WJL Intro and Topic 1 - Chrom Trans Eukaryotes (Student)

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Molecular Genetics

LSM2105

Course Introduction
&
Topic One: Chromosome in Eukaryotes

WU Jinlu

dbswjl@nus.edu.sg; 65168476; S1A-04-06 1


Download/Update Poll Everywhere mobile app for active participation during
lecture

https://www.polleverywhere.com/mobile
Responding via the web
During class, I will display a Poll Everywhere activity on-screen
on a web address: PollEv.com/wujinlu From your phone, laptop,
or tablet you can enter the web address and will be taken to a
screen that allows you to respond to the activity.

Responding via the mobile app


For quick, regular access to Poll Everywhere, it's best to
download and install the mobile response apps:
During class you can launch the app and go to the web response
page that the instructor displays on-screen. 2
3
What is genetics?

• Genetics: the scientific study of inheritance and its underlying


mechanisms.
• Genetics: The study of the structure and function of genes
and the transmission of genes from parents to offspring.
• Genetics is devoted to the study and manipulation of
heredity and variation in living organisms. (Stanford Encyclopedia of
Philosophy, Aug 13, 2019; https://plato.stanford.edu/entries/genetics/)

What is your perception and questions


about Genetics?

4
Genotype vs Phenotype
Complex traits such as eye color are the products of many genes working
in concert.

Core genes & Peripheral genes

The “omnigenic” model of complex traits (vs “monogenic” and “polygenic”)

https://www.quantamagazine.org/omnigenic-model-suggests-that-all-genes-affect-every-complex-trait-
20180620/ 5
We must be able to
explain Genetics from
both nature and
nurture perspective.

6
Epigenetics

7
Genetics Without the “Epi” Prefix Is Incomplete

8
How a scholarly spat shaped genetic research

Conrad Waddington named


(1942) this phenomenon
‘epigenetic inheritance’. That this
idea was rejected for decades is a
testament to the tenacious hold of
William Bateson (left) and Raphael Weldon had Mendelian inheritance.
distinct ideas about the nature of inheritance in
1900 9
Why study Genetics?

• To get 4 MC with A grade ?

• Genetics is everywhere in our life.

• Sydney Brenner, writing in the 100th issue of Trends


in Genetics in 1993, made the prediction that
genetics as a separate subject would have
Brenner 2002 disappeared by the year 2000, because all biology
would be gene-centred and all biologists would be
geneticists.
The Nobel Prize in
Physiology or Medicine 2002
• Geneticists believe the knowledge, methods and
Sydney Brenner techniques of genetics are applicable throughout the
H. Robert Horvitz spectrum of biological activity!
John E. Sulston
http://www.gen.cam.ac.uk/undergraduate/whygenetics 10
Foundation of modern biology
• Molecular Cell Biology
• Genes, Genomes and Biomedical
Implications
• Cell Biology
• Molecular Basis of Human
Diseases
• General Virology
• Developmental Biology
• Epigenetics in Human Health and
Diseases
• Genomic Data Analysis
• Evolution and Comparative
Genomics
• Functional Ageing
• Genetic Medicine in the Post-
Genomic Era
• Stem Cell Biology
• Reproductive Biology
• Advanced Epigenetics and
Chromatin Biology
• Tumour Biology
• ……..
11
Lecturers Key Words
Sem I & II
Dr Wu Jinlu Chromosome
Block S1A, Level 4 Transmission, Structure,
Tel: 65168476 (office) Organization, and
Email: dbswjl@nus.edu.sg Recombination

