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2007 Mutation and Cell division

M.T.Yeung P.1

Mutation
(http://www.tokyo-med.ac.jp/genet/index-e.htm)
- a sudden and relatively permanent, inheritable change in the amount or structure of genetic material (e.g.
DNA in the chromosome) of an organism
(resulting in a change in the phenotype of an organism)
-

sudden change in somatic cells (called somatic mutation) will not be inherited to individuals of the
next generation, but can be transmitted to its daughter cells inside the body via mitosis.

however, if mutation is occurred during gamete formation (i.e. germinal mutation) it might be
inherited to offspring and form new varieties.
provide raw material (variation) for natural selection in evolution.

- The mutated individuals are called mutants


show new phenotype that HAVE NEVER BE FOUND IN THEIR ANCESTORS
the change in character is due to mutation
Types of Mutation
A. Gene Mutation (Point Mutation):
- alternation in the sequence of nucleotides at a single locus on a chromosome (i.e. in a gene ) by:
1.
2.
3.
4.
5.

Insertion (addition) or extra nucleotide(s) into a gene


Deletion of original nucleotide(s) from a gene
Duplication of original nucleotide(s) in a gene
Inversion of nucleotide sequence in a gene
Substitution of original nucleotide(s) by nucleotide(s) with other base(s)

--> change the order of amino acids making up a protein


--> result may be silent / a mutated phenotype / a mutated lethal expression
- e.g.1 Sickle-cell anaemia (an inherited disease)
- RBC : normal biconcave discs ---> sickle-shaped
- Distorted shape of RBC is due to the presence of abnormal haemoglobin S (HbS) which
aggregates at low oxygen concentration.
inefficient carrying o f oxygen and clotting of small blood vessels
chronic haemolytic anaemia
Symptoms of the victims include extreme O2 shortage:
weakness, becoming thin, and sometimes may lead to kidney and heart failure
Normal Hb chains:

val-his-leu-thr-pro-glu-glu---etc.
(GAG in mRNA)
point mutation (substitution)
Sickle-cell Hb chains:
val-his-leu-thr-pro-val-glu---etc.
(GUG in mRNA)
-

the mutant gene is codominant with the wild type gene:


If heterozygous: mild anaemia (~30% -40% Hb S in blood), rarely die but more resistance
to malaria since the parasitic protozoan Plasmodium cannot easily invade the sickle-RBC
(common in Africa and Middle East where malaria is prevalent)
If homozygous : severe anaemia and frequently early death (i.e. lethal)

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- e.g 2: Cystic fibrosis


- common in Europe
- caused by a mutated recessive gene
e.g.3: Huntingtons disease ()
- caused by a mutated dominant gene
involuntary muscular movement and progressive mental deterioration
B. Chromosome Mutation
- visible changes ingross structure or number of chromosome under microscope

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1. Change in the number of chromosomes


a. Changes involve the entire set of chromosomes (genome number) / euploidy.
i. Haploidy
= the organism has only 1 genome (N)
(each kind of chromosome is represented once in a nucleus)
-- rare in animal adults, but common in plants
-- usually smaller, weaker and less vigorous,
-- highly sterile since chromosomes have no regular pairing partners during meiosis.
-- develop from unfertilized egg
ii Polyploidy
= a condition where an organism with more than two sets of chromosomes or genomes.
(>2N, i.e. each chromosome represented by > 2 homologues)

-- rare in animals, but common in plants


(one third of the angiosperms are polyploids e.g. roses, tulips and chrysanthemums)

and they often have some advantage e.g. forming larger fruits etc.
-- associated with advantageous characteristics:
greater size, hardiness, resistance to disease.
Phenotypes of polyploids:
Increased DNA content tends to increase size of cell; often translate more protein than diploids. Thus often larger
and more vigorous than diploids; flowers often more deeply coloured. Development of complex organs often
disrupted (and polyploidy is lethal in humans for this reason). Allopolyploids combine features of both parent
species and so are often more phenotypically novel than autopolyploids. Thus allopolyploids are more likely
than autopolyploids to be strongly favoured or disfavoured by selection.

-- If genome number is even (N= 4, 6...etc.; e.g. tetraploid)


--> fully fertile
If genome number is odd (N= 3, 5...etc.; e.g. triploid)
--> sterile
( since chromosomes have no regular pairing partners during meiosis)
e.g. 3n water melons are seedless.

