Genitics

GENETICSGENETICS
ANDAND
MALOCCLUSIONMALOCCLUSION
www.indiandentalacademy.com

CONTENTS:
INTRODUCTION
HISTORY
BASIC OF GENETICS
DNA
GENE
CHROMOSOME
GENE MUTATIONS
GENTIC DISODERS AND THEIR INHERETANCE
TWIN SYUDIES
GENETIC INFLUENCES ON TOOTH SIZE, MORPHOLOGY,
POSITION,
FAMILIAL AND TWIN STUDIES FOR HERITABILITY OF
DENTOFACIAL PHENOTYPE
CRANIO FACIAL SYNDROMES
CONCLUSION

Introduction:
The science of genetics is concerned with the inheritance of traits,
whether normal or abnormal, and with the interaction of genes
and the environment.
Inheritance has always interested man. Carvings in stone – 6000
years old – showing family trees and patterns of certain
inheritance have been found. The first mention of the heritability
of Haemophillia can be traced to writings 1500 years ago.
The question of whether environment or genetics exerts the greater
influence in the aetiology of malocclusion has been a matter of
debate since the origin of orthodontics. As far back as 1891,
Kingsley was unequivocal in his views in describing inheritance as
a major factor in producing malocclusion. Edward H. Angle
(1907) was equally adamant in his belief that malocclusions arise
from local causes.
None the less, the modern knowledge of genetics and patterns of
inheritance have been explained only relatively recently.

• In the early 1700s Pierre Louis Moreau de
Maupertuis was the first to propose that there
were certain hereditary particles. Each body
part is formed by 2 such particles – one from
each parent. One particle might dominate the
other, so that the trait of the offspring may
resemble one parent more than the other.
• But our present idea of genetics starts with the
work of Gregor Mendel, and his work on
various varieties of garden peas (Pisum
sativum).
• His work was not something that was never
done, but he was the first to notice that the
inheritance units obeyed certain statistical
laws. www.indiandentalacademy.com

• Mendel selected 7 pairs of contrasting characteristics in the
garden pea. (Eg. Tall or dwarf, yellow or green seeds, violet or
white flowers etc.)
• The two contrasting varieties were crossed and the first set of
offspring was known as the first filial (or F1) generation. The
next was known as the F2 generation, and so on.
• In the F1 generation, the offspring always resembled only one
parent. The character which was manifested was referred to as
the dominant, and the other as the recessive

When these were self pollinated, the offspring were seen to
have both characteristics- in the ratio 3:1.
When the F2 was self pollinated, the result was as follows-
Recessive character - all recessive
Dominant character – 1/3rd all dominant
2/3rd both characters in the ratio 3:1
Hence the ratio of the off spring in F2 is actually 1:2:1
(Dominant : hybrid : recessive).

This lead Mendel to conclude:-
• That there are 2 factors which determine a specific character
• The parent transmits only one of the pair to the offspring.
• It is only a matter of chance as to which of the transmitted
pairs unite.
This is referred to as Mendel’s 1st law, or the Law of
Segregation.

The law of Unit Inheritance – Before Mendel’s time it was
believed that the characteristics of parents blended into the
offspring. Mendel clearly stated that blending did not occur.
Also, that the characteristics of one parent may not appear in
one generation (F1) but may reappear in the next generation
(F2).
Law of Independent assortment – Members of different gene
pairs assort to the gametes (sex cells) independently of one
another. There is a random recombination of paternal and
maternal chromosomes in the gametes.

Nevertheless, Mendel’s contribution went unnoticed for a
long time. Even though Charles Darwin put forth his
theory of hereditary nature of variations, which lead to the
evolution of species, the actual mechanism of inheritance
was unknown.
At the beginning of the 20th century, 3 independent workers
*Vries in Holland, *Correns in Germany and *Tschermak
in Austria rediscovered Mendel’s laws, and that heralded
the beginning of genetics as a science.

Terminology GeneticsTour
A gene is a unit of information and corresponds to a discrete
segment of DNA with a base sequence that encodes the
amino acid sequence of a polypeptide.
The genes responsible for contrasting characters are called
alleles
Genome all the genes carried by a cell

Genotype is defined as the genetic constitution of an individual, and may
refer to specified gene loci or to all loci in general.
An individual’s phenotype is the final product of a combination of genetic
and environmental influences. Phenotype may refer to a specified
character or to all the observable characteristics of the individual.
Trait is any detectable phenotypic property
Homozygous – an individual who has the same factors for a particular
characteristic. (eg-TT or yy)
Heterozygous – individual with different factors (Tt or Yy)
In a heterozygous individual the character that is manifested is the
dominant, and the other is the recessive character.

History of Human Genetics
The human genome contains approximately 3 billion
nucleotides, making up about 100,000 alleles, which in turn
are contained on 46 chromosomes. Transcription of these
chromosomes releases the information necessary to
synthesize some 6000 proteins. These proteins make up the
trillion cells giving rise to the nearly 4000 anatomical
structures that constitute a single human being.
Mutation, the accidental alteration of the genome, may result in
heritable conditions or syndromes affecting any aspect of
growth and development.

