20. MENDELS LAW OF INHERITANCE
LAW OF DOMINANCE—
ONLY DOMINANT
CHARACTER APPEARS IN
FIRST GENERATION
LAW OF SEGREGATION—
ALLELES GET
SEPARATED DURING
GAMETOGENESIS
LAW OF INDEPENDENT
ASSORTMENT—
INHERITANCE OF ONE
FACTOR IS UNAFFECTED
BY OTHER
20
42. First step leading to gene expression.
The stretch of DNA transcribed into an RNA molecule is called a transcription
unit that encodes at least one gene
During transcription, a DNA sequence is read by RNA polymerase
produces a complementary, antiparallel RNA strand.
uracil (U) in all instances where thymine (T)
42
43. As in DNA replication, DNA is read from 3' →
5' during transcription. Meanwhile, the
complementary RNA is created from the 5' →
3' direction.
Only one of the two DNA strands, called the
template strand, is used for transcription.
The other DNA strand is called the coding
strand, because its sequence is the same as
the newly created RNA transcript (except for
the substitution of uracil for thymine).
43
45. INITIATION
Begins with the binding of RNA
polymerase to the promoter in DNA.
Five subunits: 2 α subunits, 1 β
subunit, 1 β' subunit, and 1 ω subunit.
sigma factor finds the appropriate -35
and pribnow box.
45
46. ELONGATION
Template strand is used as a template for RNA
synthesis.
RNA polymerase traverses the template strand and
uses the DNA template to create an RNA copy.
Produces an RNA molecule from 5' → 3', an exact
copy of the coding strand
mRNA transcription can involve multiple RNA
polymerases on a single DNA template
Elongation also involves a proofreading mechanism
that can replace incorrectly incorporated bases.
46
51. GENETIC CODE
The code is universal
The code is triplet.
The code is degenerate.
The code is non overlapping.
The code is commaless. .
51
52. TRANSLATION
Translation is the first stage of protein
biosynthesis .
Production of proteins by decoding mRNA
produced in transcription.
Occurs in the cytoplasm where the ribosomes
are located.
Ribosomes are made of a small and large
subunit which surrounds the mRNA.
52
53. mRNA is decoded to produce a specific
polypeptide according to the rules
specified by the genetic code.
This uses an mRNA sequence as a
template .
Transfer RNA, ribosomal RNA, and small
nuclear RNA are not necessarily
translated into an amino acid sequence.
53
55. This is a molecule of messenger RNA.
It was made in the nucleus by transcription
from a DNA molecule.
mRNA molecule
codon
A U G G G C U U A A A G C A G U G C A C G U U
12
56. A U G G G C U U A A A G C A G U G C A C G U U
.
ribosome
13
57. anticodon
U A C
A U G G G C U U A A A G C A G U G C A C G U U
Amino acid
tRNA molecule
A transfer RNA moleculearrives.
It brings an amino acid to the first three
bases (codon) on the mRNA.
The three unpaired bases (anticodon) on
the tRNA link up with the codon.
14
58. A U G G G C U U A A A G C A G U G C A C G U U
A peptide bond forms between thetwo
amino acids.
Peptide bond
15
59. A U G G G C U U A A A G C A G U G C A C G U U
The first tRNA molecule releases its amino acid
and moves off into the cytoplasm.
16
60. A U G G G C U U A A A G C A G U G C A C G U U
The ribosome moves along the mRNA tothe
next codon.
17
61. A U G G G C U U A A A G C A G U G C A C G U U
Another tRNA molecule bringsthe
next amino acid into place.
18
62. The process continues.
The polypeptide chain gets longer.
This continues until a termination (stop)
codon is reached.
The polypeptide is then complete.
A U G G G C U U A A A G C A G U G C A C G U U
19
63. • ACTIVATION,
• INITIATION,
• ELONGATION
• TERMINATION
• Amino acids are
brought to ribosomes
and assembled into
proteins
Translation
proceeds
in four
phases:
63
64. ACTIVATION
• In activation, the correct amino
acids covalently bonded to the correct transfer
RNA (tRNA).
• While this is not technically a step in translation, it
is required for translation to proceed.
• The amino acid is joined by its carboxyl group to
the 3' OH of the tRNA by an ester bond.
• When the tRNA has an amino acid linked to it, it is
termed "charged".
64
65. INITIATION
For the initiation itrequire
mRNA.
The initiator tRNA.
