GENETICS

B.Sc. Nursing

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What is Genetics?
Branch

of biology concerned

with the study of heredity and

variation in organisms

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Practical Application of Genetics in Nursing

Genetic services and education have been made available in the curricula of health professionals including nurses Efforts have been made to develop a team of nursing faculty who are well prepared in genetics These efforts are expected to substantially improve the capability of nurses to contribute more effectively in the delivery of Genetic services

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Scientific knowledge in human genetics has expanded at a remarkable rate in recent decades

The application of this knowledge in the

clinical situation to individuals and families

affected by or at a risk for genetic

disorders has rapidly followed

Genetic service programs are well established in all university medical centers throughout the world
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As scientific and technological

capabilities to identify individuals and

families at risk for genetic disease

continues to increase, the capacity of the health care system to inform them about the appropriate application of genetic tests will be severely inadequate unless healthcare

professionals are better educated about

human genetics and its clinical

applications

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Nurses have a unique potential to contribute

to the effective delivery of genetic services: They are the single largest group of healthcare providers They are employed in settings throughout the healthcare system Nurses are accustomed to providing and

1.

2.

3.

promoting a broad range of health and

related services for individuals and the families they serve
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Nursing, as an applied science, cannot

afford to lag behind current scientific

knowledge when that knowledge can

enhance and enrich the care of patients and their families. Inclusion in the nursing curriculum of genetic theory and principles is but one small advance in expanding the

dimensions of nursing practice through

increased knowledge and

understanding.Brantl and Esslinger

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Career Focus

Opportunities for clinical experience in genetics vary widely among programs

However, all nursing students encounter patients affected by or at risk of genetic disorders during their clinical training

This is especially true in pediatrics, where at

least 25% of inpatients have a disorder with

a genetic component
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However, in prenatal clinics rotation,

students also see pregnant women at

the risk of having an infant with a

genetic disorder

Educating the nursing team on clinical genetics helps them identify, analyse, and understand the genetic disorder better
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In addition, there is greater flexibility for students at the graduate level to choose elective courses related to their nursing career goals but offered outside the school of nursing (in most international universities)

This helps them to go on to doctoral studies in nursing, human genetics, or related fields, where they can apply

the working knowledge of genetics with formal course

work

Nurses specializing in maternal/child nursing can focus on genetics within their graduate nursing curriculum,
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REVIEW OF CELLULAR DIVISION MITOSIS AND MEIOSIS

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The Cell Cycle

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 Repeated

cycle of DNA replication

followed by cell division is known

as the cell cycle

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 It

is a cyclic process co-ordinated

by the cell cycle machinery to

ensure the correct ordering of the

cellular processes

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Phases of the Cell Cycle

The cell cycle consists of

Mitotic (M) phase (mitosis and

cytokinesis)
Interphase (cell growth and copying of

chromosomes in preparation for cell

division)
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Interphase (about 90% of the cell cycle) can be divided into sub phases: G1 phase (first gap/gap1)- RNA & protein synthesis S phase (synthesis) DNA replication G2 phase (second gap/gap2) RNA & protein synthesis
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Mitosis (M-phase)
Mitosis is conventionally divided into five phases: Prophase Prometaphase Metaphase Anaphase Telophase Cytokinesis is well underway by late telophase

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 Human

cells take 24hrs to

divide
G1 S

phase 9hrs

phase 10hrs

G2

phase 4.5hrs
or M-phase 30min
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Mitotic

INTERPHASE

G1

S (DNA synthesis)

G2

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The Cell Cycle Control System

The sequential events of the cell cycle

are directed by a distinct cell cycle

control system, which is similar to a

clock

The clock has specific checkpoints where the cell cycle stops until a goahead signal is received
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G0
G1 checkpoint

G1 If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues on in the cell cycle.

G1

If a cell does not receive a go-ahead signal at the G1 checkpoint, the cell exits the cell cycle and goes into G0, a nondividing state.
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Meiosis
Making Reproductive Cells

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Chromosomes
Homologous

Chromosome: The two chromosomes of a matching pair

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The Human Life Cycle

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Meiosis
Produce 4 haploid gametes through - Interphase replication of DNA - Meiosis I separation of homologous chromosomes (in 4-5 steps: prophase I, metaphase I, anaphase I, and telophase I and cytokinesis I) - Meiosis II separation of sister chromatids (prophase II, metaphase II, anaphase II, telophase II and
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MEIOSIS

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Interphase
Growth

and sythesis of DNA (and

copy organelles)
Same

as mitosis

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Meiosis I
Division

of nucleus (and cell)

to form 2 haploid cells by

splitting homologous pairs

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Prophase I

Synapsis pairing of the homologous chromosomes

Tetrad homologous pair
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Prophase I

The homologous pairs meet and join together to form a tetrad (four chromatids all together) This process is called synapsis

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Crossing over

While a tetrad is present, crossing over occurs

Which involves the

genes of one
chromatid are exchanged for the

genes of another.