Sem I Sem II
Features of DNA & RNA
A/P Cynthia He A/P Liou Yih Cherng Advanced Genetic
Block S1A Level 6 Block S3 Level 6 Methods/Technologies
Tel: 65167377 (office) Tel: 65167711 (office) Model organisms in
E-mail: dbshyc@ E-mail: dbslyc@ Genetics
……
Sem I & II
A/P Chew Fook Tim
Mendelian Genetics,
(Module Coordinator)
Population Genetics,
Block S2, Level 5
Quantitative Genetics
Tel: 65161685 (office)
…..
Email: dbscft@nus.edu.sg 12
Lecture / Tutorial (Will be webcast and recorded)
ek Month
Tue, 10-12pm, LT26 Thu, 10-12pm, LT26
Orientation: Mon, 7 Aug – Sat, 12 Aug 2023 (1 week)
15 Overview of Genetics & Chromosome 17 Cellular Division: Mitosis and Meiosis; Non-
Aug in Eukaryotes (WJL, Section 1) Disjunction and Polyploidy (WJL)
22 Chromosome in Prokaryotes, Genetic
24 Chromosome Compaction, Structure, Organizat
Transfer and Mapping Analysis in
(WJL)
Microorganisms (WJL)
29 Chromatin Remodeling and Gene
Dr Wu Expression (WJL)
31 Chromosome Recombination (WJL)

05 Continual Assessment 1 (fixed date


20% CA1 Sep and time, face to face test, no
replacement test) (WJL, Section 1 only)
07 Structure-function of DNA and RNA; (CH, Sectio

12 DNA Replication (CH) 14 Gene Transcription and RNA Processing (CH)

19 Translation of mRNA (CH) 21 Forward and reverse genetics (CH)


Recess Week: Sat, 23 Sep – Sun, 1 Oct 2023 (1 week)
05 Continual Assessment 2 (fixed date and time, fac
Oct 03 New genetic technology (CH) face test, no replacement test) (CH, Section 2 only) CA2 20%
12 Mendelian Genetics – Sex Linkage, Modes of
10 Mendelian Genetics – Terminologies,
Inheritance, Pedigree Analysis, Penetrance, Expres
Mendelian Laws (CFT, Section 3)
Pleiotropy (CFT)
17 Variations to Mendelian Genetics – 19 Variations to Mendelian Genetics – Epistasis Mo
Multiple Alleles, Epistasis (CFT) (CFT)

Dr. Wu’s part: 24 Variations to Mendelian Genetics –


Lethal Genes, Linkage (CFT)
26 Tutorial: Pedigree Analysis (SL)

31 Population Genetics – Hardy Weinberg


Oct/Nov Equilibrium, Allele Frequencies, Non- 02 Tutorial: Chi-Squared Analysis in Genetics (SL)
15% from CA random Mating (CFT)
07 Population Genetics - Population

+5% PeerWise
09 Quantitative Genetics – Statistical Description of
Nov Genetics – Mutation & Selection Forces;
Maintenance of Polymorphism (CFT)
Quantitative Traits (CFT) A/P Chew
assignment
14 Quantitative Genetics – Polygenic 16 Continual Assessment 3 (fixed date and time, fac
Inheritance, Heritability, Breeding,
Heterosis (CFT)
face test, no replacement test) (CFT, Section 3 only,
CA3 20%
All contents
OPEN book test – hard copy, no internet)
Reading Week: Sat, 18 Nov – Fri, 24 Nov 2023 (1 week)
Final Examination: Tue 5-Dec-2023, 9am (fixed date and time, face to face exam, CLOSED book, fixed date
40% Final time, no replacement exam) (All Sections included, All MCQs); venue to be announce later by Registrar’s Of
(and updated at the course Canvas site) 13
Vacation: Sun, 10 Dec 2023 -Sun, 14 Jan 2024 (5 weeks)
https://peerwise.cs.auckland.ac.nz/home/
Weekly
Timeline

Course ID 26240
The deadline is at
11:59pm on Sundays, LSM2105AY2324SemI
(Topics 1 & 2 on 27th
Aug, Topic 3 & 4 on
Your participation will contribute 5% to your final module grade
10th Sept 2023.
Wait for the details to be announced
5 marks: 4 MCQs+5 Answers+5 Comments 14
What & Why students do?
Ownership of Learning; Peer Learning; Collaborative Learning, Self-directed Learning
Pearson’s correlation coefficient between examination scores and students’ accomplishment on
PeerWise

No. of questions No. of answers No. of correct No. of comments No. of ratings
Academic Year and Semester
authored submitted answers submitted submitted

AY18/19 Sem I .042 .162** .183** .261** .118


AY18/19 Sem I -.038 .114 .134 .151* .190**
AY19/20 Sem I .109 .265** .258** .145** .262**
AY19/20 Sem II .045 .313** .330** .125 .260**
AY20/21 Sem I -.148* .259** .304** .122 .242**
AY20/21 Sem II .069 .079 .099 .098 .102