Three initiation factor(IF1,IF2, IF3).
Large and small unit of ribosome.
20
66. INITIATION PROCESS
mRNA gets bind on smaller
subunit and IF1 and IF3bind to
30S subunit
IF2 complexed with GTPthen bind
to the small subunits, forming a
complex atRBS.
The initiator tRNA can then bind to the
complexat the P site paired with AUG
codon.
The 50S subunits can now bind.
GTP is thenhydrolyzed and IFs are
released to give the 70S initiation
complex
67. ELONGATION IS
DIVIDED INTO
THREE STEPS:
1. Amino acyl
tRNA delivery.
• The 70s initiation complex contains met-tRNA in the P site and A
site is free
• Another aminoacyl tRNA is placed in the A site.
• The process requires proper codon recognition on mRNA with
EF-TU and GTP
Page
68. 2. Peptide bond formation.
Page
68
After aminoacyl-tRNA
delivery, the A- and P-
sites are both occupied
and the two amino
acids that are to be
joined are in close
proximity.
• The peptidyl transferase activity of the 50S
subunit can now form a peptide bond between
these two amino acids without the input of any
more energy, since energy in the form of ATP
was used to charge the tRNA.
81. PART-II
▰ HOMEOBOX GENES
▰ TWIN STUDIES
▰ BUTLER FIELD THEORY
▰ GENETICS IN MALOCCLUSION
▰ SYNDROMES ASSOCIATED WITH MALOCCLUSION
▰ GENETICS AND TOOTH AGENESIS
▰ GENETICS AND PALATALLY DISPLACED CANINE
▰ GENETICS AND PRIMARY ERRUPTION FAILURE
▰ GENETICS AND EARR
▰ CONCLUSION
81
82. HOMEOBOX GENES
Thomas Hunt Morgan,-- role of genes in heredity--
genes regulate body formation.
Hox genes -- same pattern of organization- same
order of gene arrangement, expressions and
functions .
Homeobox genes are characterized by a conserved
DNA sequence coding for a 60-aminoacid --
‘‘homeodomain.’’
82
83. The role of Homeobox genes --
Walter J Gehring and Matthew
Scott and Amy Weiner .
Edward Lewis --homeotic genes in
the fly Drosophila melanogaster, --
controlling the developmental
process.
In the fly, in two regions-
Antennapedia and Bithorax-on
chromosome 3
83
84. ▰ The subfamilies of Hox genes, which are of
particular interest in Craniofacial patterning
and morphogenesis include
▰ muscle segment (Msx),
▰ distal less (Dlx),
▰ orthodenticle (Otx),
▰ goosecoid (Gsc),
▰ Bar class{Barx),
▰ paired-related {Prx, SHOT)
▰ LIM homeobox
84
85. Mediated - - Growth factor family and
steroid/thyroid/retinoic acid super family.
vehicles –FGF,TGF,BMP.
Mutations -- bizarre homeotic
transformations, .
Tooth development--complex phenomenon -
--epithelium and ectomesenchyme, .
87. There are two classes of homeobox genes:
Class1 genes --high degree of identity in their homeodomain.
Class2 genes -- low degree of identity their homeodomain.
Human Hox Gene Abnormalities
A mutation in the HOX A13 gene causes Synpolydactyly (SPD).
. This rare condition was first described in 1916 in an Australian family
Hox Genes and Oncogenesis
Hox genes has significant role in Oncogenesis, the formation of cancer.
protein products --transcriptional factors --carcinogenesis
87
88. MUSCLE SEGMENT BOX (MSX 1 & MSX2)
craniofacial development.
Three subtypes are present Msx 1, Msx 2 and Msx 3;
Msx 1 and Msx 2 are expressed in craniofacial development
sutural mesenchyme and duramater
Msx 1 --higher level --level of Msx 2 expression declines.
Msx 1 -- bud stage and morphogenetic cap stage
Msx is --enamel organ,dental papilla and the follicles
88
89. Msx1 -- development of the palate
Msx1 is co- expressed with Msx2 at the site of epithelial -
mesenchymal interactions
Msx 2 -formation of the extracellular matrix and ameloblast
differentiation
Msx2 --odontoblasts, cuspal formation, and root initiation
Wolf-Hirschhorn syndrome (WHS) is a congenital human syndrome
resulting from a deletion of Msx1locus on chromosome 4
89
90. DISTAL –LESS (DLX)
Development
of the limbs.