This gives rise to genetic variability

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pairs line up in middle

Homologous pairs split

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Meiosis II

Now the chromosome number has been

reduced to haploid from diploid

The function of the second phase of meiosis is

to separate the chromosomes into four

chromatids to produce four genetically unique gametes

(this is the same as mitosis except starting with two cells with only half the chromosomes
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CHARACTERISTICS & STRUCTURE OF GENES

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Metaphase chromosome structure

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Chromosome number

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Homologous chromosomes

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Karyotype

Human male karyotype

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Human male Idiogram

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ULTRASTRUCTURE OF THE CHROMOSOME

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ULTRASTRUCTURE OF CHROMATIN
SINGLE STRANDED AND MULTISTRANDED HYPOTHESES Wide differences with respect DNA content of related species. The causes could be: 1. Lateral multiplication of chromonemata leading to multistrandedness or 2. Tandem duplication of chromonemata leading to lengthwise duplication

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Multistrandedness has been observed in

plants such as Vicia faba and salivary gland

chromosomes of dipteran insects

But this is not a general phenomenon hence the multistranded hypothesis was not accepted

Many evidences have supported the single stranded nature of chromatin

Each chromosome is formed from a single

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FOLDED FIBER

Folded-fiber model proposed by EJ Dupraw in 1965

Bulk of the chromosome is visualized to be composed of a tightly folded fiber which has a

homogeneous diameter of 200 to 300 A

The folded fiber is suggested to contain the DNA histone helix of 30 A diameter in a supercoiled condition

Histones were proposed to be bound on the

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NUCLEOSOME MODEL
Proposed by R.D. Kornberg, 1974 Confirmed and christened P. Oudet et.al., 1975 The DNA was found to wind around the histone particles (the idea of histones outside the DNA coils was found to be incorrect) Most significantly and universally accepted model

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NUCLEOSOMES AND SOLENOID MODEL OF CHROMATIN

Nucleosomes are the fundamental packing unit particles of the chromatin

They give the chromatin a beads-ona-string appearance in electron micrographs

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NUCLEOSOME
Each nucleosome is a disc-shaped particle Diameter 11nm Height 5.7nm Consists 2 copies each of nucleosome histones H2A, H2B, H3, H4 The histone octamer forms a protein core The DNA helix winds 13/4 times around the histone octamer and consists of 146 bps

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nucleosomes are connected by

a segment of DNA called as the

Linker DNA which is 54 bp long

and contains a single H1 histone

protein molecule
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Therefore, generally DNA makes 2 complete turns around the histone octamers and these 2 turns (200 bp long) are sealed off by H1 molecules

On an average nucleosomes repeat at intervals of about 200 nucleotides/bps

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SOLENOID MODELS

SOLENOID coil of coils Solenoid coiling of nucleosome containing fiber

10nm fiber packing of DNA is 5-7 fold (5-7 times more compact than free DNA)
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30nm fiber consists of closely packed nucleosomes. Formed by folding of the nucleosome chain into a solenoid

structure. Contain 6 nucleosomes per

turn

DNA of 30nm solenoid has 40 fold

packing
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Formation of metaphase chromosome

Radial Loop model Proposed by Laemmli Radial loops of 30nm fiber DNA is arranged in loops anchored to a non-histone scaffold

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Fine structure of a Gene

Classical definitions of a gene: A gene is a unit of physiological function that occupies a definite locus in the chromosome and is responsible for a specific phenotypic characteristic Gene is a unit of transmission or segregation A gene is a unit of mutation, because a spontaneous or induced mutation in it can give rise to a different phenotype

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modern working definition:

Gene

is a locatable region of

genome sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions and other functional sequence regions
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All genes have regulatory regions in addition genes coding for proteins or RNA product

A regulatory region shared by almost all genes is a promoter, which is recognized by the transcription machinery
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Many eukaryotic genes are present in multiple copies, called gene families