Total reputation Total answer Question authoring Question answering Question rating
Academic Year and Semester Badge scores
scores scores component component component
AY18/19 Sem I .355** .189** .327** .248** .209** .342**
AY18/19 Sem I .199** .138 .179* .132 .191** .200**
AY19/20 Sem I .353** .263** .262** .245** .226** .365**
AY19/20 Sem II .420** .334** .298** .316** .398** .221**
AY20/21 Sem I .316** .310** .170** .313** .274** .190**
AY20/21 Sem II .235** .104 .182* .119 .142 .175*
15
How I am going to teach?

I am not a commander
Assimilation but not Transmission

16
Climbing Mountains Together

Learning is similar to climbing

Facilitating Motivating

Teachers as Sherpa guide 17


Be organized

https://starsandjars.com/2019/02
/18/the-jar-of-life-a-story/
18
Happy Journey

19
What I am going to teach?
Four Topics on Chromosome

1.Separation and Transmission


(eukaryotes)
2. Separation and Transmission
(Prokaryotes)
3. Structure and Organization
4. Recombination and Abnormalities
20
Topic 1
CHROMOSOME REPLICATION AND TRANSMISSION IN
EUKARYOTES

Chapter 3 Chapter 2
Topic 1: Intended Learning Outcomes (ILO) and Threshold Concepts

After learning the first topic, you will be able to

1. Describe chromosome behavior in the stages of mitosis/meiosis and recognize diagrams/images


associated with this process.
2. Explain mechanisms of the chromosome alignment at metaphase and segregation at anaphase,
and the forces involved in the events.
3. Explain the synapsis and crossover in meiosis.
4. Apply the above knowledge to explain genetic variations
5. Analyze the genetic base of sterile (in mules and other hybrid organisms), Down syndrome, non-
disjunction and genetic disorders, etc.

Threshold Concepts:

• Force Balance model


• Segregation of sister chromatids
• Homolog Recognition and Synapsis
• Crossover
• Reduction division

22
Topic 1: Learning Plan

Topic Activities for online session (pre-class)


Activities for face-to-face session (F2F; Assignments/Assessments
in-class) (post-class)
Topic One • Read lecture notes and intended • Overall introduction of module • View e-tutorial (1)
(two lecture sessions) learning outcomes (ILO) to have a learning outcomes, structure, syllabus, video (10 min)
brief idea about this topic. assessment, etc. • Try Track-Learning
Cell division and • Watch video: Cell cycle and mitosis • F2F activities are planned on your questions (LumiNUS)
Chromosome https://www.youtube.com/watch?v=7NM- basic understanding of chromosome • Find your questions of
Transmission in UWFHG18 (7 min) separation of both mitosis and meiosis interest in FAQ-Topic 1
Eukaryotes • Watch video: Meiosis-plant and • Discuss selected questions from • Supplementary Video
animals students (optional)
https://www.youtube.com/watch?v=jjEcH • Explain following concepts in detail Chromosome Dynamic
ra3484 (7 min) (chromosome alignment at metaphase, during meiosis (Abby
• Try LumiNUS quizzes segregation at anaphase, synapsis and Dernburg (UC
• You are expected to know the process crossover) Berkeley)
and stages of mitosis and meiosis • Demonstrate the process of synapsis https://www.youtube.com/
• Post and discuss your questions on • Analyse genetic disorder due to non- watch?v=RMI4-C7A0sw
LumiNUS forum disjunction (15min)
• Poll Everywhere quizzes
23
Successful Learners/Teachers
• Biological Questions
• Threshold Concepts
Knowledge • Problem Solving
Skills

• Practice Learning
• Measure Learning

In-class Quiz Videos • Watch Videos before


Tutorial Qs Lecture Notes class
PeerWise Readings • Improve Understanding
during class

Constructive Alignment 24
Online Quizzes/Track learning Qs (not graded)

25
Chromosomes
GENERAL FEATURES OF CHROMOSOMES

Greek khrōma colour + sōma body


Chromosome is the structures
within cells that contain the
genetic material.