Interest in human genetics started by following
various hereditary conditions through family trees,
or pedigrees. The earliest diseases to be studied
were albinism, polydactyly (early 1700s) and
hemophilia (early 1800s). Another aspect that
received some attention was consanguineous
marriages.
The effects of “Nature and Nurture” were studied
from the mid 1800s by Galton. He also was
interested in the hereditary improvement if men
and animals by selective breeding – and coined the
term eugenics for this.www.indiandentalacademy.com

In the early 1900s Sir Garrod discovered that some families had
a condition known as alkaptonuria - in which the affected
individual secretes dark urine.
He found that it was found in families. But it was not simply
passed from parent to child. The children were usually
normal, but the disorder could reappear later in the
descendents.
Although it had been long since Mendel had done his
experiments, it was around this time that they were being
rediscovered. Garrod realized that this is a Mendelean
recessive type of inheritance. It occurs due to excretion of
homogentisic acid which is usually metabolized in normal
individuals. So the genes seemed to have something to do
with the production of the enzyme.
This was the first time that the idea that genes control the
synthesis of enzymes arose.

But even though he gained recognition, Garrod’s
contemporaries did not realize that this does not apply only
to rare inherited disorders, but was actually the basis of
life.
At around the same time, Landsteinter discovered the ABO
blood groups, and that gave rise to the branch of blood
group genetics.

The Chromosome Theory of Inheritance
It was well known for a long time that cells contained a
nucleus and that the nucleus had threadlike substances
called chromosomes (chroma = colour, chromosomes took
up certain stains very easily). In 1903, Sutton and Boveri ,
independently, proposed that it was the interaction
between these chromosomes that lead to the phenomenon
of inheritance. They behaved just like Mendel’s factors –
occur in pairs and come one from each parent.

Structure of Nucleic Acid
Nucleic acid was first isolated as early as 1869 by a Swiss doctor
named Meicher, from pus soaked bandages of wounded
solders. He found a compound which was very rich in
phosphorous, which was quite unique. Initially, he named it
nuclein. He had even postulated in 1892 that this might be the
actual hereditary factor. But few people believed in this, as
they thought it was not possible, until the structure of DNA
was proposed in 1953.
For many years it was felt that protein was the basic substance of
life. Although nucleic acid had been discovered, its
importance in protein formation was not appreciated until the
work of Griffith and later Avery Macleod and McCarthy (on
pneumococci) and Hershey and Chase (using bacteriophages).

Nucleic acid
It is composed of long chains of
molecules called nucleotides.
Each nucleotide is composed of
:-
A nitrogenous base
A sugar molecule, and
A phosphate molecule

• The nitrogenous bases are of 2 types – purines and pyrimidines.
• The purines include –
• adenine and guanine
• The pyrimidines include –
• cytosine, thymine and uracil.
• The nucleic acids can further be of 2 types depending on the sugar
molecule –
• Sugar – ribose  Ribonucleic acid or RNA
• Sugar – deoxyribose  Deoxyribonucleic acid or DNA

Structure of DNA
The structure of DNA was suggested by Wilkins, Watson and Crick.
The DNA molecule is composed of 2 chains of nucleotides arranged in a double
helix. The backbone of each chin is formed by the sugar-phosphate molecules
and the 2 chains are held together by hydrogen bonds between the nitrogenous
bases which point in towards the centre of the helix.www.indiandentalacademy.com

COMPLEMENTARY BASE PAIRING
The bases of the two polynucleotide chains interact with each other.
Thymine always interacts with adenine and guanine with cytosine (i.e.
A-T and G-C). The way in which the bases form pairs between the two
DNA strands is known as complementary base pairing. Complementary
base pairing is essential for the expression of genetic information and is
central to the way DNA sequences are transcribed into mRNA and
translated into protein.

X-ray diffraction pictures of the double helix show repeated patterns of bands
that reflect the regularity of the structure of the DNA. The double helix
executes a turn every 10 base pairs. The pitch of the helix is 34A so the
spacing between bases is 3.4A. The diameter of the helix is 20A. The
double helix is said to be antiparallel. One of the strands runs in the 5’→3’
direction and the other 3’→5’ direction. The double helix is not absolutely
regular and when viewed from the outside a major groove and a minor
groove can be seen. These are important for interaction with proteins, for
replication of the DNA and for expression of the genetic information.
.

TYPES OF DNA SEQUENCES
Analysis of human DNA have shown that approximately 60-70% of the human
genome consists of single or low copy number DNA sequences. The remainder of
the genome, some 30-40% consists of either moderately or highly repetitive DNA
sequences.
NUCLEAR DNA
(A) Nuclear genes
(i) Unique single copy genes
(ii) Multigene families – e.g. the HOX homeobox gene family.
-Classical gene families
-Gene super families
(B) Extragenic DNA
(i) Tandem repeat
Satellite
Minisatellite
-Telomeric
-Hypervariable
Microsatellite
(ii) Interspersed
*Short interspersed nuclear elements
*Long interspersed nuclear elementswww.indiandentalacademy.com

MITOCHONDRIAL DNA
Two rRNA genes
22 tRNA genes
13 genes coding for proteins involved in oxidative
phosphorylation.

