5. Genetics in Orthodontics.pptx

Dr.Akash Kencha
Dept of Orthodontics and
Dentofacial Orthopedics
S.B. Patil institute for Dental
Sciences and Research

Contents
 Introduction
 Molecular basis for inheritance
 Modes of inheritance
 Population Genetics
 Methods of studying role of genes
 Genetic Mutation
 Homeobox Genes
 Disorders in tooth morphogenesis
 Influence of Genetics in Malocclusion
 Genetic Influence on Tooth Number, Size, Morphology, Position, and Eruption
 Genetic factors in external apical root resorption
 Practical and Clinical Implications
 Human Genome Project
 Conclusion

 Genetics, (Ancient Greek γενετικός genetikos,
“genitive” and that from γένεσις genesis, “origin”)
 A discipline of biology, it is the science of heredity
and variation in living organisms .
 The fact that living things inherit traits from their
parents has been used since prehistoric times to
improve crop plants and animals through selective
breeding.

 However, the modern science of genetics, which seeks
to understand the process of inheritance, only began
with the work of Gregor Mendel in the mid-nineteenth
century.
 Although he did not know the physical basis for
heredity, Mendel observed that organisms inherit traits
via discrete units of inheritance, which are now called
genes.

 The science of genetics is concerned with the
inheritance of traits, whether normal or abnormal, and
with the interaction of genes and the environment.
 This latter concept is of particular relevance to
medical genetics, since the effects of genes can be
modified by the environment.

A gene is
a piece of DNA that has
the necessary information
to code for a protein.
Found on chromosome.
Related to characteristic
of an organism
Molecular basis for inheritance

Solenoid Model Of Chromosome Structure

James D. Watson and Francis
Crick determined the structure
of DNA in 1953, using the X-
ray crystallography work of
Rosalind Franklin and Maurice
Wilkins that indicated DNA
had a helical structure (i.e.,
shaped like a corkscrew).

Their double-helix model had two
strands of DNA with the
nucleotides pointing inward, each
matching a complementary
nucleotide on the other strand to
form what looks like rungs on a
twisted ladder.
This structure showed that genetic
information exists in the sequence
of nucleotides on each strand of
DNA

The molecular basis for genes is
deoxyribonucleic acid (DNA).
 DNA has a double helix
structure which composed of
• sugar molecule
• phosphate group and
• a base (A,C,G,T)
DNA is composed of a chain of four types of
nucleotides, :
Purines: Pyramidines:
Adenine (A) Thymine (T).
Guanine (G) Cytosine (C)

All chromosomes exist in pairs so our cells contain
two copies of each gene, which may be alike or may
differ in their substructure and their product.
Different forms of genes at the same locus or position
on the chromosome are called alleles.
An allele is a specific version of a gene.
One particular gene may exist in multiple forms.

The sum total of an organism’s genes is called
its genome.
In sexually reproducing organisms, the
genome is diploid.
This means that they have two copies of
every gene.
The copies may not be identical, so one
individual could have two different alleles

 Genotype is the genetic constitution of an individual,
and may refer to specified gene loci or to all loci in
general.
 Genotype describes the combination of alleles present
in the organism’s cells.
 Phenotype is the final product of a combination of
genetic and environmental influences, and may refer
to a specified character or to all the observable
characteristics of the individual.
 Phenotype describes the organism’s appearance.
 The proportion of the phenotypic variance attributable
to the genotype is referred to as heritability.

Genetic information exists in the sequence of
nucleotides
Genes exist as stretches of sequence along the DNA
chain and the sequence of these nucleotides is the
genetic information organisms inherit.

Modes of inheritance
 Autosomal Dominant – If trait manifests itself when affected
person carries only one copy of gene responsible
 Autosomal Recessive – If two copies of defective gene
required for expression of trait.
 X –Linked Recessive – If pedigree consists of affected male
 X –Linked Dominant
 Y –Linked/ Holandric
 Polygenic inheritance – Segregation of genes and
environmental effects on a phenotype

Autosomal Dominant
Dwarfism, Polydactyly and Syndactyly, Hypertension, Hereditary Edema

Autosomal Recessive
Congenital Deafness, Diabetes Mellitus, Sickle Cell anemia, Albinism

X linked Recessive Inheritance
Red-green colour blindness, haemophilia

Multifactorial inheritance.
The trait is determined by the interaction of a number of
genes at different loci, each with a small, but additive
effect, together with environmental factors.
Discontinuous Multifactorial traits
Traits determined by multiple gene loci which are
present or absent depending on the number or nature of
the genetic, and/or environmental factors acting.
Cleft lip and palate is a multifactorial trait.