Biochemically, chromosomes are


composed of
– DNA, which is the genetic
material
– Proteins, which provide an
organized structure
26
Eukaryotic Chromosomes Are Inherited in Sets

• Most eukaryotic species are diploid (2n), two sets of


chromosomes in somatic cells
• Haploid cells contain half of the genetic material found in
somatic cells (diploid), such as gametes, (sex/reproductive
cells)
• Members of a pair of chromosomes are called homologues

• The two chromosomes in a


homologous pair are nearly
identical in size and structure
27
CELLULAR DIVISION

• Division for growth and


replacement (mitosis)

• Division for reproduction


(meiosis)

DNA management is key

28
Please watch the two short videos on YouTube before lecture

1. https://www.youtube.com/watch?v=7NM-UWFHG18
Cell Cycle and Mitosis (must watch)

1. https://www.youtube.com/watch?v=jjEcHra3484
Meiosis - Plants and Animals (must watch)

Q1. Replicated chromosomes are called ______________


Q2. Interphase can be divided into three distinct phases: ____, ____ and ____

29
Cell Cycle and Mitosis

https://www.youtube.com/watch?v=7NM-UWFHG18
30
Cell cycle in eukaryotic cells: the sequence of growth and
division of a cell; consists of Interphase (G1, S, G2), Mitosis
(nuclear division), and Cytokinesis (cytoplasm division)

The "M" in M phase, represents a


combination of nuclear division and (mitosis & cytokinesis)
cytokinesis. It forms an entire cell
cycle with Interphase.

Not all cells are continually replicated.


Non-replicating cells are found in a
stage of the cell cycle called G0.
These cells may be quiescent
(dormant) or senescent (aging or
deteriorating). While quiescent cells
may re-enter the cell cycle, senescent
cells do not.
31
MITOSIS

Interphase = G1 + S + G2
Cells in G0 are in a non-
dividing phase

Mnemonic to
remember the order:
I Proudly Prefer Milk
And Tea 32
33
Interphase (G1, S, G2)

• A cell spends most of its


life in G0 or G1 phase, and
that is where the genome
does most of its work.
• Chromosomes are
replicated.
• The centrosomes are
replicated and divides.

34
Chromatid vs Chromosome

A chromatid is one of the replicated


copies of a chromosome.

35
0.5 µm Chromosomes DNA molecules

One chromosome,
One DNA molecule

Chromo-
Chromosome
some arm
duplication
(including DNA
synthesis)
Centromere
One chromosome,
Two DNA molecules
Sister
chromatids

Separation of
sister chromatids

Centromere

One chromosome,
One DNA molecule
Sister chromatids per cell 36
• Note that at the end of S phase, a cell has twice
as many chromatids as there are chromosomes in
the G1 phase
– A human cell for example has
• 46 distinct chromosomes in G1 phase
• 46 pairs of sister chromatids after S phase
• Therefore the term chromosome is relative
– In G1 and late in the M phase (mitosis), it refers
to the equivalent of one chromatid
– In G2 and early in the M phase (mitosis), it
refers to a pair of sister chromatids

37
Phases of Mitosis

A simplified chart to focus on the


chromosome replication and division

38
Mitosis is subdivided into five phases
(PPMAT)

– Prophase
– Prometaphase
– Metaphase
– Anaphase
– Telophase

39
Prophase

• Chromatin condenses
into chromosomes.
• Nuclear envelope
dissociates into smaller
vesicles
• The mitotic spindle
apparatus/mitotic
spindle starts forming

40
Prometaphase
• Centrosomes move to
opposite ends of the cell and
demarcate two spindle
poles.

• Spindle fibers grow from the


two poles

• The two kinetochores on a


pair of sister chromatids are
attached to kinetochore MTs
from opposite poles
41
Kinetochore structure

Contacts the centromere Inner Centromeric


plate DNA
Middle
Contacts the inner and layer
outer plates Outer
plate
Kinetochore
Contacts the kinetochore microtubules
microtubule
Spindle pole:
a centrosome
Aster
with 2 centrioles microtubules

Kinetochore

Metaphase Astral microtubules project toward


plate Sister the cell cortex, interpolar
chromatids
microtubules extend between the
Polar two spindle poles, and kinetochore
microtubules Kinetochore microtubules (k-MTs) interact with
microtubules kinetochore protein complexes

42
Mitotic Spindle Apparatus
Metaphase
• Pairs of sister
chromatids align
themselves along a
plane called the
metaphase plate
Equator
• Each pair of chromatids
is attached to both poles
by kinetochore
microtubules
44
How chromosomes are able to line up at the metaphase plate?

