Basic genetics /certified fixed orthodontic courses by Indian dental academy

Basic Genetics

INDIAN DENTAL ACADEMY
Leader in Continuing Dental Education

www.indiandentalacademy.com

Introduction

Genetics is the study of genes

This talk is intended to be an introduction to
the principles and language of human
genetics.
It was Gregor Mendel, the Austrian monk who
introduced us to the concept of heredity in
1860s


Scope of Genetics

 Barely 40 years ago Genetics was just a
fanciful branch of Medicine without much
clinical significance(of pure academic interest)
 Today genetics occupies a very important

place in medicine


Scope of Genetics
For a clinician, genetics plays role in,
1) Analysis, prediction and prevention of
disease and the days are not far off when it
will play a very important role in treating
the diseases. Already we are using many
genetically engineered products like insulin
and vaccines.
2) Today genetics occupies the most important
role in the diagnosis of diseases. Ex,
presence of even a small sequence of DNA is
enough to diagnose a disease( by PCR)

Chromosomal Basis of Basic Heredity

 Nuclear material – normally homogeneous

 During cell division-Loses homogeneity.
Number of rod shaped organelle called
chromosomes appear.
 Chromosomes contain DNA, in which units
of genetic information or genes are present



 The chromosomal constitution of a person is
known as Karyotype (Chr Nos and
morphology)
 The genes are arranged along the
chromosomes in linear pattern.
 Each gene has a precise position or locus
 Allele- alternative forms of a gene that can
occupy the same locus



 Genotype- Genetic constitution of a person
 Phenotype -expression of the genotype as
morphological, biochemical and physiological
trait.
 Genome: Full DNA content of a
chromosome set


Chromosomal basis of basic heredity

 Human chromosomes

46 chromosomes of normal human somatic cells
constitute 23 homologous pairs (same gene loci in
the same sequence), one from the father and one
from the mother
 22 pairs are alike in males and females-autosomes

 The remaining pair , the sex chromosomes differ in
males and females, males-XY & females XX

Chromosomal Techniques
 Cellsfor chromosomal analysis must be capable of
growth and rapid division in culture
 So WBCs are used ( RBCs are non nucleated)

 Heparinised blood is centrifuged to separate WBCS
 Cells are collected & placed in suitable
tissue culture
medium stimulated to divide by a mitogenic agent-
phytohemagglutin
 Culture incubated for72 hrs


 When the cells are multiplying rapidly a dilute
solution of Colchicin is added which interferes with
the action of the spindle by binding to tubulin of
spindle microtubules and also prevents centromeres
from dividing.
 Colchicin arrests mitosis at metaphase
A hypotonic solution is then added to swell the cells
and separate chromatids known as Metaphase spread



 The cells are fixed on slides & stained by various
techniques.
 This is now ready for microscopic examination,
photography and karyotyping
 WBCs are short lived. So for long-term culture
studies, fibroblasts from dermis of the skin are used


A chromosome spread prepared from a lymphocyte culture. The same
cell is shown with solid staining (left) and giemso bonding (right).



 The chromosome spread is photographed &
chromosomes are cutout from the
photograph and arranged in pairs – This is
karyotyping and the complete picture is the
Karyotype


A human male Karyotype with Giemsa banding (G bonding). The
chromosomes are individually labeled and the seven groups A to G are
indicated.


Denver classification
 Based on overall length and centromere
position
 Depending on centromere Seven groups
from A to G based on position,
Metacentric- Cm central
Submetacentric-Cm somewhat off centre
Acrocentric- Cm near the end
* Banding is done by staining

Molecular structure &
Function of chromosomes and
genes
Nucleus

Chromosomes

Segments of DNA with genetic
information


DNA
 Two polynucleotide chains, twisted to
form a double helix-Watson Crick
Double helix
 Rope ladder analogy
 Nucleotide is the unit of DNA composed
of
1) Nitrogenous base
2) Sugar-Deoxyribose
3) Phosphate molecule

DNA
 Each side is made up of
chains of sugar and
phosphate
 The ‘step’ of the ladder is
made up of 2 nitrogenous
bases from 2 poles projecting
inwards & the bases are
joined by hydrogen bond.
 Nitrogenous bases are
Purines-Adenine & Guanine
Pyrimidines-Thymine &
Cytosine

DNA

 The pairing always follows a fixed pattern,

1 purine pairs with 1 pyrimidine
Adenine always pairs with Thymine -AT
& Guanine with Cytosine-GC
 Each pair of complementary nitrogenous base
is termed as a ‘ base pair’ ( bp) E.g. AT, CG,
TA, GC
• Length of DNA is expressed as base pairs.
• 1000 bps =1 kilo base (kb)

DNA contd

 At nuclear division the two strands separate &

then each build its complement. So the genetic

information is conserved & transmitted to the

daughter cell


RNA

 DNA is mainly found in the chromosomes.