1) Replication
Replication of the DNA molecule occurs
in what is termed as the semi-conservative method.
The individual chains divide at multiple sites,
and, on account of the specific base pairing,
the complementary chain is formed.
So the daughter cell has one parent strand and one new strand.
2) Genetic code within the DNA molecule.
The Watson and Crick model of the DNA molecule also helps to explain the
genetic code.
There are 20 different amino acids. Since the function of genes is to synthesize
proteins, it is safe to assume that the genes actually code the sequence of the
amino acids needed to produce each protein.
The arrangement of the nitrogenous bases is what gives the code for the amino acids.
Since there are 4 bases and 20 amino acids, it can be calculated that groups of 3
bases are essential for coding the amino acids. The triplet code for one amino
acid is called a codon.

Transcription and translation
The information in the DNA is transmitted to a particular type of RNA
called the messenger – RNA. This occurs in a similar way to DNA
replication. Complementary bases are found in the RNA.
Cytosine with guanine,
thymine with adenine,
and adenine with uracil.
Nucleus
DNA
TRANSCRIPTION
mRNA
TRANSLATION
(rRNA, tRNA)
Cytoplasm
)
Protein

The m-RNA is then associated with Ribosome, which are
actually the sites for protein synthesis. The m-RNA forms a
template for the synthesis of the protein.
In the cytoplasm, there is another form of RNA called transfer-
RNA. For the incorporation on amino acids into a
polypeptide chain, the amino acid must first be activated by
reacting with ATP. Then the activated amino acid attaches
itself to one end of a particular transfer RNA. The other end
of the transfer RNA combines with the m-RNA. Thus a
particular triplet on the m-RNA is related through transfer
RNA to a specific amino acid. The ribosome moves along
the messenger – RNA in a zipper – like fashion, the amino
acids linking up to form the polypeptide chain.
The rule that there is transfer of genetic information from DNA
to RNA to the protein is called the “CENTRAL DOGMA”
of molecular genetics.

Gene Structure
The term gene, coined by a Danish botanist
Johannsen, represents the hereditary factors.
A gene is a unit of information and corresponds to a
discrete segment of DNA with a base sequence that
encodes the amino acid sequence of a polypeptide.
Genes vary greatly in size from less than 100 base
pairs to several million base pairs. In humans there
are an estimated 50-100000 genes arranged on 23
chromosomes.

The genes are very dispersed and are separated from each
other by sequences that do not contain genetic
information.; this is called intergenic DNA.
The intergenic DNA is very long, such that in humans gene
sequences account for less than about 30% of the total
DNA.
Only one of the two strands of the DNA double helix carries
the biological information and this is called the template
strand or sense or coding strand, which is used to produce
an RNA molecule of complementary sequence which
directs the synthesis of a polypeptide.
The other strand is called the nontemplate strand or
antisense or noncoding strand.

Gene promoters
Expression of genes is regulated by a segment of DNA
sequence present upstream of the coding sequence known
as the promoter. Conserved DNA sequences in the
promoter are recognized and bound by the RNA
polymerase and other associated proteins called
transcription factors that bring about the synthesis of RNA
transcript of the gene.

Introns and Exons
In genes coding information is usually split into a series of
segments of DNA sequence called exons. These are
separated by sequences that do not contain useful
information called introns.
The length of exons and introns varies but the introns are
usually much longer and account for the majority of the
sequence of the gene. Before the biological information
in a gene can be used to synthesize a protein, the introns
must be removed from RNA molecules by a process
called splicing which leaves the exons and the coding
information continuous.

DEVELOPMENTAL GENE FAMILIES
Several gene families have been identified in vertebrates any
mutations occurring in various members of these families
ca result in either isolated malformations or multiple
congenital anomaly syndromes .
1. Segmentation genes
2. Paired-box genes (PAX)
3. Zinc finger genes
4. Signal transduction (‘Signalling’) genes
5. Homeobox genes (HOX)

SEGMENTATION GENES
Insect bodies consist of series of repeated body segments which
differentiate into particular structures according to their position.
Three main groups of segmentation determining genes have been
classified on the basis of their mutant phenotypes.
(A) Gap mutants – delete groups of adjacent segments
(B) Pair-rule mutants – delete alternate segments
(C) Segment polarity mutants – cause portions of each segment to be
deleted and duplicated on the wrong side.
(i) Hedgehog (Vertebrates)
• Sonic Hedgehog
• Desert Hedgehog
• Indian Hedgehog
(ii) Wingless

Hedgehog morphogens are involved in the control of left-
right asymmetry, the determination of polarity in the
central nervous system, somites and limbs, and in both
organogenesis and the formation of the skeleton.
In humans, Sonic hedgehog (SHH) plays a major role in
development of the ventral neural tube with loss-of-
function mutations resulting in a serious and often lethal
malformation known as holoprosencephaly where the
facial features shows eyes close together and there is a
midline cleft lip due to failure of normal prolabia
development.