If proteins or RNA are required in large quantities e.g. rRNA or histones

In other cases distinct members of a gene family may be transcribed in different tissues at different times
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CHROMOSOMES SEX DETERMINATION

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Sex Determination
Phenomenon

where in the sex of

an individual organisms becomes

fixed soon after the formation of a

zygote, due to the specific

composition of sex chromosomes

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The process of sex determination by allosomes is called genetic or chromosomal sex determination

It is brought about by heterogametes, which is the formation of two kinds of gametes in one of the two sexes
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XX-XY Type
Females have two identical homologous sex chromosomes designated as XX Males have two dissimilar sex chromosomes designated as X and Y Females are homogametic, producing only one type of ovum, Males are heterogametic, producing two types of gametes: half carrying the X chromosome and the other half carrying the Y chromosome This type of sex determination occurs in insects and mammals including human beings

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XX-XY Type

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XX-XO Type
Females have two homomorphic sex chromosomes XX and hence they are homogametic Males have one sex chromosome and are represented as XO If the X-carrying ovum is fertilised by a Xcarrying sperm, the resulting zygote XX will develop into a female If the sperm carrying no sex chromosomes unites with the ovum, the zygote XO will develop into a male Seen in some insects such as bugs, cockroaches and grasshoppers

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XX-XO Type

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ZW-ZZ Type

Females carry two different types of sex chromosomes (ZW) and are heterogametic

Males carry identical sex chromosomes (ZZ) and are homogametic

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The ova will be of two types: Z-carrying and Wcarrying

All sperms will be only Z-carrying

The zygote which has sex chromosome

composition of ZZ, formed by a fusion of Z-

carrying sperm with a Z-carrying ovum develops

into a male

A zygote with ZW chromosomes, formed by a

fusion of Z-carrying sperm with a W-carrying
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ZW-ZZ Type of sex determination occurs in some insects like butterflies and moths. It is also known to occur in several examples of fishes, reptiles and birds

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ZW-ZZ Type

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ZO-ZZ Type
Females have only one sex chromosome and hence represented as ZO Females are heterogametic Males carry two identical sex chromosomes designated ZZ Males are homogametic On fertilization by a Z-carrying sperm the Z-carrying ovum would develop into a male (ZZ) and on fertilization, the Z-lacking ovum would develop into a female This type of sex determination is seen in some moths and butterflies

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ZO-ZZ Type

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Arrhenotoky/Haploid-diploid Mechanism

This mechanism is found in honey bee,

ants, wasps,

Egg if fertilized gives rise to female fly

The unfertilized egg develops

parthenogenetically into male

So the female flies are diploid while male

flies are haploid
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Genic Balance or X/A Balance Theory of Sex Determination

Given by C.B. Bridges According to him, Y chromosome plays no role in sex determination of Drosophila, and

It is the ratio between number of X-

chromosome and set of autosome which

determines the sex of fly
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Chromosome Constitution
AA + XXX AA + XX AAA + XXY AA + XY XX + XO AAA + XY

X/A ratio
3/2 = 1.50 2/2 = 1.00 2/3 = 0.67 1/2 = 0.50 1/2 = 0.50 1/3 = 0.33

Sex Index
Super Normal Intersex Normal (Fertile) (Sterile) Super

It was concluded that X/A ratio of > 1.0 expresses super femaleness, 1.0 femaleness, below 1.0 and above 0.5 intersexes, 0.5 maleness and < 0.5 supermaleness
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CHROMOSOMAL ABERRATIONS

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EUPLOIDY

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ANEUPLOIDY

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Trisomy 21 Downs Syndrome

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Deletion

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Cri-du-Chat Syndrome

Deletion of a portion of the short arm (2n=46,5p-) of Chromosome 5 [see karyotype]. Symptoms include a characteristic high-pitched cry ("cat cry"), low birth weight, poor muscle tone, microcephaly, and mental retardation. Children respond well to the home environment, and institutionalization is 107 26-08-2013

 Duplication

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An example of an insertion mutation

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Translocation

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PATTERNS OF INHERITANCE

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MENDELIAN THEORY OF INHERITANCE

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GREGOR JOHANN MENDEL (1822 1884) Father of Genetics

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Mendels Laws of Heredity

Dominance First law, the law of segregation When an individual produces gametes, alleles separate, so each gamete receives one member of the pair of alleles
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 Second

Law: The law of

independent assortment - states

that alleles of different genes

assort independently of one

another during gamete formation

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 Back Test

Cross

Cross 1:1

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Incomplete Dominance
When red snapdragons are crossed with white ones, the F1hybrids have pink flowers. The F2 generation produces a 1:2:1 ratio for both genotype and phenotype.

