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Early Genetics
• Carvings in stone – 6000 years old
• Haemophillia - 1500 years ago
• Regnier de Graaf -
– male and the female parent transmitted
genetic characteristics to the off spring.
• Pierre Louis Moreau de Maupertuis
-1700s
– hereditary particles
– one from each parent
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• The law of Unit Inheritance – Before
Mendel’s time it was believed that the
characteristics of parents blended into the
offspring. (Darwin)
• Blending did not occur.
• Characteristics of one parent may not
appear in one generation (F1) but may
reappear in the next generation (F2).
Mendel’s Laws
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• Law of Independent assortment –
Members of different gene pairs assort to
the gametes (sex cells) independently of
one another.
Tt
T t
• Random recombination
Mendel’s Laws
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• Work of Mendel was not widely noticed –
• Darwin’s theory – based on inheritance
But mechanism not known
• Rediscovered –
– Vries - Holland,
– Correns - Germany and
– Tschermak - Austria
Mendel’s Laws
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• Homozygous – an individual who has the same factors
for a particular characteristic. (eg-TT or yy)
• Heterozygous – individual with different factors (Tt or Yy)
– character that is manifested - dominant,
– and the other - recessive .
• The term gene - Danish botanist Johannsen, represents
the hereditary factors.
• The genes responsible for contrasting characters are
called alleles.
Terminology
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Human Genetics
• Family Studies – pedigree
• Albinism, Polydactyly (early 1700s) and
Hemophilia (early 1800s).
Consanguineous marriages.
• Effects of Nature and Nurture 1800s by
Galton
– Hereditary improvement of men and animals
by selective breeding – eugenics.
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• 1900s Sir Garrod
• Alkaptonuria - dark urine
• Children were usually normal, but the disorder
could reappear later in the descendents.
• Mendelean recessive type of inheritance
• Excretion of homogentisic acid which is usually
metabolized in normal individuals.
Human Genetics
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Human Genetics
• Connection between gene and enzyme
• This was the first time that the idea that
genes control the synthesis of enzymes
arose.
• Landsteinter ABO blood groups
Blood group genetics
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Nucleic Acid
• First isolated as early as 1869
by a Swiss doctor named
Meicher.
• Rich in phosphorous
• Nuclein
• 1892 – postulated that it is
the hereditary material.
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Nucleic Acid
• Protein was the basic
substance of life
• Importance in protein
formation was not
appreciated until the work of
Griffith and later Avery,
Macleod and McCarthy (on
pneumococci) and Hershey
and Chase (using
bacteriophages).
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Nucleic Acid - Structure
• long chains of molecules
called nucleotides
• Each nucleotide is composed
of :-
– A nitrogenous base
– A sugar molecule, and
– A phosphate molecule
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Nucleic Acid - Structure
• The nitrogenous bases are of
2 types – purines &
pyrimidines.
• The purines include –
adenine and guanine
• The pyrimidines include –
cytosine, thymine and uracil.
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Nucleic Acid - Structure
• Nucleic acids – 2 types (according
to sugar)
• Ribose Ribonucleic acid or RNA
- nucleolus and cytoplasm
• Deoxyribose Deoxyribonucleic
acid or DNA – nucleus
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A Closer Look at Genes
• But about 80% of human
DNA does not code for
proteins.
• The coding part of the
DNA is known as exons,
and the intervening non-
coding sequences are
called introns.
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A Closer Look at Genes
• These genes have a regulatory effect.
• In prokaryots (without nucleus)
– Operon = operator gene and structural gene
– Remote regulator gene
• Produces repressor.
– Repressor can be inactivated by inducer.
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• In humans – certain flanking regions
referred to as enhancers and promoters.
• Structure of Globin gene -
– CAT box = CCAAT
– TATA box = TATA
– End flanking region = AATAAA
A Closer Look at Genes
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A Closer Look at Genes
• Exon-intron pattern of a particular gene appears
to be conserved during evolution
• Two introns at precisely the same locations
since their appearance 500 million years ago
• Alterations in exons are slow, and mutations are
rarely retained
• Changes in the introns occur much more rapidly
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• There are several meters of DNA in a
human body, and the total length of the
chromosomes is less than a millimeter.