Thinking

???

Prometaphase Metaphase 45
How opposing forces may drive chromosomes to the
metaphase plate?
(Counter force balance model and Bipolar force balance model)

Expt Conclusion
Interpolar
or astral
microtubule

Astral ejection force

astral ejection force Poleward forces on


kinetochore

Depolymerization at the plus end


of the microtubules generates
poleward force (pull force)

46
http://www.ncbi.nlm.nih.gov/books/NBK26934/
Basics of Motor proteins FYI

Head domain

Tail domain

47
Dynamic instability of microtubules

Polymerization

De-polymerization

With minus ends of most microtubules anchored in the centrosome,


microtubules grow and shrink mainly through addition and loss of tubulin 48
heterodimers at their plus ends.
Synchronized movement of
chromosomes

• All chromosomes
must align on the
metaphase plate

• All sister chromatids


migrate synchronously
toward opposite poles

49
Anaphase

• The connection holding


the sister chromatids
together is broken
• Each chromatid, now
an individual
chromosome, is linked
to only one pole

50
ThePenguinProf: Cell Cycle and Mitosis
51
Mechanical force in the segregation

Shortening of kinetochore microtubules generates pull force to segregate sister chromatids;


forces generated mainly at kinetochores

+
2 +

1 kinesin

1) A sliding force is generated btw overlap microtubules from opposite poles to push
the poles apart;
2) Aster microtubules attach to cell membrane, when cell elongates, a pulling force 52
acts directly on the poles to move chromosomes apart
Anaphase A chromosome movement

Chromosomes move toward the spindle


poles along the kinetochore microtubules.
Chromosome movement is thought to be
driven by minus end-directed motor
proteins associated with the kinetochore.
The action of these motor proteins is
coupled to disassembly and shortening of
the kinetochore microtubules.

How disassembly and shortening happen ?


>>>>> next slide 53
Among many puzzling phenomena, one that
remains to be solved is

how kinetochores are able to maintain


attachment to shortening microtubule tips
during metaphase and anaphase.

54
a) Hill sleeve model: kinetochore–
microtubule bonds are arranged in FYI
series and require nearly synchronous Affinity force
detachment and re-attachment of all
bonds for relative movement of the
microtubule and the kinetochore.

b) Kinetochore motors model: a tug of war


between the plus- and minus-end-
directed motors, CENP-E and dynein,
powers the movement of the The detail
kinetochore along the microtubule is Not
lattice, whereas members of the required
kinesin-13 family depolymerases for this
shorten the lattice at both ends. module

c) Non-motor kinetochore–microtubule
coupler model: flexible non-motor
proteins, Ndc80, bind to and detach
from the microtubule independently
from one another and serve as dynamic
couplers between the kinetochore and
the spindle microtubules. 55
Spindle pole separation in anaphase B.

The separation of spindle poles results


from two types of movement. First,
overlapping polar microtubules slide past
each other to push the spindle poles
apart, probably as a result of the action of
plus end-directed motor proteins. This
requires assembly of polar microtubules at
its plus end, so that plus end-directed
motor proteins can move continuously.

Second, the spindle poles are pulled apart


by the astral microtubules. The driving
force could be either a minus end-directed
motor anchored to a cytoplasmic
structure, such as the cell cortex, or a plus
end-directed motor associated with the
spindle pole.

56
Spindle pole separation in anaphase B.
When this plus end directed
motor protein move to plus
Direction of move
end of astral microtubule, it
brings entire centrosome and
also the chromosomes move
to the cell cortex.