PAIRED-BOX GENES (PAX)
The mammalian Pax gene family consists of nine
members that can be organized into groups based upon
sequence similarity, structural features, and genomic
organization. The four groups include
1. Pax1 and Pax9
2. Pax2, Pax5, and Pax8
3. Pax3 and Pax7 and
4. Pax4 and Pax6

ZINC FINGER GENES
The term zinc finger refers to a finger-like loop projection
which is formed by a series of four amino acids which form
a complex with a zinc ion. Genes, which contain a zinc
finger motif, act as transcription factors through binding of
the zinc finger to DNA.
SIGNAL TRANSDUCTION GENES
Signal transduction is the process whereby extracellular
growth factors regulate cell division and differentiation by a
complex pathway of genetically determined intermediate
steps. Mutations in many of the genes involved in signal
transduction can cause developmental abnormalities.
Fibroblast growth factor receptors (FGFRs) belong to the
category of signal transduction genes.

HOMEOBOX GENES (HOX) AND ITS IMPORTANCE
Since their discovery in 1983, the homeobox genes were
originally described as a conserved helix-turn-helix DNA
motif of about 180 base pair sequence, which is believed to
be characteristic of genes involved in spatial pattern control
and development. The protein domain encoded by the
homeobox, the homeodomain, is thus about 60 amino acids
long. Proteins from homeobox containing, or what are
known as HOX genes, are therefore important transcription
factors which specify cell fate and establish a regional
anterior/posterior axis.
The first genes found to encode homeodomain proteins were
Drosophila developmental control genes, in particular
homeotic genes, from which the name "homeo"box was
derived. However, many homeobox genes are not homeotic
genes; the homeobox is a sequence motif, while "homeotic"
is a functional description for genes that cause homeotic
transformations. www.indiandentalacademy.com

Four homeobox gene clusters (HOXA, HOXB, HOXC, and
HOXD) that comprise a total of 39 genes have been
identified in humans. Each cluster contains a series of
closely linked genes.
In each HOX cluster there is a direct linear correlation
between the position of the gene and its temporal and
spatial expression.
These observations indicate that these genes play a crucial
role in early morphogenesis. Lower number HOX genes
are expressed earlier in development and more anteriorly
and proximally than are the higher number genes.

Homeobox gene clusters in humans
Cluster Number of genes Chromosome location
HOXA
(=HOX1) 11 (1-7, 9-11, 13) 7p
HOXB
(=HOX2) 10 (1-9, 13) 17q
HOXC
(=HOX3) 9 (4-6, 8-13) 12q
HOXD
(=HOX4) 9 (1, 3, 4, 8-13) 2q
In humans each branchial arch exhibits a specific
combination of Hox gene expression. So far no Hox genes
been detected in the brain, and researchers claim that this is
due to the highly evolved nature of the human brain.

Examples of Homeobox genes, and their effects in humans –
Msx -1  involved in the development of secondary palate
and tooth.
Failure to express this gene results in familial tooth
agenesis – features - missing 2nd premolar and 3rd
molar
(Studies in Finnish families by Nieminen et al 1995).
Msx- 2  Disruption of this gene causes Craniosynostosis
SHH (Sonic hedgehog gene)  involved in the patterning of
Neural crest and neural tube – deficiency in expression of
SHH affects midline structures – which are underdeveloped.
Excess expression of SHH results in Hytertelorism

HOMEODOMAIN
The homeodomain is a DNA-binding domain, and many
homeobox genes have now been shown to bind to DNA and
regulate the transcription of other genes. Thus homeodomain
proteins are basically transcription factors, most of which
play a role in development.
The homeodomain is a common DNA-binding structural motif
found in many eukaryotic regulatory proteins.
Homeodomain proteins are involved in the transcriptional
control of many developmentally important genes, and 143
human loci have been linked to various genetic and genomic
disorders.

X-ray crystallographic and NMR spectroscopic studies on
several members of this family have revealed that the
homeodomain motif is comprised of three α-helices that are
folded into a compact globular structure. Helices-I and II lie
parallel to each other and across from the third helix. This
third helix is also referred to as the “recognition helix”, as it
confers the DNA binding specificity if individual
homeodomain proteins. The homeodomain has been
evolutionarily conserved at the structural level. This is most
evident upon examination of divergent members of the
homeodomain family.

MUTATION
A mutation is defined as a heritable alteration or change in
the genetic material. A mutation arising in a somatic cell
cannot be transmitted to offspring, whereas if it occurs in
gonadal tissue or a gamete it can be transmitted to future
generations.
Herman Muller went on to use x-rays to cause mutations in
fruit flies – for which he won the Nobel Prize.