 RNA is found mainly in the nucleolus and
cytoplasm.
 RNA has same structure as DNA but in place
of Thymine there is Uracil and the sugar is
Ribose


Genes & Genetic information

 All genetic material (DNA) contained in a
single cell is known as human genome

 It contains all the information of life

 Human genome contains about 3 billion base
pairs(bp)



 Only 5% of DNA forms coding area.

 The coding area of human genome is called
gene
 95% of DNA contains stretches of non-coding
areas referred to as ‘junk’ or ‘redundant’ or
‘selfish DNA’



Genetic information is stored in DNA by means
of a code.
A Code is a triplet of three adjacent bases.
CODON is a coding for amino acid
E.g.-UUU,AGA etc
There are 64 such possibilities


Genes & Genetic
information
 At 5` end are promoter regions like ‘TATA
BOX’, ‘CCAT BOX’, Enhancer
 These are important in transcription,
controlling quantity of RNA & determining
the site of transcription
 At 3` end the sequence AATTAA provides a
signal for polyadenylation of RNA (poly ‘A’
tail)
 Poly A tail is essential for RNA to exit from
the nucleus for translation

How genes work?
 One strand of gene forms a template for the
synthesis of a RNA known as messenger RNA
(mRNA)-Transcription
 In the nucleus the introns are excised & the
exons are joined together & cap and tail are
added to signify the start and end of code


How genes work?
 At3` end sequence AATTAA-gives signal for
polyadenylation of RNA (poly`A` tail), after
which it exits from nucleus, for
translation( for protein synthesis)
 The mRNAin cytoplasm becomes a template in
the ribosome for translation
 ThetRNA contains anticodons complementary
to RNA codon for specific amino acid it carries.


How genes work?
 Specific amino acids , delivered by tRNA,
is added till the stop codon is reached,
forming the desired peptide, which is
released from ribosome and used by the
cell.


Transcription & translation


Formation of mRNA

Transcription and processing of a globin gene to form
mature messenger RNA

Classification of genetic disorders
1) Single gene disorder: By mutant gene.
Mutation in only one or both chromosomes,
1: 2000 or less
2) Chromosomal disorders: Due to excess or
deficiency of whole chromosome or chr.
Segments.
These can be
i. Structural
ii. Numerical
7:1000, ½ of all spontaneous Ist term abortions
3) Multifactorial:No characteristic pedigree pattern
of single gene traits. May occur in families

Symbols commonly used in pedigree chart


Patterns of single gene inheritance
 Single gene traits depend on 2 factors
1)Whether gene responsible is an
autosome or a sex chromosome
2)Whether it is dominant, i.e.expressed even
when present on only one chromosome of a
pair, OR
3) Recessive- expressed only when present
on both chromosome

Patterns of Single Gene
Inheritance
AUTOSOMAL

Dominant Recessive

X-LINKED( SEX LINKED)

Dominant Recessive


Inheritance
 The person who first brings a family to the
attention of the investigator is a Proband
(Index case)
 Sibs or siblings- brothers or the sisters of the
proband
 Alleles-Genes at the same locus on a pair of
homologous chromosomes
 When a person has

- A pair of identical alleles-Homozygous,
- Different alleles-------------Heterozygous

Inheritance

 Allele that is expressed whether hetero or

homozygous is DOMINANT

 Allele that is expressed only when
homozygous is RECESSIVE


Inheritance
Autosomal dominant inheritance
- Manifests in heterozygotes
- Person possesses both normal and
mutant gene
- Presence of any one mutant gene is
enough for the disease
- Homozygosity is rare-i.e..2 abn genes
- Normal and abn genes are alleles

Autosomal dominant and recessive


Inheritance
Autosomal dominant inheritance(contd )
- Trait transmitted from one generation to the next i.e.,
trait in every generation
- Both males and females are affected
- Risk is 50% that is, affected person has 50% chance of
transmitting.
- Unaffected members do not transmit to children
- Occurrence and transmission not affected by sex
Ex: -Achondroplasia, Adult form of polycystic kidney