Dlx 1 to Dlx 6.
Expressed in regions that
give rise to vertebrate
specific structures.
Branchial arches .
DLX 1 & DLX 2-Throughout the first and
second arches .
Dlx 3, Dlx 5 and Dlx 6 -- more distal location.
Dlx 1 and Dlx 2 in the maxillary and mandibular arch
mesenchyme--region of future molar teeth
90
91. Msx-Dlx interaction
Msx expression --cells that are proliferating or
dying
Dlx expression -- differentiation .
Msx and Dlx proteins appear to have opposing
transcriptional properties .
Msx1 and Msx2 each can form a protein
complex with Dlx 2 and Dlx 5 --neutralizing
effect .
91
92. Role of Msx - Dlx in Tooth Development
Msx and Dlx genes --
tooth development by
reciprocal epithelial
mesenchymal
signaling.
Activation of Msx1,
Msx2, Dlx1 and Dlx2 in
Dental mesenchyme
occurs in response to
BMP 4 and FGF signals
from the overlying
epithelium
a point mutation --Msx1
-- agenesis of second
premolars and third
molars .
92
93. Goosecoid (Gsc)
Transcription factor
Isolated from Xenopus.
Mutants exhibited a hypoplastic mandible--lack of
coronoid and angular process --defects on other bones
like maxilla, palatine bone and pterygoid plates.
93
94. Barx genes
Ectomesenchyme of the first branchial arch.
Barx expression --mesenchymal regions around the developing molars--
folding pattern of the dental epithelium that produce molar cusps.
Development of central nervous system .
. Barx1 appears in the mesenchyme of the maxillary and the mandibular
process
Mutations of Barx 2 which can produce cleft of secondary palate
Etiology of cleft lip and palate.
94
95. LIM HOMEOBOX DOMAIN (Lhx)
cell type
specification
and
differentiation
during
embryogenesis
Ectomesen
chyme of
the
maxillary
and the
mandibular
process
control
patterning
of the first
brachial
arch.
craniofacial
developme
nt and
patterning
of
mammalian
dentition.
Lh x6, Lhx 7
are the
earliest
mesenchyma
l markers of
tooth
development
.
95
96. Prx genes (Pair related gene)
Prx1 --central nervous system derived mesenchyme of Fronto nasal
process, first and second branchial arches,maxillary process.
Prx1 in combination with Prx2 --stabilize and maintain cell in craniofacial
mesenchyme.
Another paired related homeobox gene --SHOT was mapped to human
chromosome 3q25-q26 --Cornelia-de- lange syndrome
Pax a family of 9 genes. Regulators of organogenesis, maintains
pleuripotency of stem cell--earliest mesenchymal gene--localizes site of
tooth bud.
96
97. Sonic Hedgehog (Shh)
first expressed in axial mesendoderm, mutations --abnormal patterning
of neural plate --holoprosencephaly and cyclopia.
Expressed in the ectoderm of frontonasal process (FNP) and maxillary
process (MXP). loss of these signals--collapse of the facial midline
and hypotelorism.
Disrupting Shh signaling in FNP and MXP -- cleft lip/palate.
Regulates patterned outgrowth of the FNP and MXP --specifying the
mediolateral axis of the face.
Shh expressed in Bud stage, cap stage,HERS.
97
98. Lymphoid Enhancing Factors (Lef-1)
Lef-1 gene is involved in Wnt signaling pathway --
function in hair cell differentiation and follicle
morphogenesis.
Expressed in condensing mesenchyme in bud
stage & adjacent basal cells of epithelium.
Essential in initiation and cytodifferentiation
98
99. TWIN STUDIES
▰ Useful in study of population genetics.
▰ To determine the role of genetic and
environmental factors.
▰ Twins can be dizygotic or monozygotic
99
102. TWIN STUDIES FOR OCCLUSAL AND DENTOFACIAL STRUCTURES
Lundstorm (1948)-concluded that genetic factors
have greater influence on craniofacial structures.