The parents of a cleft lip and palate are often
unaffected, and there may be no family history of cleft
lip and palate, but by producing an affected child the
parents are deemed to have some underactive genes
for lip and palate formation
The parents must have sufficient normally active
genes to have normally formed lips and palates.
 Only when the balance exceeds a certain threshold
will the malformation occur, and the further the
threshold is exceeded, the greater the extent of the
malformation.

Continuous multifactorial traits.
Many normal human characteristics are determined as
continuous multifactorial traits.
These traits have a continuously graded distribution.
for height there is a range from the very tall to the
markedly short
malocclusion should be regarded not as
abnormality or as a disease, but as a variation of
occlusion in a continuous multi-factorial trait

Population Genetics
Population genetics deals with the study of the mode of
inheritance of traits and the distribution of genes in
populations.
Penetrance is a statistical term and indicates the
proportion of individuals carrying a certain gene who
can be detected.
 As our ability to detect the expression of a gene improves,
the penetrance increases.
 Expressivity refers to the degree of expression of a
gene in an individual

Full expressivity for osteogenesis imperfecta would
include fragile bones, dentinogenesis imperfecta, blue
sclerae, and deafness
The presence of one or two of these findings
comprises Partial expressivity
The absence of all four, which is occasionally found
in carriers of this gene, is Zero expressivity.

Methods of studying role of genes
Twin Studies:
The classic way to determine to what extent a
characteristic is determined by inheritance is to
compare monozygotic (identical) with dizygotic
(fraternal) twins.
Familial studies: Pedigree Studies

Twin Studies
Monozygotic twins occur because of the early division
of a fertilized egg, so each individual has the same
chromosomal DNA and the two are genetically
identical. (have identical genotypes)
Any differences between them should be solely the
result of environmental influences
Monozygotic twins are identical, whereas dizygotic twins
are only as alike as siblings.

 Dizygotic twins occur when two eggs are released at
the same time and fertilized by different spermatozoa.
These dizygotic twins are not more similar than
ordinary siblings except that they have shared the
same intrauterine and family environment.
 The procedure of study is based on the principle that
observed differences within a pair of monozygotic
twins which will be only due to environmental
influence and in dizygotic twins due to both
environment and genotype

If condition has no genetic component, e.g. trauma,
concordance rates would be similar for both types of
twins.
For single gene trait monozygotic concordance will be
100%.whereas dizygotic rate will be less than this and
equal to the rate in siblings.
For discontinuous multifactorial traits with both
genetic and environmental contributions, the rate in
monozygotic twins, although less than 100%, will
exceed the rate in dizygotic twins.

In cleft studies, the monozygotic twin concordance
rate for CL(P) and for CP is 35 and 26 per cent,
respectively, and for dizygotic twins 5 and 6 per cent,
respectively (Connor and Ferguson-Smith, 1993)
Differences within pair of dizygotic twins(share 50%
of gene complement) are due to both environment and
genotype.
Comparison of within pair differences for twins in 2
categories provide measure of degree to which
monozygotic twins are alike than dizygotic.
Greater the difference between two twin categories
greater is genetic effect in variability of trait, so higher
is heritability of trait.

Familial studies: Pedigree Studies
Definite trait studied along family tree.
Study of the family members observing similarities and
differences between -mother and child ,father and child
and among siblings.
Based on the recurrence of some easily seen trait in
different generations of the same family. e.g Hapsburg
jaw.

Genetic Mutation
 Gene alleles are usually transmitted unaltered from one
generation to the next, rare events occur that cause changes
within them -these events are called mutations
 Allele that has undergone such a change is transmitted in its
new mutant form.
 If it occurs during gametogenesis the mutant allele will
appear in a gamete and, consequently, in cells throughout
the body of any resulting individual.
 If it occurs after fertilization, as a somatic mutation, only a
proportion of cells will be affected.

Mutations of DNA
 Length mutations - gain or loss of genetic material
 Point mutations - alteration of the genetic code, but no gain
or loss of genetic material.
Chemicals which cause DNA mutations:
1. Base analogues which mimic standard bases, but pair
improperly (e.g. 5-bromouracil);
2. Alkylating agents which add alkyl groups to bases and so
hamper correct pairing (e.g. nitrogen mustard or ethyl
methanesulphonate);
3. Intercalating agents which intercalate with DNA and
distort its structure (e.g. deamination by hydroxylamine).

