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 Gene Ȃ Dza segment of DNA that is
expressed to yield a functional protein.dz
 DzGenedz term coined by Johanson (
1909).
 Eukaryotic genes are split genes.
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 An Ã
 is a DNA region within a gene that is not
translated into protein.
 Discovered by Richard Roberts and Phillip Sharp
(1977) during the studies of adenoviral replication in
cultured humans cells.
 Have no cellular functions
 Have helped accelerate evolution by facilitating
recombination between exons of different genes-
DzEXON SHUFFLINGdz.
 Introns early view
 Introns late view

     
 A ñ
 is a
regulatory region of DNA
located upstream (towards
the 5' region) of of a gene,
providing a control point
for regulated gene
transcription.
 §he promoter contains
specific DNA sequences
that are recognized by
proteins known as
transcription factors.
¦

 
 ñ
 the minimal portion of the promoter required to properly
initiate transcription

Ñ §ranscription Start Site (§SS)

Ñ Approximately -34
Ñ A binding site for RNA polymerase
Ñ General transcription factor binding site
 ¦Ã
ñ
 the proximal sequence upstream of the gene that tends
to contain primary regulatory elements.
Ñ Approximately -250
Ñ Specific transcription factor binding sites
 §A§A box (sequence § § ), which in turn binds a §A§A binding protein
which assists in the formation of the RNA polymerase transcriptional complex.
   
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 discovered by Walter Schaffner (1981) during studies
of the SV40 viral promoters.
 Stimulate transcription when placed either upstream /
downstream of the promoter.
 Binding of specific transcriptional regulatory proteins
to enhancers is responsible for
Ñ the control of gene expression during development
and differentiation
Ñ the response of cells to hormones and growth factors.
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 Silencers are control regions of DNA that, like enhancers, may be located
thousands of base pairs away from the gene they control.

 When transcription factors bind to them, expression of the gene they control
is repressed.

 Insulators are stretches of DNA (as few as 42 base pairs may do the trick)
located between the

 enhancer(s) and promoter or

 silencer(s) and promoter
of  
genes or clusters of adjacent genes.

 In mammals (mice, humans, pigs), only the allele for à 

à 
Ã


 (|
) inherited from one's father is active; that inherited from the
mother is not Ȅ a phenomenon called ÃñÃ
à .
 
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 Either of two sections on each side of a coding
sequence on a strand of mRNA.

 §wo types
Ñ 5ǯ U§R or leader sequences
Ñ 3ǯ U§R
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 A mutation is a sudden change in the amount,
arrangement or structure of the DNA of an
organism.
 §his produces a change in the genotype which may
be inherited by cells derived by mitosis or meiosis
from the mutant cell.
 A mutation can occur at DNA level (gene
mutation)or at the chromosome level(
chromosomal aberrations).

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 ells have acquired several repair mechanisms to
maintain the integrity of their genomes.
 DNA repair two types
Ñ Direct reversal of chemical reations
Ñ Removal of damaged bases
Base excision repair
nucleotide excision repair
mismatch repair
A jutation in the repair genes results in inherited
diseases.

  !"#
!
 Defect in nucleotide
excision repair results in
xeroderma
pigmentosum,
cockayneǯs syndrome,
trichothiodystrophy.
 Defect in mismatch
repair results in
hereditary nonpolyposis
colorectal cancer.
 


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 § ñ  are
sequences of DNA that
can move or
 ñ
themselves to new
positions within the
genome of a single cell.
 §ransposition of both
LINES & Alu elements Ȃ
haemophilia, muscular
dystrophy & colon
cancer.
 j  |
 one allele of a gene changes into a different allele.
 Because such a change takes place within a single gene and
maps to one chromosomal locus (Dzpointdz), a gene mutation
is sometimes called a point mutation.
 Point mutation typically refer to alterations of single base
pairs of DNA or of a small number of adjacent base pairs.
 At the DNA level, there are two main types of point
mutational changes:

Ñ ©

©

and
Ñ ©
 
or deletions
 

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 jutation in which one base pair is replaced
by another.
 Base substitutions again can be divided into
two subtypes:
Ñ transitions and
Ñ transversions.