• Lundstorm (1955)-genetic factors have greater
influence on sagittal apical base relationship
Krause Wise&Frei (1959)-concluded that
morphology of craniofacial bones are under strong
genetic influence
102
103. Krupanidhi &V.Surendra Shetty(1989)-assessed amount of genetic &
environmental influence on dental measurements in twins
Statistically insignificant intrapair difference in MZ twins in 11 out of 13
parameters(PMBAW,PMD,basal arch width,tooth material,arch
perimeter,intercanine width,overjet,overbite,curve of spee, rugae position
&midline) Intermolar width & palatal depth showed significant difference.
significant difference in DZ twins for 5 parameters - premolar diameter,
upper tooth material, intercanine width; lower intermolar width, overbite and
curve of spee
May be due to different genetic material
103
104. ▰ Ferguson –Smith(1993) cleft study ,the monozygotic twin
concordance rate for CLP& CP was 35 &26 % respectively
dizygotic twins 5& 6 % respectively
104
107. TWIN STUDIES REVEALS ?????
Genetic factors—more influence than non genetic
Genetics has effect on arch width and length,arch
shape
Genetic basis for tooth size and shape
Identical twins were not occlusally
identical,indicating enviornmental influences
107
110. ▰ Association of the Pro561Thr (P56IT)
variant in the growth hormone
receptor (GHR) gene with craniofacial
measurements on lateral
cephalometric radiographs by --
Yamaguchi et al
▰ those who did not have the GHR P56IT
allele had a significantly greater
mandibular ramus length (condylion-
gonion) than did those with the GHR
P561T allele in a normal Japanese
sample of 50 men and 50 women.
110
111. CLASS II DIV 1
Cephalometric studies by Harris --
polygenic inheritance
class II malocclusions are heritable
and that there is a high
resemblance to the skeletal
patterns in their siblings
Environmental factors can also
contribute to the etiology
Digit sucking habit can produce
class II division 1 malocclusion
even if the underlying skeletal base
relationship is class I.
111
113. CLASS II DIV 2
Twin studies showed
that the identical twins
-- 100% concordance
for Class II division 2
malocclusion,
indicating a strong
genetic influence
Impact of PAX9 on the
development of class II
division 2 with hypodontia
RUNX2 on the
development of class II
division 2 but not
occasionally
associated hypodontia
.
113
114. CLASS III MALOCCLUSION
The familial nature of mandibular
prognathism was first reported by
Strohmayer (1937) as noted by Wolff
et al (1993) in their analysis of the
pedigree of the Hapsburg family.
The Hapsburg jaw was seen in
European royalty in which
mandibular prognathism recurred
over multiple generations.
114
119. Pierre Robin sequence is an etiologically
heterogeneous disorder and shows autosomal
recessive inheritance. An X-linked form also exists
119
120. Treacher Collins
syndrome is an
autosomal dominant
monogenic disorder
caused by mutation in
the treacle gene
(TCOF1) .
It affects the craniofacial
development and
expresses itself as
micrognathia,
hypoplastic zygomatic
bones and frequently
cleft palate
120
122. Hallermann-Streiff
Syndrome is also known
as the François
Dyscephalic Syndrome,
Hallermann-Streiff-
François syndrome,
Oculomandibulodysceph
aly with hypotrichosis
and
Oculomandibulofacial
syndrome.
It is a congenital
disorder associated with
gene GJA1.
It affects growth, cranial
development, hair
growth and dental
development.
122
124. Marfan syndrome is fibrous connective tissue heritable
disorder.
Increased height, disproportionately, long limbs and
digits, mild to moderate joint laxity, increased overjet,
retrognathia, micrognathia, narrow and highly arched
palate with dental crowding and dentinogenesis
imperfecta-like tooth conditions are frequent skeletal and
dental features of this syndrome.
Westling et al reported that about 70% of the patients
with Marfan syndrome had been referred for orthodontic
treatment because of crowding and large overjet
124
125. MALFORMATION SYNDROMES ASSOCIATED WITH PROBLEMS OF FACIAL
HEIGHT
Beckwith
Weidemann
syndrome.
20 % Beckwith-
Wiedemann
syndrome are
caused by
a genetic
change known
as paternal
uniparental
disomy (UPD).
Mutations in the
CDKN1C gene
cause Beckwith-
Wiedemann
syndrome.
This gene
provides
instructions for
making a
protein that
helps control
growth before
birth
125
127. Human craniofacial
malformations such as
Crouzon, Apert and Pfeiffer
syndromes have
craniosynostosis, maxillary
hypoplasia, relative
mandibular prognathism and
related dental problems and
malocclusions in common
caused by discrete point
mutations in the fibroblast
growth factor receptor-2
(FGFR-2) genes which are
known to affect suture
development.
