Genetics

WHAT IS GENETICS?????
 The branch of biology that deals with
heredity, especially the mechanisms of
hereditary transmission and the
variation of
inherited
characteristics among
similar or related
organisms
Terminology:
 Gene.
 Alleles- Dominant.
- Recessive.
 Nucleotides.
 Codon.
 Genetic Code.
 GENE
 Biological unit of heredity.

 Gene hold the information to build and

maintain their cells and pass genetic traits to
offsprings

In
cells, a gene is portion of
DNA
 Gene (DNA)

RNA formation

Protein formation

Cell structure Cell enzymes

cell function
 ALLELE
 Is one member of a pair or series of
different forms of a gene.
 Homozygous-an organism in which 2 copies
of genes are identical i.e. have same alleles
 Heterozygous-an organism which has different
alleles of the gene
Chromosomes:
 Chromatin: DNA, RNA &
proteins that make up
chromosme

 Chromatids: one of the

identical parts of the
two
chromosome.
 Centromere: the point where two
chromatids attach

 46 chromosomes. 22 pairs
Autosomes and 1 pair Sex
chromosomes.
 NUCLEOTIDE: group of molecules that
when linked together, form the building blocks
of DNA and RNA; composed of phosphate
group, the bases:adenosine,cytosine,guanine and
thymine and a pentose sugar.In case of
RNA,thymine base is replaced by uracil.
 CODON: series of three adjacent bases in one
polynucleotide chain of a DNA or RNA
molecule which codes for a specific amino acid.
 GENETIC CODE: the sequence of
nucleotides in a DNA or RNA molecule that
determines the amino acid sequence in the
synthesis of proteins.
 Congential Disease.
Diseases which are present at birth.

 Hereditary/Familial Disease.
Diseases which are derived from one’s
parents and trasmitted in the gametes through
the generations.

Not all congenital diseases are genetic( congenital

Syphilis) and not all genetic diseases are congenital
(Huntington disease).
Mutations.
 Definition:
Permanent changes in the DNA.
Those that affect germ cells are
transmitted to the progeny. Mutations in
the somatic cells are not transferred to the
progeny but are important in the causation
of cancer and some congenital diseases.
 CAUSES OF MUTATIONS
 Chemicals
 Nitrous acid
 Alkylating agents
 5- bromouracil
 Antiviral drug iododeoxy uridine
 Benzpyrene in tobacco smoke
 X – rays & ultraviolet light
 Certain viruses such as bacterial virus
Types Of
Mutations.
• Point Mutation:
Substitution of a
single nucleotide base
by a different base.
• Categorized as:
• Transition
• transversion
 Missense
Mutations.

 Nonsense
Mutations.
• Frameshift
Mutations:

Insertion or
deletion of one or
two base pairs
alters the reading
frame of the
DNA strand.
Trinucleotide Repeat
Mutations:
set of genetic
disorder caused by
trinucleotide repeat in
certain genes
exceeding
normal,stable
threshold e.g. Fragile
X Syndrome.
Classification Of Genetic
Diseases:
 Single Gene Defects/Mendelian Disorders.

 Disorders with Multifactorial or Polygenic

inheritance.

 Cytogenetic Disorders.

 Disorders showing atypical patterns

of inheritance.
 Mendelian
Disorder
s
A genetic disease caused by a single
mutation in the structure of DNA,
which causes a single basic defect with
pathologic consequences
Patterns Of Inheritance:
 Autosomal Dominant.

 Autosomal Recessive.

 X-Linked Recessive.

 X-Linked Dominant.
Autosomal
Dominant
Disorders.
 Manifested in heterozygous states.

 Individuals with these diseases usually have one

affected parent .*

 Variable to late onset.

 These disorders usually involve non-enzymatic

proteins;
• Proteins involved in metabolic pathway regulation.
• Structural Proteins.
Inheritance Pattern:
•Typical mating pattern is a
heterozygous affected
individual with a
homozygous unaffected
individual.

•Every child has one chance

in two of having the disease

•Both sexes are affected

equally..
Disorders:
Structural Protein Defects:

 Marfan’s Syndrome.

 Ehler-Danlos Syndrome.
Marfan’s Syndrome:
Mutation in the fibrillin gene.

Fibrillin
important component
of microfibrils in Elastin.

Tissuesaffected are Skeleton,

Eyes and the CVS.

C/F include tall stature, long

fingers, pigeon breast deformity,
hyper-extensible joints,high
arched palate, BL subluxation of
lens, floppy Mitral valve, Aortic
aneurysm and dissection, defects
in skin,lungs.
Ehler-Danlos Syndrome(Cutis
Hyperelastica):

 Characterized by defects in collagen synthesis.