TYPES OF MUTATIONS
Mutations occur in two forms:
Point mutations - involve a change in the base present at any
position in a gene
Gross mutations - involve alterations of longer stretches of
DNA sequence.
The location of the mutation within a gene is important. Only
mutations that occur within the coding region are likely to
affect the protein. Mutations in noncoding or intergenic
regions do not usually have an effect.

Point mutations
1. Missense mutations
2. Nonsense mutations
3. Frameshift mutations
4. Silent mutations
Gross mutations
1. Deletions
2. Insertions
3. Rearrangements

Missense mutations
These point mutations involve the alteration of a single base
which changes a codon such that the encoded amino acid is
altered. Such mutations usually occur in one of the first two
bases of a codon. The redundancy of the genetic code means
that mutation of the third base is likely to cause a change in
the amino acid.
The effect of a missense mutation on the organism varies.
Most proteins will tolerate some change in their amino acid
sequence. However, alterations of amino acids in parts of
the protein that are important for structure or function are
more likely to have a deleterious effect and to produce a
mutant phenotype.

Nonsense mutations
These are point mutations that change a codon for an amino
acid into a termination codon. The mutation causes
translation of the messenger RNA to end prematurely
resulting in a shortened protein which lacks part of its
carboxyl-terminal region. Nonsense mutations usually
have a serious effect on the activity of the encoded protein
and often produce a mutant phenotype.

Frameshift mutations
These result from the insertion of extra bases or the deletion
of existing bases from the DNA sequence of a gene. If the
number of bases inserted or deleted is not a multiple of
three the reading frame will be altered and the ribosome
will read a different set of codons downstream of the
mutation substantially altering the amino acid sequence of
the encoded protein.
• Frameshift mutations usually have a serious effect on the
encoded protein and are associated with mutant
phenotypes.

Silent mutations
Mutations may occur at the third base of a codon and, due to
the degeneracy of the genetic code, the amino acid will not
be altered. Silent mutations have no effect on the encoded
protein and do not result in a mutant phenotype. They tend
to accumulate in the DNA of organisms where they are
known as polymorphisms. They contribute to variability in
the DNA sequence of individuals of a species.

Deletions
These involve the loss of a portion of the DNA sequence. The
amount lost varies greatly. Deletions can be as small as a
single base or much larger in some cases corresponding to
the entire gene sequence.
Insertions
In this case the mutation occurs as a result of insertion of extra
bases, usually from another part of a chromosome.

Rearrangements
These mutations involve segments of DNA sequence within or
outside a gene exchanging position with each other. A
simple example is inversion mutations in which a portion of
the DNA sequence is excised then re-inserted at the same
position but in the opposite orientation.
Gross mutations, because they involve major alterations to
gene sequences, invariably have serious effect on the
encoded protein and are frequently associated with a mutant
phenotype.

FUNCTIONAL EFFECTS OF MUTATIONS ON THE
PROTEIN
Mutations exert their phenotypic effect in one of two ways,
either through loss or gain of function.
Loss-of-function mutations
Loss-of-function mutation can result in either reduced activity
or complete loss of the gene product. The former can be the
result of either reduced activity or of decreased stability of
the gene product and is known as a hypomorph, the latter
being known as a null allele or amorph. Loss-of function
mutations in the heterozygous state would, at worst, be
associated with half normal levels of the protein product.

Haploinsufficiency
Loss-of function mutations in the heterozygous state in which
half normal levels of the gene product result in phenotypic
effects are termed haploinsufficiency mutations. There are
number of autosomal dominant disorders where the
mutational basis of the functional abnormality is the result
of haploinsufficiency, in which, homozygous mutations
result in more severe phenotypic effects.

Gain-of-function mutations
Gain-of-function mutations, as the name suggests, result in
either increased levels of gene expression or the
development of a new function(s) of the gene product.
Mutations which alter the timing or tissue specificity of the
expression of a gene can also be considered to be gain-of-
function mutations.
Gain-of-function mutations are dominantly inherited and the
rare instances of gain-of-function mutations occurring in
the homozygous state are associated with a much more
severe phenotype, which is often a prenatally lethal
disorder.

Structure of Chromosomes
Each chromosome is not composed of a single Watson-Crick
double helix. The width of a chromosome is much greater
than the diameter of the helix.
There are several meters of DNA in a human body, and the
total length of the chromosomes is less than a millimeter.
Finch and Klug suggested the “SOLENOID MODEL” of
chromosome structure.

Each DNA duplex is coiled around itself – primary coiling
This is coiled around histone ‘beads’ – secondary coiling –
called nucleosomes
Nucleosomes are coiled to form chromatin fibres, around a
protein matrix or scaffold – tertiary coiling
Chromatin fibres are coiled to form loops – quaternary
coiling
The loops are further wound in a tight helix to form the
chromosome – that can be seen under a microscope.
The clusters of chromomeres can be seen as darkly staining
bands, or G bands on the the chromosomes.