127
128. Hemifacial microsomia --
resulting in facial asymmetry,
hypoplasia of facial musculature
and mandibular deficiency.
Common birth defect
involving first and second
branchial arch derivative.
Exhibits autosomal
dominant, autosomal
recessive or X-linked
inheritance
128
129. TOOTH SIZE AND AGENESIS
▰ Based on epithelial mesenchymal
interactions—sonic hedge hog gene
expression—influence on crown width and
and cusp number
▰ SHH gene—candidate gene for class I
malocclusion with crowding
▰ EDA2R gene—dental crowding greater
than 5 mm 129
130. Mutations in transcription factors—dental
agenesis—including PAX 9 and MSX 1
Mutations in PAX 9—non syndromic AD
inheritence for oligodontia
PAX -9 mutation—peg shaped central or
lateral incisors
PAX9 Ala240pro gene mutation—third
molar agenesis
130
131. AXIN2 gene mutation –oligodontia
EDARADD MUTATION—
INCISORS,CANINE,PREMOLAR development
LTBP3 GENE—Influence short stature,AR
hypodontia
Mutations in tooth developmental genes –AXIN 2
gene--colon cancer,breast cancer,gastric cancer
131
132. CANINE IMPACTION/DISPLACEMENT
Labial to buccal in 15 % cases,often asso with dental crowding
PDCs –influenced by genetics
Greater existence of PDCs on same side of
missing/small maxillary lateral incisor
Cause appears to be multifactorial—
genetic and enviornmental
Candidate genes
proposed—influence
PDCs—MSX1 and PAX 9
132
133. PRIMARY FAILURE OF ERRUPTION
PFE—all teeth distal
to most mesially
involved tooth donot
errupt or respond to
orthodontic force
PTHR1 gene –
candidate gene
133
134. GENETIC FACTORS AND EXTERNAL APICAL ROOT
RESORPTION
Degree and severity of
EARR—Orthodontic
RX—
complex,involving host
and enviornmental
factors
Bruxism,nail
biting,anterior open
bites,tongue thrusting
–increased EARR
before ortho RX
Retrospective twin
studies on EARR—
evidence for both
genetic and
enviornmental factors
134
135. 30 % EARR variabilty –
treatment
duration,HYRAX
appliance,premolar
extractions,sex,P2RX7
gene
Minor contributions—
age,overjet,tongue
thrust,skelatal class II
Longer length of RX and
specific genotypes for
P2RX7 SNP rs
208294—explained 25%
of EARR concurrent with
orthodontic RX
135
136. ▰ P2RX7 protein is upregulator of activation
of IL1B that was a focus of initial studies
▰ Inbred mouse model with P2RX7 gene
knocked out showed an increase in
histological resorption with ortho force
136
138. AIMS OF GENETIC COUNSELLING
• The genetic
counseling
aims to
provide the
family with
complete and
accurate
information
about genetic
disorders.
1. Promoting
informed
decisions by
involved
family
members
2. Clarifying
the family’s
options
available
treatment and
prognosis
3. Explaining
alternatives
to reduce the
risk of
genetic
disorders
4. Decreasing
the incidence
of genetic
disorders
5. Reducing
the impact of
the disorders
138
139. INDICATIONS FOR GENETIC COUNSELLING
Hereditary disease & Birth defects
Mental retardation
Advanced maternal age
Early onset of cancer in family
Miscarriages
Malformations
Tendency to develop a neurologic conditions
139
140. HOW TO IDENTIFY A GENETIC DISEASE
BUILD UP
PEDIGREE
TREE
ANALYSE
PEDIGREE
CHART
CALCULATE
RISK OF
RECURRENCE
DECISION
MAKING
140
142. REFERENCES
▰ Proffit WR, Fields HW, Sarver DM (2007). Contemporary
Orthodontics. St. Louis, MO, Mosby Elsevier.
▰ Sathyanarayan,Essentials of biochemistry
▰ Graber vanarsdall.orthodontics,current principle and
technique, Mosby Elsevier
▰ Srinivasan K,Chitra S .Homeobox genes and orofacial
development -a review,Eur j orthod
▰ Krishnan V. Neural crest cells, homeobox genes and
craniofacial development. J Ind Orthod Soc, 2002;
35: 42-50.
▰ Goodman. Limb Malformations and the Human HOX
Genes. American Journal of Medical Genetics, 2002; 112:
256-265. 142