• Finch and Klug suggested the “Solenoid
model”
Structure of Chromosomes
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• Each DNA duplex is coiled around itself – primary coiling
• This is couled around histone ‘beads’ – secondary coiling
– called nucleosomes
• Nucleosomes are coiled to form chromatin fibres, around
a protein matrix or scaffold – tertiary coiling
• Chromatin fibres are coiled to form loops – quaternary
coiling
• The loops are further wound in a tight helix to form the
chromosome – that can be seen under a microscope.
Structure of Chromosomes
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Human Chromosomes
• 46 chromosomes in the normal human – 23 pairs.
– 22 pairs are alike in males and females – known as autosomes
– 1 pair differs – the sex chromosomes.
• Pair of chromosomes are microscopically
indisdtinguishable, except the x and y chromosomes.
• Y is smaller than x, but the 2 are thought to have a
homologous short segment.
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• The location of the centromere can be
used to classify the chromosomes –
– Metacentric – central centromere
– Submetacentric - off –centre
– Acrocentric – towards one end
– Telocentric – terminal centromere (does not
occur in man)
Studying Chromosomes
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• Acrocentric - small masses of chromatin known
as satellites attached to their short arms by
narrow stalks (secondary constrictions)
• Stalks contain the genes for 18S and 28S
ribosomal RNA (rRNA).
• The rRNA transcribed from these areas, along
with 5S rRNA (from another location), is utilized
in the nucleolus to synthesize ribosomes.
Studying Chromosomes
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• Autoradiography
• radioactive thymidine
• cell divisions are stopped
• not all chromosomes replicate at the same
time. But this process is laborious and
time consuming, and is rarely used.
Studying Chromosomes
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• After 1970
• Q banding - quinacrine mustard or related
compounds
– fluroscence microscopy.
• G banding – widely used
– tripsin to denature the protein
– Giemsa stain
– dark bands correspond to the bright Q bands
Studying Chromosomes-
Staining
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• R banding
– less widely used
– heat treated
– then stained with Giemsa
– results are the REVERSE of G banding
• C banding – centromere
– regions of the chromosome containing constrictive
heterochromatin
– secondary constrictions of chromosomes 1, 9, 16
Studying Chromosomes-
Staining
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• NOR staining –
– ammoniacal silver to stain the nucleolus
• High resolution banding -– used for
staining cells in prophase – shows much
more bands than the metaphase staining.
Studying Chromosomes-
Staining
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• Clinical diagnosis – congenital
malformations, mental retardation
disorders of sexual development etc.
• Linkage and Mapping – Assignment of
specific human genes to their
chromosomal positions.
Studying Chromosomes- Medical
applications
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• Polymorphisms – Minor heritable
differences in chromosomes are
common, especially in chromosomes 1,
9, and 16 and the Y chromosome.
• Highly specific genetic marker
Studying Chromosomes- Medical
applications
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• Chromosomes and Neoplasia –
Philadelphia chromosome
• Reproductive problems
• Prenatal Diagnosis – Amniocentesis
– Useful in older pregnant women, and families
with a history of chromosomal abnormalities.
Studying Chromosomes- Medical
applications
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• Nuclear material is conserved in the
daughter cell
• Cytoplasm seem to split
• Nuclear division – 4 stages
– Prophase
– Metaphase
– Anaphase
– Telophase
Mitosis
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Mitosis
• Prophase
– chromosomes can be seen
and easily discerned
– chromatids can be seen
– centriole,
– each one migrates to the
opposite pole of the cell
– nuclear membrane
disappears and the
nucleus begins to loose its
identity.
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Mitosis
• Metaphase
– chromosomes are
maximally contracted and
deeply staining
– 2 dimensional metaphase
plate
– spindle is now formed
– (microtubles of protein)
– spindle fibres centrioles to
kinetochores (sites of
attachment at the
centromere)
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Mitosis
• Prophase
– chromosomes can be seen
and easily discerned
– chromatids can be seen
– centriole,
– each one migrates to the
opposite pole of the cell
– nuclear membrane
disappears and the
nucleus begins to loose its
identity.
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• Zygotene
– pairing (synapsis)
– bivalents
• Pachytene
– chromomeres become
more prominent
– bivalent
– actually a tetrad
– crossing over occurs
Meiosis I - Prophase
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• Diplotene –
– Two components of the
bivalent begin to
separate
– Centromere of each
chromosome remains
intact
– Chromatids seem to be
contact at several
places, called chiasmata
• Diakinesis – more
condensation
Meiosis I - Prophase
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Meiosis I
• Metaphase I –
– the nuclear membrane
disappears, and the
chromosomes move to
the equatorial plane.