Cell cortex

This motor protein is to


exert pulling forces on
the plus ends on astral
microtubules

57
Nondisjunction

Nondisjunction is the failure of


homologous chromosomes or sister
chromatids to separate properly during
cell division.

a). Produce a trisomic (having a single extra


chromosome in the cell in addition to the
normal diploid number)and a monosomic
cell (A diploid cell missing a single
chromosome.)

b). Produce a normal and a monosomic


daughter cell

58
Telophase and Cytokinesis
• Chromosomes reach
their respective poles
and decondense

• Nuclear membrane
Contractile ring
reforms to form two (myosin and actin)
separate nuclei

• In most cases, mitosis is


quickly followed by
cytokinesis
59
Mitosis Animation

60
http://www.youtube.com/watch?v=VlN7K1-9QB0&feature=related
Summary
of mitosis

Cell cycle (cell-division or cycle reproductive): the orderly sequence of events by which a
cell duplicates its contents and divides into two.

The M phase (cell division) includes various stages of nuclear division (prophase,
prometaphase, anaphase, and telophase), and also cytoplasm division (cytokinesis),
which overlaps the final stages of mitosis.

Chromosome set (n): The chromosomes of a haploid genome. Sperm and egg cells carry a
single chromosome set and are said to be haploid (they have n chromosomes and a DNA
content of C). For human cells, n=23 and C is about 3.5 pg.

Mitosis maintains the cell's original ploidy level (for example, one diploid 2n cell producing
two diploid 2n cells; one haploid n cell producing two haploid n cells; etc.).
61
Summary
of mitosis

62
Key Concepts of mitosis

Prometaphase to Metaphase Anaphase

Kinetochore–microtubule interactions
63
Move beyond the syllabus FYI

Microtubule Sliding within the Bridging Fiber Pushes Kinetochore


Fibers Apart to Segregate Chromosomes
Developmental Cell, 2017

64
MEIOSIS

Meiosis I and II

Special type of cell division by


which eggs and sperm cells are
produced. It comprises two
successive nuclear divisions
(meiosis I and II) with only one
round of DNA replication, which
produces four haploid daughter
cells from an initial diploid cell.

65
Cell Cycle and Mitosis

https://www.youtube.com/watch?v=jjEcHra3484
66
MEIOSIS

Germline Cells
(Germ Cells in Gonads)

Gametogonium
(plural gametogonia)
(2n)
(mitosis)

(spermatocyte) Gametocytes (oocytes)


(2n)

Spermatogenesis / Oogenesis
(meiosis)

Sperm / Egg
(gametes, n) 67
Sister Chromatids vs Homologous Chromosomes

A chromatid is one of the replicated copies of a chromosome. Identical sister chromatids


are produced as a result of DNA replication. In contrast, homologous chromosomes
derive from either the mother or the father of the organism, and although they contain the
same set of genes, they usually have genetic differences. 68
II

69
Meiosis I
Prophase I
Homologous maternal and paternal chromosomes pair, synapse, and exchange genetic
information (by homologous recombination), forming at least one crossover per
chromosome

• Prophase I is further subdivided into stages known as


(LZPDD)
– Leptotene (thin threads)
– Zygotene (paired threads)
– Pachytene (thick threads)
– Diplotene (two threads)
– Diakinesis (moving through)
70
STAGES OF PROPHASE OF MEIOSIS I

Chiasma is to
establish physical
connections
between
homologous
chromosomes,
thereby ensuring
accurate
Tetrad chromosome
segregation and
producing
haploid germ cells

A physical exchange of chromosome pieces 71


How do they pair up?

Meiotic chromosomes: it takes two to tango 72


Homolog Recognition
and Synapsis

The Chromosomal Courtship Dance


— homolog pairing in early meiosis

The “Holy Grail” of meiosis

Microtubules Mediate
Meiotic Pairing and Synapsis

Spindle assembly checkpoint (SAC) components


73
Model of the “pairing center”

KASH-
Zygote defective protein 12

Sad-1/UNC-84 (SUN) domain

Zinc finger in Meiosis (ZIM)


Serine/threonine-protein kinase plk-2
Tumor suppressor serine/threonine-
protein kinase involved in synaptic
plasticity, centriole duplication and G1/S
phase transition.
74
Klarsicht/ANC-1/Syne/homology (KASH) domain
Chromosomes dance and pair up on the nuclear membrane

This simple model of a nucleus with only one pair of chromosomes illustrates the process of synapsis