Inheritance
Autosomal dominant inheritance(contd )
 Some autosomal dominant traits are
extremely variable in severity-the variability
is referred to as expressivity.
Ex- Osteogenisis imperfecta can vary from
just blue sclera to full blown syndrome with
deafness & multiple fractures.
Penetrance: A person may carry a mutant
gene & yet not exhibit any of its effects; the
gene is then said to be non-penetrant. The
degree of expression depends on penetrance

Autosomal dominant disorders
 Achondroplasia  Neurofibromatosis
 Huntington`s chorea  Tuberous sclerosis
 Marfan`s syndrome  Osteogenesis
 Acute intermittant imperfecta(some
porphyria forms)
 Myotonic dystrophy  Fascio-scapulo-
 Adult polycystic humoral dystrophy
 Familial
kidney disease
 Noonan`s syndrome hypercholesterolemi
a


Inheritance
Autosomal recessive inheritance
- Trait only in sibs (brothers & sisters) & not in
their parents, offspring or other relatives
- On an average ¼ th of the siblings of the proband
are affected
- Males & females are equally affected, but only in
homozygotes-those with double dose of mutant
gene.
- Inbreeding increases the risk of this inheritance


Inheritance
Autosomal recessive inheritance
- Heterozygotes with only one affected gene are
healthy
- Offsprings of affected people are usually
normal as it is less likely that an affected
person marries another heterozygote for the
same mutant gene
- Generally affected individuals cannot be traced
from one generation to next
Ex; Cystic fibrosis

Autosomal recessive disorderes

 Congenital adrenal hyperplasia

 Cystic fibrosis

 Galactesemia

 Sickle cell disease

 Phenyl ketonuria


Sex linked inheritance

 Due to the situation on either X or Y
chromosomes(sex chromosomes)
 Genes on X chr are X-linked and Y are Y-
linked
 There are no examples of Y-linked single
gene disease.
 Sopractically all sex –linked disorders are
X-linked

Patterns of Single Gene Inheritance

X-linked recessive trait
Ex: Hemophilia
- X-linked recessive trait is expressed by all
males who carry the gene
- A mutant gene present on the single X is
always manifest because it is unopposed by
the modifying effect of a normal gene on the
second X chromosome as happens in a female


Patterns of Single Gene Inheritance

X-linked recessive trait
- Expression in female theoretically possible if
they are homozygous
- Practically restricted to males
- Heterozygous carrier is usually healthy
- Affect males &transmitted by healthy female
carriers
- Never transmitted from father to son but his
daughters will be carriers


X-Linked recessive
 Hemophilia A & B  Lesch-Nyhan
 Duschenne muscular syndrome
dystrophy  Ocular albinism
 Anhydrotic  Menke`s syndrome
ectodermal dysplasia  Fabry`s disease
 Colour blindness
 Hunter`s syndrome
 G6PD deficiency


Inheritance
X-linked dominant
- Manifest in both in males who carry mutant
gene on X chromosome and females who are
heterozygous for the mutant gene
- More common in females-twice
- Affected male transmits the gene to all his
daughters and none to his sons.
- Affected female will transmit to half her
offsprings of either sex. Ex: Vit D Res Rick

CHROMOSOMAL DISORDERS

 Lejeune in 1959 demonstrated that children
with Down`s syndrome had 47 chromosomes
 When to suspect a chromosomal disorder?

1) Congenital malformations, esp. if more
than one system is involved
2) Mental retardation of unknown origin


 When to suspect a chromosomal disorder?....contd

3) Odd facies
4) Abnormal ears
5) Heart and kidney malformation
6) Abnormalities of hand and feet
7) Simian crease and single crease on the 5th
finger
8) LBW
1:150 newborn infants have chromosomal
abnormalities

 Chromosomal abnormalities can be
1) Numerical
2) Structural
NUMERICAL ABNORMALITIES:
- A cell withy exact multiples of haploid
number(46,69,92) is known as euploid
- Euploid with more than normal diploid
numbers are polyploid
- Other than euploid number-aneuploid
- Ex of aneuploidy-trisomy 21, monosomy etc



 NUMERICAL ABNORMALITIES contd
- Monosomy is lack of a chromosome
- Trisomy is due to non- disjunction of
chromosomes in meiosis
- Polyploidy is lethal in human beings
i.e.. fertilization of one ova by two
sperms

Disjunction



- Commonest type of aneuploidy is Trisomy-3
homologous instead of the normal pair
- Lack of a chromosome –monosomy
- During meiosis synapses occurs between each
chromosome and its homologue.
After separation each proceeds to an opp. Pole
of the dividing cell.
Failure of synapses or failure to separate
(non-disjunction) may result in aneuploidy