Homeobox Genes
 Homeobox genes are genes
which are highly conserved
throughout evolution of
diverse organisms and are now
known to play a role in
patterning the embryonic
development

Fundamental in evolution of specialised body parts of
many animal species and the differences between
different organisms can be explained by the different
modes of action of the homeobox genes
master genes of head and face controlling patterning,
induction, programmed cell death, and epithelial
mesenchymal interaction during development of
craniofacial complex.

Homeobox genes in craniofacial development :
Hox group
Msx1 and Msx2 (muscle segment)
Dlx (distalless)
 Otx (orthodontical)
Gsc (goosecoid), and
Shh (sonic hedgehog).
The proteins encoded by these homeobox genes are
transcription factors which control the transcription of
RNA from the DNA template within the cell nucleus.

Transcription factors can switch genes on and off by
activating or repressing gene expression, and therefore
control other genes producing a co-ordinated cascade
of molecular events which, in turn, control patterning
and morphogenesis (Thesleff, 1995).
Regulatory proteins:
Growth factor family
Steroid/ thyroid/ retinoic acid super family (Evans,
1988)

Vehicles through which homeobox gene information
is expressed in the co-ordination of cell migration and
subsequent cell interactions that regulate growth
(Johnston and Bronsky, 1995).
Fibroblast growth factor (FGF),
Epidermal growth factor (EGF),
Transforming growth factor alpha (TGF ),
 Transforming growth factor beta (TGF ),
 Bone morphogenetic proteins (BMPs)

Control of tooth development.
 Homeobox genes have particular implications in tooth
development and, therefore, on Orthodontics.
 Muscle specific homeobox genes
 Msx-1 and Msx-2 appear to be involved in epithelial
mesenchymal interactions, and are implicated in
craniofacial development, and in particular in the
initiation, developmental position (Msx-1) and further
development (Msx-2) of the tooth buds (MacKenzie et
al., 1991; Jowett et al., 1993)

Further evidence of the role of Msx1 comes from gene
knock-out experiments which results in disruption of
tooth morphogenesis among other defects (Satokata
and Maas, 1994).
Pax9 is also transcription factor necessary for tooth
morphogenesis (Neubuser et al.,1997).

Bone morphogenetic proteins (BMPs) are members of
the growth factor family (TGF ) and they function in
many aspects of craniofacial development with tissue
specific functions.
BMPs have been found to have multiple roles not only
in bone morphogenesis, (BMP 5 for example induces
endochondral osteogenesis in vivo), but BMP 7
appears to induce dentinogenesis (Thesleff, 1995).

Disorders in tooth morphogenesis.
 Advances in the field of molecular genetics have made great
progress in the understanding of a number of dental anomalies
with a genetic component.
 Amelogenesis imperfecta (AI): Group of genetically
heterogeneous disorders affecting enamel formation.
Heterogeneous, hypoplastic, hypocalcified and
hypomaturation
In humans, two amelogenes, AMGX and AMGY, have been
cloned and mapped to the X and Y chromosomes, respectively
 mapped the ameloblastin gene within the critical region for
autosomal dominant AI at chromosome 4q21.

Dentinogenesis imperfecta (DI): Brownish
discolouration of the teeth, crowns susceptible to
rapid attrition, fragile roots and pulp chamber
obliteration due to abnormal continuous production of
dentine matrix (Shields, 1973).
Have mutations and deletions for amino acid
substitutions in genes with encode for sub-units of
type 1 collagen ( Ganguly et al., 1991; Nicholls et al.,
1996).

 Hypodontia: muscle specific homeobox gene (MSX1) is
strongly expressed in the dental mesenchyme throughout the
bud, cap and bell stages of odontogenesis
 Satokata and Maas (1994) found that mice with the Msx1
gene knocked out had amongst other defects, complete
failure of tooth development at the bud stage.
 Vastardis et al. (1996) demonstrated that a mutation in
MSX, the human counterpart of murine msx1, caused
familial tooth agenesis, and genetic linkage analysis of a
family with autosomal dominant agenesis of second
premolars and third molars identified a locus on
chromosome 4p as the site of the MSX1 gene.

Ectodermal dysplasia (EDA): Heterogeneous disorder
with many clinically distinct types, and is characterized
by the triad of hypotrichosis (sparse hair), hypohydrosis
(lack of sweat glands), and hypodontia (reduced number
of teeth).
Kere and his colleagues (1996) identified the gene
responsible for X linked EDA, and it was found to be
expressed in keratinocytes, hair follicles, sweat glands,
and in other adult and foetal tissues.