• Anaphase I
– 2 members of the
bivalent disjoin, and
one member goes to
each pole
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Meiosis II
• Resembles mitosis,
but without DNA
replication
• Without an interphase
• Centromeres divide,
and the sister
chromatids disjoin,
passing to opposite
poles and produce 2
daughter cells.
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Crossing Over
• Reorganization of genes among the
chromosomes hence increases genetic
variability.
• Chiasmata sites of cross over
• 2 chromatids take part in any crossover. But all
4 chromatids of the bivalent may be
simultaneously involved in crossovers at
different sites.
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Crossing Over
• Sometimes crossing over can also occur
between the sister chromatids.
• Bloom Syndrome
– growth retardation, prenatally and postnatally,
and a butterfly rash is seen on the face
• But the correlation of these findings to the
sister chromatid exchange is unknown.
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Recombinant DNA Technology
• Genetic Engineering
• Portion of DNA cut introduced into another host
cultured
• Discovery on restriction endonucleases (Smith in
1970).
• A restriction endonulease is an enzyme that cuts
DNA at specific sequences, called restriction
sites. Over 200 such enzymes are known.
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Recombinant DNA Technology
• Principles of the technique
– Use of the restriction enzyme to cut away a DNA
fragment which includes certain gene/genes.
– Incorporation of these fragments into a carrier or
vector.
– Transformation of a host organism eg-E. coli by the
vector.
– Culturing of the host organism in a suitable medium.
– Selection of the bacteria containing the relavent DNA
fragment.
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Recombinant DNA Technology
• DNA fragment vector.
– Phage, or a plasmid
(circular mass of DNA in
bacteria, which replicate
independent of the main
bacterial chromosomes).
• The vector DNA is usually
cleaved with the same
enzyme as the DNA
fragment, and the
complementary base
pairs that result are
combined together.
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Recombinant DNA Technology -
Applications
• Analysis of gene structure
• Restriction fragment length polymorphisms (RFLPs)
– small changes in the nucleotide sequences without phenotypic
effects (small deletions or insertions)
• length of the fragments generated by a particular
restriction enzyme will be different,
• inherited as Mendelian characters
– As genetic markers – which can be used to study genetic
structure – similar to blood groups and serum proteins.
– In the prenatal diagnosis of any genetic disorder which is linked
to an RFLP, or to identify carriers of the disorder.
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• In detecting the products of various
genes
• In producing probes to diagnose viral
diseases like Hepatitis B or HIV
Recombinant DNA Technology -
Applications
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• Biosynthesis of gene products
– no antigenic properties, and free from contamination
by HIV etc.
• Gene therapy
– The missing gene is created and introduced into the
host
– single gene disorders
• most genetic problems are multifactorial, this
seems to have only limited application.
Recombinant DNA Technology -
Therapeutic Applications
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Mutations
• Single Base Substitutions
– alter the triplet codon
– one amino acid to be replaced
• Deletions and insersions
– if a single base pair is deleted or inserted, the
entire frame of the DNA strand gets shifted
• Single base substitutions – proteins
produced
• Frame shift mutations – no proteins
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Mutations
• Chain termination mutations –
– Termination codons can be added
prematurely or be deleted
• Splice Mutations –
– These interfere with the way
introns are removed from the
messenger RNA.
• Mutations in regulatory
sequences
– These affect the TATA box and the
CAT box regions of the gene.
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• Indications that a condition has a genetic
etiology (Neel and Schull 1954)
1. Occurrence of a disease in definite
proportions in families when environmental
factors can be ruled out.
2. Absence of disease in unrelated lines
3. Characteristic age of onset, absence of
precipitating factors
Inheritance
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4. More in monozygotic than dizygotic
twins.
5. Demonstration of characteristic
phenotype and chromosomal
abnormality, with or without family
history.