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-- Autopolyploidy(occurs within the same species)


http://www.biols.susx.ac.uk/ugteach/cws/evol1/polyploid.htm
This may be due to:
1.errors in meiosis producing unreduced diploid gametes (all the chromosomes at
metaphase end up in the same nucleus) which then fertilize
2. errors in mitosis that cause a somatic doubling of the chromosome number so
that body cells produced that are tetraploid. This can lead to polyploid offspring if
those body cells or their cell descendents:
-

contribute to asexual or vegetative reproduction


produce gametes (Thanks to the 'segregation of the germ-line' into gonads,
few cells in animals can do this. But many cells in plants can do so)

3. multiple fertilisation (called polyspermy in animals); for example triploidy in


humans (the cause of about 15% of spontaneous abortions) is mainly due to two
sperm fertilizing an egg rather than a haploid and diploid gamete fusing (although
latter also occurs).
Mitosis and meiosis can be interfered by chemicals (colchicines : blocks
spindle formation and thus prevent anaphase movement) or environmental
conditions (starvation, cold)

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Allopolyploidy (Addition of genome of different species)


-- Cross between 2 distinct taxonomic groups ---> hybrid
-- hybrid from 2 diploid parents of different species (case A below) genomes so
different that each kind of chromosome lacks a homologue to act as its pairing
partner at meiosis ---> sterile

Chromosome
withtwo
chromatids

-- Fertile allopolyploidy offspring may be resulted when


--- Diploid gametes are obtained from tetraploid parents (case B above) or
--- meiosis occurs after non-disjunction of chromosomes in mitosis of sterile hybrid
parent cells.
---

fusion between unreduced gametes from sterile hybrid parent cells

Endoreduplication of polyploidy zygote develop and produce further polyploidy


gametes.
e.g. : Common bread wheat is an example of fertile allopolyploid.
(http://www.ansi.okstate.edu/course/3423/buchanan/corr/lesson/lesson4.htm)
Many crops are polyploids. (http://www.biols.susx.ac.uk/ugteach/cws/evol1/polyploid.htm)
Wild Einkorn Wheat Triticum boeoticum is a diploid.
Emmer Wheat (T. turgidum) is an allotetraploid (4 x 7 chromosomes) between Einkorn (2N gamete
from endoreduplication) and a wild-grass (2N gamete from endoreduplication).
Bread Wheats (e.g. Triticum aestivum --- the most common wheat species today) are allohexaploids (6
x 7 chromosomes, in this case from three different species) between T. tauschii (2N gamete from
endoreduplication) and T. turgidum (4N gamete from endoreduplication)

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Reference ( ) :
:
(1) (nondisjunction:

(2) (chromosomeloss):

(3) (chromosomebridge)

(4(endoreduplication):

(http://antioxy.fmmu.edu.cn/chapter6.htm)

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b. Changes in the chromosome number in a genome (/Aneuploids)


- involve only parts of a set of chromosomes
- produced by non-disjunction of a pair of chromosome
(failure of the members of a pair of chromosome to segregate)
-->
establish progeny with chromosome one more or one less than normal
(2n+1 trisomy, 2n-1 monosomy )
- chance increased by radiation and other chemicals
- e.g. Down's Syndrome (Mongolism)
(http://www.ansi.okstate.edu/course/3423/buchanan/corr/lesson/lesson4.htm)
-- one extra chromosomes in genome(i.e. 47 chromosomes)
, located at the 21st pair (Trisomy21)
--> abnormalities of face, eyelids, tongue and other part of body; some speech
difficulties, greatly retarded physically and mentally, short life expectancy
This disorder is not likely to be passed from generation to generation since the individuals
seldom live long enough to reproduce.
-- very common : 0.15% of all births, but the exact reason is unknown.
(a relatively high incidence when mothers age>35; Frequency highest when mother's
age is > 40)
Down's syndrome()Trisomy 21mongolism
() Down syndrome
(genetic birth defect)DNA()
(chromosomal abnormality)
DNAG21DNA()Trisomy 21
DNA4746
5%21DNADNA
translocationDNA46(compound)DNA

(carrier)10%
2.5%
5060

30364248
900300601216
(aminocentesis)(John L. Down, 1828-1896)19

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2. Change in Chromosome Structure


- during meiosis a chromosome may break into one or more segments at chiasmata and
rejoin with corresponding portion of chromatid on its homologous partner
---> change in the gross structure of the chromosome
a. Changes in the number of gene within a chromosome
http://www.tokyo-med.ac.jp/genet/cai-e.htm
i. Deficiency (Deletion)
- loss of small segment(s) of chromosome
(i.e. loss of 1 or more genes)
---> usually lethal, especially if involve considerable part
ii. Duplication (Addition)
- addition of 1 or more genes
---> may results in abnormal body character if organism survives
b. Changes in the Arrangement of Gene Loci
i. Translocation
- a fragment of chromosome becomes attached to another non-homologous chromosome
---> phenotypically normal unless gene interaction that affect phenotype expression
ii. Inversion
- the reversal of the order of a block of genes in a given chromosome
- usually requires 2 breaks in a chromosome followed by re-insertion of the segment in
the reversed direction.