Influence of Genetics in Malocclusion
The Nature of Malocclusion
Malocclusion may be defined as a significant deviation from
what is defined as normal or ‘ideal’ occlusion (Andrews,
1972).
Population groups that are genetically homogeneous tend to
have normal occlusion.
In pure racial stocks, such as the Melanesians of the
Philippine islands, malocclusion is almost non-existent.
In heterogeneous populations, the incidence of jaw
discrepancies and occlusal disharmonies is significantly
greater

 Stockard (1941) carried out breeding experiments with
dogs, and produced gross orofacial deformities and
associated malocclusions.
 He concluded that individual features of the craniofacial
complex could be inherited according to Mendelian
principles independently of other portions of the skull, and
that jaw size and tooth size could be inherited
independently, and as genetically dominant traits.
 Criticized on the basis that the
gene for achondroplasia is likely to have contributed and in
the context of inheritance of malocclusions in humans,
extrapolation to conclude that racial cross-breeding may
explain tooth size/arch size discrepancies is entirely
unjustified.

Class II Division 1 Malocclusion
 Harris, 1963,1975: mandible is significantly more retruded than
in Class I patients, with the body of the mandible smaller and
overall mandibular length reduced
 showed a higher correlation between the patient and his
immediate family than data from random pairings of unrelated
siblings, thus supporting the concept of polygenic inheritance for
Class II division 1 malocclusions.
 Environmental factors
a . Soft tissues
b . Digit sucking
c. lip incompetence
Family Studies of Heritability of Dentofacial Types

Class II Division 2 Malocclusion
 Familial occurrence of Class II division 2 has been
documented in several published reports including twin
and triplet studies (e.g. Kloeppel, 1953; Markovic,
1992) and in family pedigrees from Korkhaus
(1930), Rubbrecht (1930) Trauner (1968) and Peck et
al. (1998). Markovic (1992)
Studies point to incontestable genetic influence,
probably autosomal dominant with incomplete
penetrance and variable expressivity

Ballard(1963),
and others considered that a high lip line, and a particular lip
morphology and behaviour were the main aetiological
factors.
Graber (1972), stressed the predominant role of genetic
factors in the aetiology of Class II division 2
malocclusions
Aspects of skeletal and muscle morphology are
genetically determined and experimental evidence from a
twin study indicating strong genetic factors in certain
aspects of masticatory muscle behaviour.

Class III Malocclusion
 Most famous example of a genetic trait in humans passing
through several generations is the pedigree of the so-called
Hapsburg jaw.
 This was the famous mandibular prognathism demonstrated
by several generations of the Hungarian/Austrian dual
monarchy
 Strohmayer (1937) concluded from his detailed pedigree
analysis of the Hapsburg family line that the mandibular
prognathism was transmitted as an autosomal dominant trait.
 Suzuki 1961 studied 1362 persons in 243 Japanese families
which had mandibular prognathism and showed higher
incidence of trait in other members of family(34.3%) than
families of individuals with normal occlusion (7.5%).

 Familial studies of mandibular prognathism are
suggestive of heredity in the aetiology of this
condition
 Various models have been suggested, such as autosomal
dominant with incomplete penetrance
 Simple recessive (Downs, 1928), variable both in
expressivity and penetrance with differences in different
racial populations.

Genetic Influence on Tooth Number, Size,
Morphology, Position, and Eruption
 Twin studies have shown that tooth crown dimensions are
strongly determined by heredity (Osborne et al., 1958).
 Molecular genetics of tooth morphogenesis with the
homeostatic Hox 7 and Hox 8 (now referred to as MSX1
and MSX2) genes being responsible for stability in dental
patterning (Mackenzie et al., 1992)

Gruneberg 1965 suggested that tooth germ should reach
a critical size during particular stage or structure will
regress.
Spence and Suaraz showed that hypodontia and
decreased tooth size are controlled by same gene.
Butler and Sperber speculated that transposition is
indicative of faulty field gene function, so increased
incidence of variations in teeth on either side of
transposed teeth.

Supernumerary teeth
Niswander and Sugaku 1963 analysed data from
family studies and suggested genetics of
supernumerary teeth is under control of number of
gene loci.