The chromosomes attached by their pairing centers to proteins on the nuclear envelope,
which are linked to the cytoskeleton of the cell. The microtubules in the cytoskeleton
facilitate movement of the protein complex and associated chromosomes, promoting
encounters between chromosomes. Once the chromosomes come together, a protein
called dynein assesses whether or not the chromosomes are homologous and, if yes
(means that affinity force btw the pairing center is stronger than dynein force), allows
formation of a zipper-like synaptonemal complex between the two. If no (means that
affinity force btw the pairing center is weaker than dynein force, they are not homologues),
the dynein force will drive them apart, and searching homolog continues.
75
It takes two to tango
An analogy to teach biology concept

A short video clip from the movie “Scent of a Woman” (starring Al Pacino)

76
STAGES OF PROPHASE OF MEIOSIS I

Chiasma is to
establish physical
connections
between
homologous
chromosomes,
thereby ensuring
accurate
Tetrad chromosome
segregation and
producing
haploid germ cells

A physical exchange of chromosome pieces 77


Summary: a key event in prophase I

The homologous chromosomes recognition and pairing (synapsis) involves


following steps

1. Proteins complex (red dots shown on slide is the study from C. elegans) binds
to chromosome ends to form pairing centers.
2. The paring center is connected to microtubule cytoskeleton via protein bridges
(SUN and KASH proteins complex) that span the nuclear membrane.
3. Dynein (a motor protein) drives the chromosome moving around along the
nuclear membrane
4. When the two homologous chromosomes meet, pairing centers recognize each
other, then synaptonemal complex starts to form to enforce the pairing

78
https://www.youtube.com/watch?v=RMI4-C7A0sw; play first 4:30min min
79
MEIOSIS I Spindle apparatus completed.
Chromatids attached to KM.
Centrosomes Sister
with centrioles chromatids
Bivalent
Meiotic spindle

EARLY PROPHASE LATE PROPHASE PROMETAPHASE


Paired Nuclear
Synapsis of homologues membrane
homologous attached to Fragmenting
chromatids and kinetochore into vesicles
crossing over microtubules
80
Metaphase I
• Bivalents are organized along
Metaphase
the metaphase plate plate

– Pairs of sister chromatids are


aligned in a double row,
rather than a single row (as in
mitosis)
– Furthermore
• A pair of sister chromatids is
linked to one of the poles
• The homologous pair is linked
to the opposite pole
81
How chromosomes are able to line up at the metaphase
plate? Can the balanced models be applied for meiosis?

Thinking
Crossover is to
establish physical
connections between
homologous
chromosomes, thereby
??? ensuring accurate
chromosome
segregation and
producing
haploid germ cells

Prometaphase I Metaphase I
82
Independent assortment
refers to the random arrangement of pairs of chromosomes. The diagram
below shows four possible arrangements of chromosomes during metaphase 1
from an individual that has 6 total chromosomes. Suppose that the pink
chromosomes are those that the individual inherited from its mother and the blue
colored ones were inherited from its father. For each chromosome pair, the
chromosome that is on the left (maternal or paternal) is determined randomly. As
can be seen, there are several alignment possibilities.

A mathematical explanation of the possible number of different, random alignments, 2n where


the n equals the number of chromosomes per set; In this example, n=3, 8 possible
assortments of chromosomes in the gametes
The formula 2n

n=3

When n=3, it produce 8 different combinations of chromosome after meiosis , that


is 2^3
To illustrate this concept, consider the variety derived from just three hypothetical
chromosome pairs, as shown in the following example (Hirsch, 1963). Each pair consists of
two homologues: one maternal and one paternal. Here, capital letters represent the
maternal chromosome, and lowercase letters represent the paternal chromosome:
•Pair 1: A and a
•Pair 2: B and b
•Pair 3: C and c
When these chromosome pairs are reshuffled through independent assortment, they can
produce eight possible combinations in the resulting gametes:
•A B C; A B c; A b c; A b C; a B C; a B c; a b C; a b c
A mathematical calculation based on the number of chromosomes in an organism will also
provide the number of possible combinations of chromosomes for each gamete. In
particular, Sutton pointed out that the independence of each chromosome during meiosis
means that there are 2n possible combinations of chromosomes in gametes, with "n" being
the number of chromosomes per gamete. Thus, in the previous example of three
chromosome pairs, the calculation is 23, which equals 8. Furthermore, when you consider
all the possible pairings of male and female gametes, the variation in zygotes is (2n)2,
which results in some fairly large numbers.
85
The two pairs of sister chromatids Sister chromatids reach their
separate from each other (i.e respective poles and decondense
separate synapsed homologues) Nuclear envelope reforms to produce
However, the connection that two separate nuclei
holds sister chromatids together
does not break