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MULTIPLE ALLELES

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Human blood groups ABO system

Blood Antigen Antibodies Can give Can groups in RBCs in plasma blood to receive (Phenotype) groups blood from group O None Anti-A Anti-B O,A,B, AB O Genotype

ii IAIA\IAi
IBIB\IBi I A IB
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A
B AB

A
B A and B

Anti-B
Anti-A None

A,AB
B,AB AB
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O,A
O,B O,A,B, AB

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SEX LINKED INHERITANCE

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Sex linked inheritance

Genes are carried on the sex chromosomes (X or Y) Sex-linked notation

XBXB normal female XBXb carrier female XbXb affected female XBY normal male XbY affected male

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Sex linked inheritance Dominant

Dominant gene on X chromosome Affected males pass to all daughters and none of their sons Genotype= XAY

If the mother has an X- linked dominant trait and is homozygous (XAXA) all children will be affected

If Mother heterozygous (XAXa) 50% chance of each child being affected

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Sex linked Inheritance Recessive Recessive Gene located on the X

chromosome More males than females affected (males inherit X from mother) Females can only inherit if the father is affected and mother is a carrier (heterozygous) or affected (homozygous) An affected female will pass the trait to all her sons Daughters will be carriers if father is not affected Males cannot be carriers (only have 1 X so either affected or not) Can skip generations E.g. colour blindness, haemophilia,
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Color Blindness
Deficiency to percieve colors
Problem with color-

sensing pigments in certain nerve cells of the eye About 1 in 10 men have some form of color blindness. Sex-linked disorder
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Hemophilia

Bleeding disorder, where it takes a long

time for blood to clot (body lacks

proteins involved in clotting)

Sex-linked (carried on the X

chromosome)

Treatment involves injection with missing clotting protein

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MUTATIONS

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Definition
A mutation

is a sudden change in

the genetic material of a cell that

can be passed on from the cell to

its daughter cells during the

process of cell division

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 Mutations

are important for several

reasons.
First

mutations are the source of new

variation important for evolution.

Mutations

are considered to be one of

the ways that evolution happens.

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 Mutations

can lead to various human

medical conditions.
Mutations

can happen on a number

of different scales.

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 Mutations

involving only a single

base pair in a DNA molecule are called point mutations.

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Somatic vs germ cell mutations

In

multicellular organisms such as

plants or animals mutations may

occur in the somatic cells of the organism.
Somatic

cells are the cells involved in

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growth and repair and maintenance

 A mutation

in these cells may lead

to cancer and certain types of

chromosomal mutations may be

involved in aging.

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 Other

mutations happen in the germ

cells
These

mutations may appear in the

gametes and then in the offspring

produced by sexual reproduction
These

sorts of mutations are called

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germ cell/line mutations.

Causes of mutations
Mutations 1. 2.

are often classified as:

Spontaneous and

Induced

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SPONTANEOUS & INDUCED MUTATION

Spontaneous mutationnaturally
occurring mutations, which arise because

of errors in the DNA duplication process..

Induced mutationoccur when an

organism is exposed to physical or

chemical agents, known as mutagens,

that interact with DNA to cause mutation.

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Mechanism of spontaneous mutation

Proposed by Watson & Crick Structures of bases in DNA are not static

H atoms can move from one position to another (from an amino group to a ring Nitrogen) tautomeric shifts

Can alter pairing potential of the bases

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Keto

Enol
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 Thymine

and Guanine more stable

keto forms
Adenine

and Cytosine more stable

amino forms
Tautomeric

shifts less stable enol

and imino forms respectively

(infrequently)
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Bases are expected to be in their less stable tautomeric forms for only very short periods of time

If the base existed in the rare form at the time of replication results in a mutation

adenine-cytosine and guanine-thymine base pairs

AT to GC or a GC to AT base pair substitution

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Types of Mutations
Transitions Substitution Transversions Mutations Mutations Frameshift mutations

Point

These types are observed under spontaneous mutations

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Mutations resulting in the bases of DNA involve the replacement of a purine in one strand of the DNA with the other purine and the replacement of a pyrimidine in the complementary strand with the other pyrimidine

Such base pair substitutions are called

transitions
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Base pair substitutions involving the substitution of a purine for a pyrimidine and pyrimidine for a purine are called transversions

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Types of substitution mutations

Substitution mutations may vary in effect on the polypeptide resulting from translation.