 .Clinical Features include fragile, hyper-extensible skin,

hyper-mobile joints, grotesque contortions, rupture of
internal organs like the colon, cornea and large
arteries, poor wound healing.
Defects in metabolic pathway proteins:
 Familial Hypercholesterolemia:
• One of the most common mendelian disorders.

• Mutation in the LDL receptor gene.

• Hypercholesterolemia due to impaired LDL transport into

cells.

• Increased risk of atherosclerosis and coronary artery

disease.
• Increases Cholesterol leads to formation of Xanthomas.
Autosomal
Recessive
Disorders
 Largest group of Medelian Disorders

 Affected individuals usually have unaffected (carrier)

parents.

 Uniform, early age of onset.

 These disorders usually involve Enzymatic Proteins.

Pattern Of
Inheritance:
Typicalmating pattern is two
heterozygous unaffected (carrier)
individuals.

The triat doesnot usually affect the

parent, but siblings may show the
disease

Siblings have one chance in four of

being affecte

 Both sexes affected equally.

Disorders:
Glycogen Storage Diseases.
Category Disease Enzyme
Hepatic Type. Von Gierke’s Glucose-6-
Disease type 1. phosphotase.

Myopathic Type. McArdle Syndrome. Muscle

Phosphorylase.

Miscellaneous Type. Pompe’s Disease Lysosomal

type II Glucosidase.
 X-Linked
Recessive
Disorders
.
 Most common X-linked disorders.

 Usually expressed only in males.

 Rarely, due to random X-inactivation, a female will

express disease, called manifesting heterozygotes.
Pattern Of
Inheritance:
•Disease usually passed on from
carrier mother.

•Expressed in male offspring,

females are carriers.

•Skipped generations are commonly

seen.

•Inthis case, Recurrence risk is half

of sons are affected, half of the
daughters are carriers.
•Recurrence risk:
•Allthe daughters are
heterozygous carriers
and all the sons are
homozygous normal.
Disorders:
 DISORDERS WITH
MULTIFACTORIAL
(POLYGENIC)INHERITANCE
 Involved in many physiologic characteristics of
humans e.g. height, weight, hair color

 Defined as one governed by additive effect

of two or more genes of small effect but
conditioned by environmental, non genetic
influences
 The disorder becomes manifested only when a
certain number of effector genes, as well as
conditioning environmental influences are
involved

 Rate of recurrence is 2 to 7%
COMMON DISEASES ASSOCIATED:
 Diabetes mellitus
 Hypertension
 Gout
 Cleft lip and palate
 Schizophrenia
 Bipolar disorder
 Congenital heart disease
 Skeletal abnormalities
 Neural tube defects
 Coronary artery disease
Cytogenetic
Disorders
.
KARYOTYPING
 Basic tool of cytogeneticist

 Karyotype is a photographic representation

in which chromosomes are arranged in order
of decreasing length

 Giemsa stain (G banding) technique—each

chromosome can be seen to possess a distinctive
pattern of alternating light and dark bands of
variable widths
Shorthand of Cytogenetics:
 Short arm denoted as p, long
arm denoted q.

 Each arm divided into numbered

regions from the centromere
onwards.

 Each region numerically

arranged into bands.

 For e.g., 5p24 would denote

chromosome 5, short arm,
region 2 and band 4.
 Cytogenetic disorders may result from structural
or numeric abnormalities of chromosomes

 It may affect autosomes or sex chromosomes

Numeric Abnormalities:
 Normal Chromosomal number is 46. (2n=46). This
is called euploid state. (Exact multiple of haploid
number).

 Polyploidy: posession of more than two sets of

homologous chromosomes. Chromosomal numbers
like 3n or 4n. (Incompatible with life); generally
results in spontaneous abortion

 Aneuploidy: Any Chromosomal number that is not

an exact multiple of haploid number . E.g 47 or 45.
Aneuploidy:
 Most common cause is nondisjunction of
either a pair of homologous chromosomes
during meiosis I or failure of sister
chromatids to separate during meiosis II.

 The resultant gamete will have either one less

chromosome or one extra chromosome.
 Fertilization of such gamete will result in
zygote being either trisomic ( 2n+1 ) or
monosomic
( 2n-1 ).

 Monosomy in autosomes is incompatible with

life. Trisomy of certain autosomes and
monosomy of sex chromosomes is
compatible with life.
Mosaicism:
 The presence of two or more types of cell
populations in the same individual.