METAPHASE TELOPHASE AND CYTOKINESIS


ANAPHASE

Cleavage
furrow
Metaphase
plate Nuclear
membrane
A dyad re-forming

At the beginning of Meiosis I In Each Cell after Meiosis I,


6 chromosomes Reductive Division 3 chromosomes
12 chromatids 6 chromatids 86
12 DNA molecules 6 DNA molecules
Meiosis II

At the beginning of Meiosis II, each cell has After Meiosis II, each cell has
3 chromosomes Equational Division 3 chromosomes
6 chromatids 3 chromatids
6 DNA molecules 3 DNA molecules

The two cells that begin meiosis II, each have 6 chromatids that are joined as three pairs of
sister chromatids. The sorting events that occur during meiosis II are similar to those that occur
during mitosis 87
COMPARE
of meiosis I and II

the mechanisms
of chromosome
alignment (at
metaphase) and
separation (at
anaphase) in
meiotic division I
and meiotic
division II

88
Nondisjunction during meiosis I and II

89
Applications
Down syndrome

Trisomy 21 90
Numerical chromosomal
aberrations of human

91
Why is the error rate is higher in female meiosis?

Thinking

How old are you?


Chromosome segregation in female
meiosis I (MI) is error-prone.
diplotene

Average % of genetically normal embryos


92
Drosophila melanogaster
Meiosis I (MI)
oocytes

“Our finding supports the


model that chiasmata
are destabilized by
gradual loss of cohesion
over time.”

Subramanian VV, Bickel SE (2008)


Aging Predisposes Oocytes to
Meiotic Nondisjunction When the
Cohesin Subunit SMC1 Is Reduced.
PLoS Genet 4(11): e1000263.
https://doi.org/10.1371/journal.pgen.
1000263 93
~1 in 600

Watch this video


for details

https://www.youtube.com/watch?v=4_8nmveyl1A

~1 in 2000

94
Summary: Meiosis

95
Summary: Meiosis

Watch Videos online


http://www.youtube.com/watch?v=R_LUJSqeSrI
http://www.youtube.com/watch?v=D1_-mQS_FZ0&feature=related 96
Summary: Mitosis vs Meiosis

• Mitosis produces two diploid daughter cells


• Meiosis produce four haploid daughter cells

• Mitosis produces daughter cells that are genetically


identical
• Meiosis produces daughter cells that are NOT
genetically identical

97
Critical thinking
/application
Infertility of mules
Mules are the result of a cross
between a horse (2n = 64) mother
http://www.horsegroomingsupplies.com/horse-
and donkey (2n = 62) father forums/attachments/horse-chat/45122-mules-
dressagemule.jpg

Liger Zonkey 98
What we did not touch/know

1. Cell cycle control


2. Mechanics
3. Other organelles
4.……

Ordinary bull or incredible hulk:


Muscles, Mutations, and
Myostatin
99
Jui-He Tsai, Bruce D. McKee
Homologous pairing and the role of pairing centers in
meiosis
J Cell Sci 2011 124: 1955-1963; doi: 10.1242/jcs.006387

Ofer Rog and Abby F Dernburg


Chromosome pairing and synapsis during
Caenorhabditis elegans meiosis
Current Opinion in Cell Biology 2013, 25:349–356
We are investigating how chromosomes are reorganized during this unique cell cycle by combining high-resolution
imaging of chromosomes in situ and in vivo with the molecular genetic advantages of C. elegans. A fundamental
goal of our work is to understand how specific DNA sequences confer not only gene expression patterns but also the
large-scale 3-dimensional organization of the genome.
100
~ The End ~
Wu Jinlu
dbswjl@nus.edu.sg
Tel: 65168476; S1A-04-06

101

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