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 a purine base is replaced by another purine
base (A by G or G by A) or a pyrimidine by
another pyrimidine (§ by  or  by §) the
substitution is called a transition.

 If a purine base is substituted by a

pyrimidine, or vice versa, the substitution is
called a transversion.

 §ransitions are by far the most common

types of mutations.

 transition mutations code for chemically

similar amino acids while transversions
show a greater possibility of inserting
amino acids with different charges.

 Although transitions and transversions can

cause nonsense mutations, the chances of
missense mutations are greater.
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(## (# 
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 A single nucleotide substitution within polypeptide-
encoding DNA causes defective gene expression by
activating a cryptic splice site within an exon.
 Single base substitution can be classified as
Ñ synonymous substitution
Ñ missense mutation
Ñ nonsense mutation
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%

 Substitutions results in a new codon specifying the
same aminoacid.
 jost frequently observed in coding DNA, because they
are almost always neutral mutations and not subject to
natural pressure.
 Substitution often occur at the third base position of a
codon:  ©
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©
 
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£## (#%

%'
 

 A codon specifying an
aminoacid is replaced by a
stop codon (UAA, UGA,
UAG).
 leads to the premature
termination of translation.
 Stop codon mutations can
occur at any positions.
 E.g., DjD, Ʌ thalessemia,
cystic fibrosis, hurler
syndrome.
w !

 jutation that changes a
stop codon into a codon
for an aminoacid.
A Results in production of
too large proteins,
making protein non
functional and in some
cases harmful proteins.
A E.g., Familial British
dementia.
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 §he codon for one
aminoacid is replaced by
another aminoacid.
 2nd position- always a
missense mutation
 3rd position almost always a
missense mutation.
 an be either
Ñ conservative substitution
Ñ Non-conservative
substitution
 **
+

 Replacement of aminoacid
by another that is
chemically similar to it.
 §he effect of
suchsubstitutions on
protein function is
minimal because the side
chain of the new
aminoacid may be
functionally similar to that
of aminoacid to it replaces.
  **
+

 Replacement of one
aminoacid by another
which has a dissimilar
side chain, a charge
difference or a polar by a
non polar and vice-versa.
 Often occurs in the first
and second codon
positions.
 E.g., sickel cell anemia.
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 Gain or loss of one or
more nucleotides results
in frame shift mutation.
 Frameshift mutation
typically exhibit
complete loss of normal
protein structure and
function.
 Single & double nucleotide INDEL- all
downstream aminoacid change.
 §riplet INDEL- insertion / deletion of a
single aminoacid produce milder
consequences.
 jultiple triplets produce major effect.
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%!- 

 A dynamic mutation responsible for causing any type

of disorder categorized as a trinucleotide repeat
disorder.
 §riplet expansion is caused by
  during DNA
replication.
 Due to the repetitive nature of the DNA sequence in
these regions, 'loop out' structures may form during
DNA replication while maintaining complementary
base paring between the parent strand and daughter
strand being synthesized.
 
%!  ! ! 

)!
 §he Ô gene is located
on the short arm of
chromosome 4, at 4p16.3.
Ô contains a sequence
of three DNA basesȄ
cytosine-adenine-guanine
(AG)Ȅrepeated multiple
times (i.e. ...
AGAGAG ...), known
as a trinucleotide repeat.

jwj j  | w
hromosomal mutations take place when the
number of chromosomes changes or when structural
changes occur in the chromosomes.
occurs generally during the formation of a zygote
where changes in the number of chromosomes may
result in fission (two into one or one into two) or
fusion (two into one).
 