Inheritance
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• Autosomal dominant
– Rare
– Patient usually heterozygous
– Parent affected
– New mutation
– Achondroplasia, Osteogenesis imperfecta
– Porphyria variegata – one couple (1688)
– ½ the children affected – irrespective of sex
Inheritance – Single gene
disorders
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• Experssivity – polydactyly
• Non – penetrance
• Sex influence
– Gout
– Presenile baldness
– “Eunuchs neither get gout nor grow bald”
Hippocrates
• Viral etiology? – Alzheimer’s disease.
Inheritance – Single gene
disorders
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• Consanguineous marriages
– Chance that cousins will carry the same
genes is 1 in 8
– The rarer the disease more probability of
consanguineous marriage of parents.
–Eg – Alkaptonuria
• Most common autosomal recessive
disorder – Cystic fibrosis – 1 in 22 is a
carrier.
Inheritance – Single gene
disorders
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• X linked dominant
– Similar to autosomal dominant
– Male transmits disease to all daughters but
none of his sons – Vit. D resistant Rickets
Inheritance – Single gene
disorders
X Y
X
X
XX XY
XX XY
Xh Y
X
X
XXh XY
XXh XY
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• Y linked inheritance
– Hairy pinna
– Transmitted from father to all his sons
– Females not affected
Inheritance – Single gene
disorders
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• Establishing modes on inheritance
• Autosomal dominant – Verical pattern
• Autosomal recessive – Horizontal
• Sex linked – Oblique if male does not
produce offspring
Inheritance – Single gene
disorders
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• Multiple alleles
– Some characters may have more than one
allele
– Blood group genes
• A1 A2 B O
– Any one may be transmitted to the offspring.
Inheritance – Single gene
disorders
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• Deletions
– Results in partial monosomy
• Lejeune – ‘cri du chat’
• Deletion of short arm of chromosome 5
• Formation of ring chromosomes
Inheritance – Chromosomal
Abnormalities
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• Sex chromosome abnormalities
– Kleinfelter’s syndrome – XXY
– Turner’s syndrome – XO
– Multiple X
– XYY males
• Structural abnormalities
– Isochromosome – long X
Inheritance – Chromosomal
Abnormalities
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• More than one gene involved + environment
• Familial tendency
– Incidence in family more than in general population
– Less common than unifactorial disorders
• Normal traits – intelligence, skin colour, blood
pressure, etc.
• Abnormal traits – schizophrenia, diabetes, peptic
ulcer, ischemic heart disease, ankylosing
spondylitis etc.
Inheritance – Multifactorial
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• The incidence is greater among relatives
of individuals with more severe form of the
disease
– Pt. with bilateral cleft lip – 6%
– Pt. with unilateral cleft lip – 2.5%
• Similarly, subsequent children have more
chance of being affected.
Inheritance – Multifactorial
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• Heritability –
proportion of the
total variation of a
character which
can be attributed to
genetic factors.
– Greater the
heritability, greater
the genetic
component.
Inheritance – Multifactorial
Disorder Heritability
(%)
Asthma 80
CL/CP 76
Hyper-
tension
62
Peptic
Ulcer
37
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Homeobox Genes
• These genes contain a specific 180 base
pair region called the homeobox.
• Produces proteins – transcription factors –
bind to DNA and regulate its expression.
• First experiments on Drosophilla
melanogaster later found in vertebrates.
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Homeobox Genes
• Msx -1 development of secondary
palate and tooth.
– familial tooth agenesis –
missing 2nd
premolar and 3rd
molar
• Studies in Finnish families
(Nieminen et al 1995).
• Msx- 2 Craniosynostosis
• SHH Patterning of Neural crest and
neural tube – Affects midline structures
• Hytertelorism
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Cloning
• Cloning is the process of making a
genetically identical organism through
nonsexual means.
• First animal cloned in 1997, at the Roslin
Institute in Scotland
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Cloning
• Proposed benefits of cloning
– Use of clones as donors – cloning only organs
– Saving endangered species –Noah the gaur
– Cloning of stem cells
• Claims of first cloned baby born on 26 Dec
2002.
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Human Genome Project
• Begun formally in 1990,
the U.S. Human Genome
Project is a 13-year effort
coordinated by the U.S.
Department of Energy
and the National
Institutes of Health
• Expected completion date
–sometime in 2003
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Human Genome Project
• Microbial Genomics
– Use of bacteria useful in
energy production (like
photosynthesis), toxic
waste reduction, and
industrial processing.
– Better understanding of
micro-organisms and
hence development of new
drugs