Human Chromosomes
There are 46 chromosomes in the normal human – 23 pairs.
The members of each pair match with respect to the genetic
information they carry.
One chromosome of the pairis inherited from the father, and
one from the mother, and further, one is transmitted to the
child.
22 pairs are alike in males and females – known as autosomes
1 pair differs – the sex chromosomes.

The members of a pair of chromosomes are microscopically
indisdtinguishable, and the same is true for the female sex
chromosomes – the X chromosome.
In the male, there is one X chromosome and one Y
chromosome which is smaller than the X chromosome, but
it is thought that the two have a shout homologous segment.
There are 2 types of cell division –
Mitosis – normal cell division, by virtue of which the body
grows – it results in 2 daughter cells, identical to the parent
cell in genetic makeup, and number of chromosomes.
Meiosis – This results in the production of reproductive cells
(gametes). Each of which have only 23 chromosomes.

Classification of Chromosomes
When prepared for analysis, the chromosomes appear under
the microscope as a chromosome spread. The
chromosomes are then cut out from a photomicrograph and
arranged in pairs in a standard classification. This process is
called karyotyping, and the complete picture is called the
karyotype.
In 1960, at a conference in Denver a classification system was
devised to distinguish 7 chromosome groups (A through G)
based on length and centromere position. But with more
advanced staining, other methods of classification have
arisen. Each chromosome has been identified by its banding
pattern and each band numbered according to a standard
system. The Paris classification is currently in use.

The chromosomes have a primary constriction known as the centromere.
The location of the centromere
can be used to classify the chromosomes
• Metacentric – central centromere
• Submetacentric - off –centre
• Acrocentric – towards one end
• Telocentric – terminal centromere
CHROMOSOME NOMENCLATURE
Each chromosome arm is divided into regions and each region is subdivided
into bands numbering always from the centromere outwards. A given
point on a chromosome is designated by the chromosome number, the arm
(p or q), the region and the band, e.g. 15q12. Sometimes the word region
is omitted so that 15q12 would be referred to simply as band 12 on the
long arm of chromosome15.

Chromosome Analysis
For chromosome analysis, the cells to be studied must be able to grow
and divide rapidly. White blood cells are readily obtainable.
WBCs are separated from blood by centrifugation, and placed in a
suitable culture medium with phytohemagglutinin, a mitogenic
agent. When the cultured cells are dividing rapidly, a very dilute
solution of colchicine is added to the medium. This stops mitosis
in the metaphase, and metaphase cells accumulate in the culture.
A hypotonic solution is then added to swell the cells and to separate
the chromatids while leaving the centromeres intact. The cells are
fixed, spread on a slide and stained. They can then be examined
under a microscope, stained and then photographed. The
individual chromosomes are then cut from the photo, and
arranged according to a particular manner (ie- karyotyped). After
this, the karyotype can be examined for abnormalities of number
or structure.
WBC cultures are usually short lived, and skin cultures are usually
used for biochemical and histochemical studies.www.indiandentalacademy.com

• Staining methods
• Autoradiography – The cultures are exposed to radioactive thymidine, and
then after a given time, the cell divisions are stopped. The chromosomes
which replicate, incorporated the thymidine. This procedure has shown that
not all chromosomes replicate at the same time. But this process is
laborious and time consuming, and is rarely used.
• After 1970, several special staining techniques have developed for staining
chromosomes in banded patterns. Some are:-
• Q banding – the chromosomes are stained with quinacrine mustard or
related compounds and examined by fluroscence microscopy. Each pair
stains with a specific pattern of bright and dim bands – the Q bands.
• G banding – widely used. Chromosomes treated with tripsin to denature the
protein, and then stained with Giemsa stain. The chromosomes develop
bright and dark bands – G bands. The dark bands correspond to the bright
Q bands.
• R banding – less widely used. The chromosomes are heat treated, and
then stained with Giemsa – the results are the REVERSE of G and Q
banding, and gives much the same information.

• C banding – This results in staining the centromere and
other regions of the chromosome containing constrictive
heterochromatin, ie- secondary constrictions of
chromosomes 1, 9, 16 and the distal segment of the long
arm of the chromosome. (heterochromatin is chromatin
that stains differently from other chromatin).
• NOR staining – This refers to the use of ammoniacal
silver to stain the “nucleolar organizing regions, ie – The
stalks of the chromosomes which contain the ribosomal
genes
• High resolution banding – used for staining cells in
prophase – shows much more bands than the metaphase
staining. www.indiandentalacademy.com

Medical applications of Chromosome analysis
• Clinical diagnosis – in patient with congenital
malformations, mental retardation disorders of sexual
development etc.
• Linkage and Mapping – Assignment of specific
human genes to their chromosomal positions.
• Polymorphisms – Minor heritable differences in
chromosomes are common, especially in
chromosomes 1, 9, and 16 and the Y chromosome.
These can be used to trace individual chromosomes
through families, and hence serve as markers to
trace certain genetic defects and determine their
source.