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Types of Mutation According to Their Origin


1.

Spontaneous Mutation
- without a known cause, It may be due to the effect of cosmic ray from the outer space but also
probably caused by physical and chemical agents.
- usually infrequent and very slow in nature
e.g. in man: ~ 1 mutation / 100,000 gametes
- over a period of time, these mutations accumulate in population.

2. Induced Mutation
- mutation rate can be speeded up by applying mutagenic agents (mutagens)
- caused by the mutagenic agents (mutagens) artificially.
a. Physical mutagens
- UV radiation, heat and ionizing radiations (e.g. -, -, -, x-ray... etc.)
b. Chemical mutagens
- chemical substances which increase the mutability of genes
e.g. nitrous acid, mustard gas, formaldehyde, colchicines, base analogs
- base analogs are chemically similar to the nucleic acid bases ( incorporated into DNA
molecule by mistake)
Significance of Mutation
- most mutations confers disadvantages. few are useful
- exerts very slight effect on the characteristics of an organism
- mutant gene is usually recessive.
- It is a kind of discontinuous variation and hence the basis for evolution.
-

Variation and Evolution of species


Beneficial mutation increases the number of alleles within a population (very rare in fact)
more inheritable variations can be acted upon by natural selection, variations provide a
population with new features and abilities to adapt to the constantly changing environment. Through
natural selection, more and more favorable characters would accumulate, shaping the population to
become more and more adaptable to the environment. Mutation and variations are thus the basis of
the evolution within the population.
Harmful mutation (majority)
-- Inheritable diseases or lethal effect
cause serious problems for organisms. For example, in humans, some mutant genes produce
inheritable diseases like haemophilia, colour blindness, albinism, etc.. Each person may
have several hidden recessive alleles which, when becoming homozygous, will have a lethal
or deleterious effect.
-- antibiotic resistance of bacteria
antibiotic resistant strains of many bacterial species, has already destroyed the usefulness of
several drugs.
-- cancer
it is believed that cancer can be caused by multiple mutation in several genes in cells. Hence the
cells will keep dividing without control.

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Cell Division
Cell Theory was extended by Rudolph Virchow in 1855:
" every cell is from a cell"
i.e. all new cells are derived from other cell
so all cells in all organisms have been formed from successive divisions of some original ancestral cells.
A. Chromosomes in cell division
-

responsible for the transmission of hereditary information from generation to generation

may staining with certain basic dyes

Chromatin
-- fibers containing proteins and DNA
-- extremely long and thin
-- dispersed throughout the nucleus and individual threads cannot be seen in non-dividing eukaryotic cells

Chromosome
-- made up of chromatin
-- involved in controlling of all materials in the cell
-- during cell division:
- highly condense and become shorten, so individual chromosomes can be seen under microscope
- control of materials synthesis in the cell ceases

Homologous Chromosomes
They are the similar chromosomes in diploid cells:
-- contain the same number and linear sequence of genes
-- with similar morphology under microscope (same length and some centromere position, except the sex
chromosomes)
-- one derived from the male parent and the other from the female parent
-- pair up to from a bivalent during meiosis

Chromatid
-- each of the two identical double helix chains of DNA from replication 'surrounded' by protein 'coat' at
onset of cell division lying side by side
-- attached to each other by a non-staining region 'centromere' where for attachment of microtubules of
spindle fibres.

Number of chromosomes in various species


-- each individual of a given species contains a characteristic number of chromosomes in most nuclei of
the body
-- it is not the number of chromosomes that differentiate the various species, but rather the information
specified by genes
-- most species of animals and plants have chromosome number between 10 and 50, number above and
below this are not common
-- normal human being having exactly 46 (23 pairs) chromosomes

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B. The Cell Cycle


- is the period from the beginning of one mitotic cell division to the beginning of the next and is
customarily represented in diagrams as a circle.
-

the length of time for a complete cell cycle is termed the generation time

can be used to describe the activities of actively growing and dividing cells (some cells are not capable
of dividing once they reach a certain size, e.g. red blood cells, nerve, skeletal muscle)

3 main stages:
i. Interphase / Resting phase
- Chromosomes are not visible but only chromatins can be seen after staining.
First growth phase (G1) : cell organelles and biochemicals and protein synthesis
(cell growing and developing)
Synthesis phase (S)
: DNA replication
Second growth phase (G2) : condensation of chromatin, centriole duplication (in animals),
increase energy storage
Mitosis (Division of nucleus)
1. Prophase:
- Chromosomes shorten and thicken gradually and become visible
- centrioles (not in plants) move to two poles
- aster (not in plants) appear
- spindle fibres (they are microtubules) form spindle
- nucleolus disappears
- nuclear envelope disintegrates

ii.