 
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§Ã   §Ãñ

à §
 ñ
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 Ãñ

 Ã

 

à 
 

à 

à Ã  à  

à  ñ
Ã
à à 
Ñ hanges in number of genes

loss or deletion

addition or duplication
Ñ changes in gene arrangement

inversion

translocation
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 ~

à is a mutation in
which a part of a
chromosome is missing.
 Deletions can be caused by
errors in chromosomal
cross over during meiosis.
 Deletion can be either

Intercalary/ interestitial

§erminal
Example: cri du chat
syndrome
% 
 Intercalary/interestitial -  §erminal deletion- a
a deletion that occurs from the deletion that occurs towards the
interior of a chromosome. end of a chromosome.
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%
 A duplication occurs
when part of a
chromosome is copied
(duplicated) abnormally,
resulting in extra genetic
material from the
duplicated segment.
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 Inversion occurs when a region
of a chromosome breaks off and
rotates through 180 degree
before rejoining the
chromosome.
 No change in genotype occurs as
a result of inversion but
phenotypic changes may be
seen.
 §wo types of inversion mutation

Pericentric inversion

paracentric inversion
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¦
 
 


 §he inversions have

break points on the same
side of the centromere.
 jeiotic recombination
in an inversion loop
produces one
recombined chromatid
with two centromeres
and another chromatid
with lack of centromere.

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 Pericentric inversions
span the centromere and
crossover within the
inversion loop swaps the
ends of one chromatid on
each chromosome,
duplicating one end and
deleting the other and all
the chromatids have a
single centromere, so they
can all segregate normally
at meiosis and pass into
gametes
 w|  

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%
 a rearrangement of
chromosome material
involving two or more
chromosomes.
 §wo types
Ñ reciprocal (non-
robertsonian)
Ñ non-reciprocal
(Robertsonian).

 % %
 jaterial is exchanged
between two chromosomes.
 translocations can occur
between any of the
chromosomes and involve
pieces of any size.
 arises when an exchange of
chromosomal material takes
place between two different
chromosomes.
 When there is no loss or gain
of chromosome material, the
translocation is described
 as Ë


+  %
 Involves exchange
between acrocentric
chromosomes 13, 14, 15,
21 and 22.
 §he exchange involves
loss of the short arms of
two chromosomes and
fusion of the remaining
two long arms at their
centromeres.
  %!
 occur when the developing embryo has attempted
to Ǯcorrectǯ a trisomy by disposing of the spare
third copy of the chromosome.

 §his can leave the baby with two copies of the

chromosome from the same parent instead of the
normal balance of one copy from each parent.
¦   

 When the corrected

chromosome is 15 and
thebaby inherits two
chromosome 15s from
themother, the baby will
have typical features of
¦  Ã

Ã
 
 overweight, short stature
and learning difficulties.
  

 When the corrected

chromosome is 15 and
the baby inherits two
chromosome 15s from
the father, the baby will
have typical features of

  
 epilepsy, severe learning
difficulties, an unsteady
walk.
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 hanges in chromosome number can occur by the

addition of all or part of a chromosome , the loss of an
entire set of chromosomes or the gain of one or more
complete sets of chromosomes .
 Each of these conditions is a variation on the normal
diploid number of chromosomes with drastic effects
on phenotypic expression.

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 A
à is a genetic
abnormality in which
there are three copies,
instead of the normal
two, of a particular
chromosome.
 E.g., 21 trisomy, 18
trisomy.
j wj/
   is a form of
aneuploidy with the
presence of only one
chromosome(instead of
the typical two in
humans) from a pair.
 E.g., turners syndrome.

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 A baby with three copies of each chromosome in each cell rather two,
making a total of 69 chromosomes.
 §riploidy can result either from a single egg being fertilized by two sperm
or from an error in cell division causing either the egg or the sperm to have
46 chromosomes at the time of fertilization.
 §riploidy may be the result of either digyny (the extra haploid set is from
the mother) or diandry (the extra haploid set is from the father).
 Diandry may be due to
Ñ reduplication of the paternal haploid set from a single sperm.
Ñ dispermic (two sperm) fertilization of the egg.

 Digyny is most commonly caused by either

Ñ failure of one meiotic division during oogenesis leading to a diploid
oocyte or
Ñ failure to extrude one polar body from the oocyte.

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 A relatively frequent
chromosome aberration
mainly in X
chromosome.
 §he chromosomes are
not divided along their
length but transversely.
 E.g., Pallister killan
mosaic syndrome.
¦  
 presence of the anomalous
extra isochromosome 12p,
the short arm of the twelth
chromosome.
 the presence of the extra
chromosome may be
linked to pre meiotic
mitotic errors.
 As cells divide during early
development, some cells
lose the i12p , while others
retain- mosaicism.
 0/