• Chromosomes and Neoplasia – The relation of
chronic myelogenous leukemia to the Philadelphia
chromosome. Chromosomal defects are present in
most neoplasias.
• Reproductive problems – A small proportion of
parents experiencing spontaneous abortions or
infertility have some chromosomal abnormality.
• Prenatal Diagnosis – Amniocentesis is used to
obtain fetal cells, and analyze the chromosomes for
abnormalities. This is particularly useful in older
pregnant women, and families with a history of
chromosomal abnormalities.

Genetic disorders and inheritance
Genetic disorders can be of 3 main types :-
• Single gene disorders – these occur due to mutations of
single genes. They show typical pedigree patterns and are
rare - 1 in 2000 or less.
• Chromosome disorders – the disorder occurs due to an
excess or deficiency of whole chromosomes or chromosome
segments. They show characteristic features, and are
relatively more common than single gene disorders - 7 in
1000 births.
• Multifactorial inheritance – These are caused due to a
combination of genetic and environmental factors. They are
the most common of the genetic disorders and do no show the
typical pedigree patterns on single gene disorders.

Indications that a condition has a genetic etiology
(Neel and Schull 1954)
• Occurrence of a disease in definite proportions in
families when environmental factors can be ruled
out.
• Absence of disease in unrelated lines like spouses
or in-laws.
• Characteristic age of onset, and course in the
absence of precipitating factors
• More in monozygotic than dizygotic twins.
• Demonstration of characteristic phenotype and
chromosomal abnormality, with or without family
history.

Single Gene disorders.
These can be –
Autosomal dominant
Autosomal recessive
Sex linked (gonosomal) dominant
Sex linked (gonosomal) recessive

Autosomal dominant
• In this the mutant gene manifests itself in the homozygote as
well as the heterozygote. These disorders are quite rare – Eg:-
Osteogenesis imperfecta, Achondoroplasia.
• The person is usually heterozygous, and one of the parents is
affected. It is inherited as a simple mendellian dominant factor.
• Autosomal dominant characteristics can also occur as new
mutations in some children whose parents are not affected by
the disorder. The possibility of a new mutation should always be
kept in mind when considering a genetic etiology.

• Another characteristic of many autosomal dominant disorders
is expressivity. This is a variability in clinical manifestation. In
polydactyly, there may be no more than a small wartlike
appendage in the side of the hand but at the other extreme,
another affected person may have an entire extra finger.
• Sometimes the gene may not express itself at all, which is
known as non penetrance. This explains why sometimes the
disorder may skip a generation.
• Some autosomal genes are expressed more frequently in one
sex than another. This is called sex influence. Eg – gout and
pre senile baldness in males. The influence of sex is probably
due to the influence of sex hormones.
• Some disorders which have an apparent autosomal dominant
type of inheritance have been postulated, in recent times to
have a viral etiology. Eg – Alzheimer’s disease.

Autosomal Recessive inheritance
• These are only expressed when the gene is present in a homozygous
genotype. The heterozygote is healthy, because the normal gene is
expressed rather than the mutant gene. The disorder is normally
expressed if a heterozygote marries another heterozygote, but due to
the rarity of the mutant gene, this possibility is remote. But the
chances are much higher in cases of consanguineous marriages – the
chances that cousins will posses the recessive mutant gene is 1 in 8.
• So the rarer the mutant gene, the more the chances that the affected
individual has parents who are cousins.
Eg of autosomal recessive disorders – alkaptonuria.
The most common autosomal recessive disorder is cystic fibrosis.

Intermediate inheritance
• Some mutant genes are only partially expressed in the
heterozygote. This is known as incomplete dominance, or
intermediate inheritance. An example is sickle cell anaemia. A
person homozygous for the mutant gene, shows typical sickling
of the RBCs. The heterozygote on the other hand shown normal
RBCs in normal condition. But if the heterozygote is exposed to
low oxygen tension, as in high altitude travel etc, the RBCs
change from the normal shape to sickle shape. These people are
said to have the sickle cell trait.
•
Codiminance.
• In some cases, the alleles for a particular characteristic may be
different, but both may be expressed. This is known as co-
dominance. Eg – both the antigens A and B are present is blood
group AB.

Sex linked inheritance.
• This refers to the pedigree pattern of genes carried on either
the X chromosome or the Y chromosome.
X-Linked recessive
• This gene manifests in the female only if she is
homozygous for the gene, but always manifests in the male
as he has only one X chromosome (said to be hemizygous).
• If the female is heterozygous, she is healthy but said to be a
carrier.
• The disorder is passed from a healthy female carrier to all her
sons. An affected male has healthy sons, and females who
are carriers. Eg - hemophillia
• Some cases in which females may be affected –
– Turner’s syndrome – the female has only 1 X chromosome
– Manifesting heterozygote - the gene manifests even in the
heterozygous state.