STRUCTURAL ABNORMALITIES
NOMENCLATURE:
- Short arm of a chromosome-p
- Long arm-q
- Any addition or loss of chromosomal material
is denoted by + or – sign placed before the
chromosome number, if a whole chromosome
is involved Ex. +21
- After a no. if any increase or decrease in
length is involved Ex. Cri-du-chat(5p-)


STRUCTURAL ABNORMALITIES-cond

-These abnormalities result from chromosome
breaks and rearrangements

-All structural abnormalities require at least
two chromosomal breaks followed by reunion
of the broken ends



- STRUCTURAL ABNORMALITIES-cond
- The breakage may be :
1.Stable: Capable of passing through cell
divisions unaltered
Ex:Deletions, duplications, inversions,
translocations, insertions and
isochromosomes
2.Unstable –Not capable of passing through
the cell division unaltered. Ex. Dicentric,
accentric rings

- Deletion: Loss of a portion of chromosome
- Deleted portion if it lacks centromere-
acrocentric fraction. This fragment fails to
move on the spindle in cell division due to the
absence of centromere and is lost n
subsequent cell divisions. This structurally
abn chr lacks whatever genetic information
was present in the lost segment.
EX- Cri-du-chat syndrome in which part of the
short arm of chromosome is deleted
46XXorXY, 5p-


Duplication :
Presence of extra segment of chromosome-More
common, less harmful
Inversion:
Inversion involves fragmentation of a
chromosome by two breaks , followed by
reconstruction with inversion of a section of the
chromosomes between the breaks


Inversion contd;
If single arm is involved-paracentric

If involves centromere-pericentric

Inversion alone may not lead to an abn.
phenotype, more true of paracentric as there is
no change in arm ratio, whereas in pericentric
there will/may be change of proportion of
chromosomal arms

Structural disorders




Translocation: Exchange of segments between
two non-homologous chromosomes-reciprocal
or balanced translocation diagram



Isochromosomes:

During cell division the centromere of a
chromosome sometimes mistakenly divides
so that it separates the two arms rather than
the two chromatids diagram


Translocation and isochromosome



Mosaicism:
If non-disjunction occurs at an early cleavage
division(mitotic division) of the zygote rather
than during gametogenesis, an individual with
2 or more cell lines with different chromosome
numbers, in the same individual is produced
giving rise to a mosaic.


Transcription and processing of a β globin gene
to form mature messenger RNA.

A diagrammatic representation of ultrastructure
of a chromosome and the relationship between
DNA, histones and the chromatin fibre.

Classification of chromosomes based on the position
of the centromere, and how they appear at anaphase
stage of cell division.

The structure of nucleosomes: DNA is wound round a
histone octamer to produce a nucleosome.


James D.Watson, F.H.C. Crick and M.F.H. Wilkins:
Nobel Laureates of 1962.


Formation of nucleotide and the
formation of a polynucleotide
strand.

Semiconservative method The process of DNA replication. Both parental
of DNA replication: One
strands act as templates. While on the leading
original strand is
conserved and a new strand the replication is continuous, on the
strand is synthesized. lagging strand it is synthesized in short pieces.

The process of RNA synthesis or transcription,
wher RNA is synthesized on one of the strands of
DNA. There are different sites for synthesizing
diferent types of RNAs.

The mRNA Codons Adenine (A):
Guanine (G): Cytosine (C ) :
Uracil (U)

The code-codon-polypeptide relationship in
transcription and translation.


Genetic engineering or
Bio-engineering
 It is modification of genetic structure of an
organism at the molecular level to alter its
characteristics
 The basic process of genetic engineering
is called recombinant DNA technology


Recombinant DNA technology
It consists of
* Inserting, foreign DNA, carrying genes for
valuable enzymes, hormones or other proteins,
into DNA of some other organism so that it
makes the desired product.
*The essences of rDNA technology is process
called gene cloning.
*Cloning is a method of obtaining identical copies
& cloning aims at obtaining identical copies of a
desired gene


Applications of genetic engineered
bacteria
1) Human insulin
2) Human growth hormone
3) Gene therapy-Person's genes are altered to
combat a disease by inserting gene into a cell
or into a germ cell.-Somatic cell gene therapy
is being tried in cystic fibrosis
4) Genetic or DNA finger printing in dispute
arising out of babies, parents etc
5) Polymerase chain reaction


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