2. Metaphase:
- chromosomes line up at equator
- spindle fibres attach to centromere
- chromatids are slightly apart
3. Anaphase:
- centromere split and chromatids are totally separated by shortening of spindle fibres (partial
depolymerization of microtubules into tubulin molecules)

- chromatids of each chromosome move towards two poles


4. Telophase:
- new nuclear envelope forms
- chromatids loosen to form chromatin
- spindle fibres breakdown (depolymerization)
- new nucleolus form
iii. Cytokinesis (Cytoplasmic Division)
--> equal splitting of cytoplasm into two new daughter cells that each contain a newly formed
nucleus
- animal cells : constriction of the center of the parent cell from the outside inwards.
- plant cells :
fusion of Golgi vesicles (containing constitute of middle lamella and primary cell wall)
forming cell plate across the equator from the center outwards until reaching the edges of the cell
membrane of vesicles becoming new cell membranes and cell plate becomes the middle lamella
cellulose is laid down on both sides of the plate to form the new cell wall

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C. Mitosis and Meiosis


- various phases in mitosis (see above)
- various phases in meiosis
-- Interphase (DNA replication)
-- Prophase I
--- chromosome shorten and visible, synapsis of homologous pair to form a bivalent (each bivalent
consist of two pair of sister chromatids, and can be called a tetrad = 2 x 2 strands )
--- chiasma(ta) (allow crossing over and exchange of genetic materials between the members of a
pair of homologous chromosomes) to occur) may occur at various points
--- nucleolus disappears and nuclear envelope disintegrates
--- centriole (not in plants) move towards two poles
--- spindle fibers forms
-- Metaphase I
--- bivalents line up randomly in respect to their order and orientation at equator
--- homologous chromosome apart slightly and limited by chiasmata
-- Anaphase I
--- members of homologous chromosomes separated and move towards two poles
-- Telophase I (in some cells this stage does not occur)
--- nuclear envelope forms
--- spindle disappear
--- chromtids loosen
-- Meiosis II (Prophase II, Metaphase II, Anaphase II, Telophase II)
--- similar to mitosis
- differences between mitosis and meiosis
Prophase:
1. synapsis in meiosis I but not in mitosis
2. chiasma may occur in meiosis I but not in mitosis
Metaphase:
3. bivalent (homologous pair) line up at equator in meiosis I while single line of individual chromosme
at equator in mitosis
4. separation of homologous chromosomes limited by chiasma in meiosis I while separation of
chromatids of a chromosome limited by centromere in mitosis
Anaphase:
5. separated homologous members move towards two poles in meiosis I while separated sister
chromatids move towards two poles in mitosis
Telophase:
6. telophase I may not occur during meiosis I in some cells while telophase is the last essential step in
mitosis.
Karyokinesis (nuclear division)
7. two nuclear division in meiosis but one nuclear division in mitosis
Daughter cells
8. four daughter cells in meiosis but two daughter cells in mitosis
9. for a diploid parent cell, daughter cells resulted from meiosis are haploid cells (half of the parent)
while daughter cells resulted from mitosis are diploid cells (same as the parent).

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Summary of differences between various stages of mitosis and meiosis:


Characteristics
Mitosis
I

Prophase
Pairing of homologous chromosomes
(synapsis forming bivalent)
Stage

Metaphase

Anaphase

Telophase

Meiosis
II

Chiasmata formation (crossing over)

Lining of homologous pairs of


chromosomes at the equator of spindle

Lining of pairs of sister chromatids


(individual chromosomes) at equator of
spindle

Separation of homologous chromosomes

Separation of sister chromatids (splitting


of centromere)

Number of chromosomes in daughter


cells compared with that in parent cell

Same

Amount of DNA in daughter cells


compared with that in non-dividing
parent cell

Same

Presence of homologous pairs of


chromosomes in a daughter cell

Both
members
of each
pair

Half
Same

Half

One member of each One member of


pair
each pair
(with two sister
(with one of the
chromatids
separated sister
connected at
chromatids)
centromere)
*telophase I may not occur during meiosis I in some cells while telophase is the last essential step in mitosis.

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significance of mitosis and meiosis respectively


Mitosis
Meiosis
genetic stability
gametes for sexual reproduction and increase genetic variation
- daughter cells are genetically identical to
their parent cell
- segregation of a pair of alleles and independent assortment of
results in genetic stability within
unlinked genes allows random combination of genetic materials
in daughter nuclei
population of cells derived from
parental cells
- crossing over of non-sister chromatids in bivalent allow
recombination of genes in a linkage group
- allow fertilization (without double of DNA) of haploid gametes
from different parents and preservation of a constant number of
chromosomes from generation to generation.
growth, repair and replacement of tissues
or body parts
- the number of cells within an organism
increases and replaces by mitosis
asexual reproduction and regeneration of
lost body parts