrosome chromosomes are pulled to more than two poles
Different chromosome number.
Bridge formation (anaphase lag)
A chromatid is pulled from two poles.
Breakage of chromosome (structural chromosomal aberration)
Non-disjunction Lacking of kinetochor microtubules of a chromatid.
Change of chromosome number.
Strebhardt et al. Nature Reviews Cancer 6, 321–330 (April 2006) | doi:10.1038/nrc1841
Transmission of genetic information from generation to generation
- asexual reproduction – offsprings are genetically identical with the parent (clones)
- sexual reproduction – offsprings differs from the parents and from each other (genetic variability)
Genetically identical cells in an organism
Genetically different cellsGenetically different individuals
Genetic variability
- significance
- is increased by – mutations
– sexual reproduction
meiosis (generation of gametes)
- homologous recombination (crossing over) - independent assortment of homologous chromosomes
fertilisation
Genetic variability is important in prokaryotes,too
Provided by horizontal gene transfer
Significance of meiosis
- genetic variability (genetically different cells)
- chromosome number is halved (2n n)
Meiosis
DNA replication (S) - Meiosis I – prophase metaphase anaphase telophase DNA replication
- Meiosis II – prophase metaphase anaphase telophase
Meiosis I. Prophase
Leptotene
Bouquet arrangement = by their telomeres chromosomes bind to nuclear envelope later gather at one site - possible role of cytoskeleton - significance: chromosomes are closer to each other
telomeres
MTOC
Zygotene
Synapsis (pairing) of homologous chromosomes by the help of synaptonemal complex Bivalent chromosomes - tetrads formation,pseudoreduction
Paternal chromosome maternal chromosome2 sister chromatids 2 sister chromatids
By Chung-Ju Rachel Wang, Department of Molecular and Cell Biology, University of California, Berkeley, USA. 2nd Prize.Olympus BioScapes Digital Imaging Contest
Zygotene
Pairs of chromosomes
Homologous chromosomes
similarity – same shape, size and genes
differences – different origin, (maybe) different allele of a gene
In a diploid human cell:22 pairs autosomes1 pair sex chromosomes XX or XY
Pachytene
Homologous recombination = crossing over
Crossing over is obligatory (between non sister chromatids) Number of crossing overs: 13/chromosome pair
Pachytene Homologous recombination = crossing over
paternal maternal
Recombination of paternal and maternal DNA sequences (genes)
Centromere–blueRecombination -yellow
Pairing and recombination even between X an Y
Diplotene
Kiazmákchiasmata
Separation of chromosomes (detachment of synaptonemal complex)
Sites of crossing overs = chiasmatabecome visible
Meiosis I prophase
Több száz DSB DBS-ek axiálisan DBS-ek többsége kijavítódik szinapszis megszűnik(hot spot-ok, SPO11 szinapszis néhány crossing over crossing over maradIndukálja) kialakul kiazma
DNAs are bound by cohesin
DBS= double stranded DNA break
Kohezin csak a centromer regióban marad a karokról leválik
Meiosis I prophase
Several hundreds DSB DBS-ek axiálisan DBS-ek többsége kijavítódik szinapszis megszűnik(hot spots, induced by SPO11) kiazma
DNAs are bound by cohesin
DSB= double stranded DNA break
Kohezin csak a centromer regióban marad a karokról leválik
Synaptonemal complex
Appears
Meiosis I prophase
Several hundreds DSB DSB-s are axial DSB-ek többsége kijavítódik szinapszis megszűnik(hot spots, induced by SPO11) kiazma
DNAs are bound by cohesin
DSB= double stranded DNA break
Kohezin csak a centromer regióban marad a karokról leválik
Synaptonemal complex Synaptonemal complex
Appears
Meiosis I prophase
Several hundreds DSB DSB-s are axial DSB-s are repaired szinapszis megszűnik(hot spots, induced by some become CO SPO11)
DNAs are bound by cohesin
DBS= double stranded DNA break
Kohezin csak a centromer regióban marad a karokról leválik
Appears
Synaptonemal complex
Meiosis I prophase
Several hundreds DSB DSB-s are axial DSB-s are repaired(hot spots, induced by some become CO SPO11)
DNAs are bound by cohesin
DBS= double stranded DNA break
Kohezin csak a centromer regióban marad a karokról leválik
Appears diappears
Synaptonemal complex
Meiosis I prophase
Several hundreds DSB DSB-s are axial DSB-s are repaired(hot spots, induced by some become CO SPO11) chiasmata are visible
DNAs are bound by cohesin
DBS= double stranded DNA break
cohesin detaches from arms, remains only at centromere
Appears diappears
Synaptonemal complex
Meiosis I. Meta-, ana-, telophase
Metaphase
sister chromatids are bound by cohesin (at centromer) homologous chromosomes are bound by chiasmata
homologous chromosomes are arranged in the equatorial plane
Anaphase
Independent alignment of
homologous pairs
independent (random) assortment of
homologous chromosomes
or
Number of variations in human 223= 8 x 106, Increased by homologous recombination (not shown in the figure)
Kinetochore orientation and separase activity in meiosis I
Meiosis I
shugosin
shugosin
Cooriented sister chromatids of a chromosome (bioriented bivalents)
Telophase and cytokinesis
2 haploid (2 sister chromatids) (halving of chromosome number =
reduction division)
What does ensure chromosome number reduction (in meiosis I)?