Silent mutation the mutation does not alter the polypeptide at all.

While, nonsense mutations may lead to a radically altered polypeptide.

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Normal
TAC GTG ATA CCA AAG TAG ACT

AUG CAC

UAU

GGU UUC

AUC

UGA

met

his

tyr

gly

phe

ile

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Missense mutation
TAC GTG ATA GCA AAG TAG ACT

AUG

CAC

UAU

CGU

UUC

AUC

UGA

met

his

tyr

arg

phe

ile

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Nonsense Mutation
TAC GTG ATT CCA AAG TAG ACT

AUG

CAC

UAA

GGU UUC

AUC

UGA

met

his

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EFFECTS OF MUTATIONS

Missense mutations
Amino acid sequence is altered
e.g., GAA GTA (glu val)

Phenotype may be affected

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 Addition

or deletion of one or a

few base pairs - collectively

referred to as frameshift
mutations

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The effects of frameshift mutation

In

frameshift mutations, since a base

is either added or removed from a codon, the effect is to shift the codons

as read during translation by one

position which radically alters the

meaning of the mRNA in terms of

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 Frameshift

mutation changes all

the amino acids after the first one

because codons are in groups of

three non overlapping RNA

bases.
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If messenger RNA resulting from the original DNA

can be thought of as the following string of letters decoded by reading each group of three non overlapping letters: THEBIGCATATETHERAT = THE BIG CAT ATE THE RAT If the third letter(E) in the string is deleted we have: THBIGCATATETHERAT = THB IGC ATA TET

HER AT

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3 1.

key factors influencing mutations:

Accuracy of DNA replication

machinery
2.

Efficiency of DNA repair

mechanisms
3.

Degree of exposure to mutagenic agents present in the environment

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CHEMICAL MUTAGENS

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Base Analogs

Mutagenic Chemicals Can substitute for purines and pyrimidines during nucleic acid biosynthesis

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5-Bromouracil (5-BU)

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5-Bromouracil (5-BU)
Behaves as a thymine analog It gets incorporated into DNA in place of thymine 5-BU base pairs with Guanine

A = T G C transition

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Analog of Adenine
Base pairs with Cytosine

Leads to A = T G C Transitions
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Alkylating agents

They Donate an Alkyl group such as

CH3 or CH3CH2 to amino or keto groups

in nucleotides

Changes base pairing affinities

Results in transition mutations
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Examples: containing mustard gases

Sulphur

discovered during world war I, first groups of chemical mutagens identified in chemical warfare studies
Ethylmethane

Sulfonate adds alkyl

groups to guanine and thymine

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Nitrous Acid
Causes Amino

deamination

group is converted to a

keto group
It

alters base pairing specificities

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Nitrous Acid

[A = T]
[G C ]

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Acridine Dyes
They have the same dimension as a nitrogenous base pair These intercalate/wedge between the purines and pyrimidines of intact DNA The intercalation induces contortions in the DNA helix Causes deletions and insertions and hence results in frameshift mutations

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Acridine Dyes

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PHYSICAL MUTAGENS

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UV Radiation

Visible light and longer radiations are benign when it interacts with most organic molecules

Shorter wave lengths than the visible light are more energetic and have a disruptive impact on organic molecules
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In 1934 it was discovered that UV is

mutagenic studies were done on

the eggs of Drosophila

In 1960, in vitro studies showed that

UV had an effect on the

components of nucleic acids

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Major effect of UV involves formation of pyrimidine dimers

Particularly between two thymidine residues it forms thymine-thymine dimers

Cytosine-Cytosine dimers, thyminecytosine dimers can also be formed, but these are less prevalent
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UV Radiation

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Thymidine Dimer
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Dimers distort DNA conformation

Inhibit normal replication

Hence errors can be introduced into the

synthesized DNA

When the effect is extensive results in the

death of the cell the killing effects of UV

radiation on microorganisms is due to this

effect
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 DNA repair

mechanisms for the

correction of UV induced lesions have

evolved
But

mutations that inactivate one UV

repair mechanism results in a disease condition called as Xeroderma pigmentosum

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Xeroderma Pigmentosum
DNA repair disorder
Inability to repair UV induced mutation Children of the night High proneness to epidermal malignancy on exposure to sunlight
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