 Postzygotic mitotic nondisjunction will result in one

trisomic and one monosomic daughter cell.

 The descendants of these cells will produce a mosaic.

Structural Abnormalities:
 Usually result from chromosomal breakage, resulting
in loss or rearrangement of genetic material.

 Patterns of breakage:

• Translocation.
• Isochromosomes.
• Deletion.
• Inversions.
• Ring Chromosomes.
TRANSLOCATION
 Transfer of a part of one chromosome
to another chromosome
 Translocations are indicated by t
 E.g. 46,XX,t(2;5)(q31;p14)
 Balanced reciprocal translocation is not harmful
to the carrier, however during gametogenesis,
abnormal gametes are formed, resulting in
abnormal zygotes
 Centric fusion type or robertsonian translocation:
 The breaks occur close to the centromere,
affecting the short arms of both
choromosomes
 Transfer of the chromosome leads to one
very large and one extremely small
chromosome
 The short fragments are lost, and the carrier has
45 chromosomes
 Such loss is compatible with survival
 However, during gametogenesis difficulties arise
ISOCHROMOSOMES
 Result when one arm of a chromosome is lost and the
remaining arm is duplicated, resulting in a chromosome
consisting of two short arms only or of two long arms.

DELETION
 Loss of a portion of chromosome
 This can be terminal (close to the end of the
chromosome on the long arm or the short arm), or it can
be interstitial (within the long arm or the short arm).
 A ring chromosome is a variant of deletion.It
occurs when break occurs at both the ends of
chromosome with fusion of the damaged ends.
INVERSIONS
 Occur when there are two breaks within a single
chromosome with inverted reincorporation of
the segment.
 Since there is no loss or gain of
chromosomal material, inversion carriers are
normal.
 An inversion is paracentric if the inverted
segment is on the long arm or the short arm
.
 The inversion is pericentric if breaks occur
on both the short arm and the long arm .
General Features of Cytogenetic Disorders:
 Associated with absence, excess, or abnormal
rearrangements of chromosomes.

 Loss of genetic material produces more

severe defects than does gain.

 Abormalities of sex chromosomes

generally tolerated better than those of
autosomes.
 Sex chromosomal abnormalities are usually
subtle and are not detected at birth.

 Most cases are due to de novo changes (i.e.

parents are normal and recurrence in
siblings is low).
Cytogenetic Disorders
involving Autosomes.
Trisomy 21/Down’s Syndrome:
 Most common chromosomal disorder.

 Down syndrome is a chromosomal

abnormality characterized by the presence
of an extra copy of genetic material on
the 21st chromosome

 Trisomy 21 is caused by a meiotic

nondisjunction event.
 With nondisjunction, a gamete (i.e., a sperm or
egg cell) is produced with an extra copy of
chromosome 21; the gamete thus has 24
chromosomes
 When combined with a normal gamete from the
other parent, the embyo now has 47
chromosomes, with three copies of
chromosome 21.
 About 4% of cases are due to
Robertsonian translocations.
 Maternal age has a strong influence
Karyotype for trisomy Down syndrome. Notice the three copies of
chromosome 21
Other Trisomy Syndromes:

 Trisomy 18 :Edwards Syndrome.

 Trisomy 13 :Patau Syndrome.

Cytogenetic Disorders
involving Sex
Chromosomes.
 Extreme karyotypic variations seen frequently
with Sex Chromosomes, with females having
4-5 extra X Chromosomes.

 Males with two to three Y chromosomes have

also been identified.
Klinefelter’s Syndrome:
 Defined as Male Hypogonadism, develops when
there are at least two X chromosomes and one
or more Y chromosomes.

 Usual karyotype is 47,XXY. The extra X may be

maternal or paternal.
 Results from nondisjunction of
sex chromosome during meiosis.

 Risk factors include advanced maternal age

and a history of exposure to radiation in
either parent.
Clinical Manifestations:
 Increase in body length between soles and pubis.

 Reduced facial, body and pubic hair. Gynecomastia.

 Testicular atrophy.

 Infertility.

 Mild mental retardation.

Turner Syndrome:

 Primary
hypogonadism in
phenotypic females.

 Results
from partial or complete monosomy
of the X chromosome.
 Most
common cause is absence of one
X chromosome.

 Lesscommonly, mosaicism, or deletions

on the short arm of the X
chromosome.
DIAGNOSIS OF GENETIC DISEASE

 Conventional Cytogenetic Analysis

 FISH
 Molecular Analysis