• Synapsis (- recombination – chiasma) connecting
homologous chromosomes
• Cooriented sister chromatids of a chromosome (bioriented bivalents)
• Cohesin is separated only from arms
Significance of synapsis
A spermatocyte from an infertile man immunostained with antibodies against SCP1 and SCP3 (red) to observe synapsis, MLH1 (green) to visualize sites of recombination, and CREST antiserum (blue) to identify centromeres. Meiotic defects, such as abnormal recombination and an increase in unpaired regions (arrows) were observed in some members of the infertile population.
No synapsis,
no segregation
Abnormal chromosome number
Meiosis II.
- before it there is NO DNA replication
- Meiosis II. is like mitosis
4 haploid (1 sister chromatids), genetically different cells
Kinetochore orientation and separase activity in meiosis II
Meiosis I Meiosis II
shugosin
shugosin
Homologous recombination and independent assortment of homologous chromosomes
Segregation of sister chromatids
Significance of meiosis
- genetic variability (genetically different cells)
- chromosome number is halved (2n n)
Atypical meiotic processes
• May cause chromosome abnormalities in gametes
• Which in turn may cause genetic diseases
Meiosis II
Non-disjunction
Meiotic non-disjunction and its consequence
Aneuploid genom mutation
If non-disjunction occurs in spermatogenezis
Meiosis I meiosis II
Meiosis is part of gametogenesis
-gonium (46)
Primary gonocyte (46)
Spermium (23)
In embryo
From Puberty
Zygote (46)
polocytes
Secondary gonocyte (23)
polocyte
spermatid
Spermatocyte Oocyte
synapsis starts
At the end of chromosomes
Inside the chromosomes
Synaptonemal complex
compact Less compact
shorter longer
Sites of chiasmata
(green in figures)At the end of chromosomes
Inside the chromosomes
Number of chiasmata
less more
Primary spermatocyte
Primary oocyte
Sex specific differences in meiosis I prophase
Sex differences differences in non-disjunction
Meiotic (I and II) non-disjunction may occur both in oogenesis and spermatogenesis
BUT
More frequent in oogenesis
Sex chromosome non-disjunction is more frequent in spermatogenesis
Regulation
Regulation of meiosis in oogenesis
main regulator is MPF (maturation promoting factor)
Causes of major specificities of
female meiosis
Retinoic acid (RA) induces meiosis in female embryo
Meiosis inhibiting factor
Inaktív MPF
Arrest in prophase I diplotene (in embryo) cAMP
Inhibitory kinasez phospatase
InactiveMPF
Unknown ligand or constituvily active receptor
Adenylylcyclase (active)
meiosis stops
Primary oocyte
cAMP may enter the cells throug gap junctions from neighboring cells
phosphodiesterase (inactive)
Green – activered - inactive
Release from meiosis I prophase (from puberty) Effect of LH (from granulosa cells):
Inhibitory kinase phosphatase
Aktive MPF
Meiosis continues
cAMP
Green – activered - inactive
Adenylylcyclase (inactive)
Primary oocyte
phosphodiesterase (active)
C mos protein synthesis
MAPK activation
APC inhibitor
APC inhibition
Stop in metaphase II
Arrest in metaphase II(secondary oocyte)
caused by CSF-cytostatic factor (?)
Regulation of meiosis in oogenesis
Regulation of meiosis in oogenesis
Release from metaphase II(secondary oocyte) arrest
due to fertilisation
Ca ion inactivation of APC inhibitor APC activation completion of meiosis
Genetically identical cells in an organism
Genetically different cellsGenetically different individuals