Abnormal shape
 Alvesalo and Portin 1969 supported that malformed and missing
lateral incisors maybe result of common gene defect.
 Peg lateral , microdontia ,missing teeth all have familial trends,
female preponderance, association with other dental anomalies.
 So polygenic aetiology is suggested.

Ectopic maxillary canines
 Peck et al in 1994 concluded that palatally ectopic
canines were inherited trait along other anomalies.
Mossey et al in 1994 showed association between
ectopic canine and classII div 2 malocclusion.
Familial occurrence, bilateral occurrence, increased
frequency with other anomalies as peg laterals, tooth
agenesis.

Hypodontia
Maybe part of syndrome e.g ectodermal dysplasia.
Msx1 and Pax9 genes involved in non syndromic
autosomal dominant hypodontia.
Missing maxillary lateral incisor – polygenic model
maybe autosomal dominant with incomplete
penetrance and variable expressivity.
Markovic 1982 found high rate of concordance for
hypodontia in monozygotic twins.

Submerged primary molar
In monozygotic twins there is high concordance rate
providing evidence for genetically determined failure of
eruption (Helpin and Duncan 1986)
Variety of anomalies are associated with tooth
submergence.
Taurodontism may form a part of this syndrome(Winter et
al 1997)

Genetic factors in external apical root resorption
External apical root resorption (EARR) is a common
clinical complication of orthodontic treatment.
The analysis of 35 families indicated that the IL-1B
polymorphism accounts for 15% of the total variation
seen for EARR seen in the maxillary central incisor in
the sample studied.

Practical and Clinical Implications
Skeletal jaw discrepancies and malocclusion of
genetic origin can be successfully treated
orthodontically, except in extreme cases where
surgical intervention is required.
It is possible to modify the direction of dentofacial
growth using orthodontic appliances and therefore
change or forestall morphogenetic abnormalities
(Graber, 1969; Harvold et al., 1981; Moss and
Salentijn, 1997)

Orthodontic correction of a malocclusion is in
effect altering the phenotypic expression of a
particular morphogenetic pattern.
The degree to which this can be successfully achieved
depends on
(a) the relative contribution of each factor to the
existing problem, and
(b) the extent to which skeletal pattern can be
influenced by orthodontic and orthopaedic appliances.

Diagnostic goal
To determine the relative contribution of genetics and the
environment.
The greater the genetic component, the worse the
prognosis for a successful outcome by means of
orthodontic intervention.

Human Genome Project
 Started in 1990, as international effort to sequence
entire human genome and genomes of several other
model organisms as Escherichia coli, Drosophila
melanogaster
 Completed in 2003, the Human Genome Project (HGP)
was a 13-year project coordinated by the U.S. Department
of Energy and the National Institutes of Health.
 During the early years of the HGP, the Wellcome Trust
(U.K.) became a major partner; additional contributions
came from Japan, France, Germany, China, and others.

Project goals were to
identify all the approximately 20,000-25,000 genes in
human DNA,
determine the sequences of the 3 billion chemical base
pairs that make up human DNA,
store this information in databases,
improve tools for data analysis,
transfer related technologies to the private sector, and
address the ethical, legal, and social issues (ELSI) that
may arise from the project.

Conclusion
Multiple factors and processes contribute to the
response to orthodontic treatment. Some patients will
exhibit unusual outcomes linked to polymorphic genes.
The influence of genetic factors on treatment outcome
must be studied and understood in quantitative terms.
 Conclusions from retrospective studies must be
evaluated by prospective testing to truly evaluate their
value in practice.

References
 The Heritability of Malocclusion: Part 1—Genetics, Principles and
Terminology. P. A. M O S S E Y, British Journal of Orthodontics/
Vol. 26/1999/103–113
 The Heritability of Malocclusion: Part 2- Influence of Genetics in
Malocclusion. P. A. M O S S E Y, British Journal of Orthodontics/
Vol. 26/1999/195–203
 Personalized Orthodontics, The Future of Genetics in Practice, James
K. Hartsfield, Jr., Seminars in Orthodontics, Vol 14, No 2 (June), 2008: pp
166-171
 Genetic Factors and Orofacial Clefting Andrew C. Lidral, Lina M.
Moreno, and Steven A. Bullard, Seminars in Orthodontics, Vol 14, No 2
(June), 2008: pp 103-114
 Investigation of Genetic Factors Affecting Complex Traits Using
External Apical Root Resorption as a Model Shaza K. Abass and James
K. Hartsfield, Jr. Seminars in Orthodontics, Vol 14, No 2 (June), 2008: pp
115-124

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