X linked Dominant
• The expression of these disorders is similar to
autosomal dominant – the heterozygote and
homozygote are both affected. Additionally, an
affected male transmits this disorder to all his
daughters, but the sons are always healthy. A
female hetrozygote has a 50% chance of having an
affected child
Y linked inheritance
• These disorders are transmitted directly from father
to son. All the sons are affected. Females are not
affected as they do not have a Y chromosome

Chromosomal abnormalities
Chromosomal abnormalities can be of the following
types:-
Abnormality in Number
Autosomes
Sex chromosomes
Abnormality in - Structure
Autosomes
Sex chromosomes

Numerical Abnormalities in Autosomes
Loss or gain of a single chromosome is known as aneuploidy
Polyploidy – is a gain of the whole chromosome set – ie – 3N or
4N number of chromosomes. While this is common in plants, it
is lethal in humans.
Monosomy – is the loss of a single chromosome. This is also a
lethal condition in man.
Trisomy – This is the gain of a single chromosomy. Lejeune
(1959) was the first to show that patients with Down’s
syndrome had an extra Chromosome 21.
The main cause of trisomy is the failure of homologous
chromosomes to separate during meiosis. This is known as
non-disjunction.
Other syndromes caused due to trisomy are
Edward’s syndrome – Trisomy 18
Patau’s syndrome – Trisomy 13

Structural abnormalities in
Autosomes2 types –
Translocations – exchange of segments between non
homologous chromosomes.
Deletions – Loss of a segment of a chromosome.
Translocations
Translocations can further be of 2 types
-Robertsonian
- Reciprocal.

An example of Robertsonian translocation is a case in
which the long arms of chromosome 14 and 21 get
translocated, and the short arms are lost. In this
person there will be –
1 normal Chromosome 14
1 normal Chromosome 21
1 abnormal chromosome (14/21)
But since the amount of genetic material is still the
same (there are still 2 chromosome 14s and 2
chromosome 21s) the affected person is still
normal. But the gametes of this person will not be
normal –
(14/21) 14 21
14/21 14 21www.indiandentalacademy.com

The possible combinations of these chromosomes and
their outcomes after combining with normal
chromosomes 14 and 21 are shown below –
14/ 21 21 downs syndrome
14/21 carrier
14 21 normal
14 monosomy (death)
In case of reciprocal translocation, since the amount of
DNA is conserved, again, the person affected will be
normal, but the gametes will be abnormal

Deletions
Although monosomy is lethal, some people with
genetic disorders have been found to have partial
monosomy. This is due to removal or deletion of a
part of a chromosome. Eg – Deletion of the short
arm of chromosome 5 – causes ‘cri du chat’ –
characterized by a cat like cry at birth.
Also, if a deletion occurs at 2 ends of a chromosome,
such that the resultant ends have complementary
base pairs, they tend to join, and form a ring
chromosome.

Sex chromosome abnormalities
Abnormality of number
Seen in many syndromes –
• Klinefelter’s syndrome – XXY
• Turner’s syndrome – females with only 1 X
chromosome
• Multiple X – females with 3 or 4 X chromosomes
XYY males
Abnormalites of Structure
Isochromosome X – a long X chromosome – which
results from deletion of the short arms of the X
chromosome and duplication of the long arm.

Multifactorial Inheritance
These disorders are the most common type of genetic
disorders. They occur due to the effect of many
genes, and also have a component of environmental
influence.
These disorders show a definite familial tendency, the
incidence among relatives being greater than that of
the general population, but less than that of a single
gene disorder.
Normal traits having a multifactorial influence are -
intelligence, skin colour, blood pressure, etc.

Relatives have a higher incidence of these disorders,
because their genetic makeup is such, that they are
more prone to the disorder. The graph below shows
the liability to a particular disorder. (Liability = the
sum total of genetic + environmental factors
influencing a disorder.)
It can be seen that the threshold for a disease
occurring in the general population is much higher
than that of the relatives. This indicates the
increases risk of relatives to the disorder.

• It is also seen that if an
individual is affected by a
severe form of a disorder,
the chances that someone
else in the family has it, or
will develop it in the future,
is greater.
• Eg-
– Pt. with bilateral cleft lip – 6%
chance of another relative
having it
– Pt. with unilateral cleft lip –
2.5% chance.

Heritability
Defined as – proportion of the total variation of a
character which can be attributed to genetic factors.
In other words, it is an estimate of how much of the
etiology of a disorder can be ascribed to genetic
influences rather than environmental factors.
Greater the heritability, greater the genetic
component.

TWINNING
Twins can be identical or non-identical → monozygotic
(MZ) or dizygotic (DZ) – depending on whether they
originate from a single conception or from two
separate conceptions.
MONOZYGOTIC TWINS
Monozygotic twins originate from a single egg which
has been fertilized by a single sperm. A very early
division, occurring in the zygote before separation
of the cells which make the chorion, results in
dichorionic twins. Division during the blastocyst
stage from days 3 to 7 results in monochorionic
diamniotic twins. Division after the first week leads
to monoamniotic twins.www.indiandentalacademy.com

DIZYGOTIC TWINS
Dizygotic twins result from the fertilization of two ova by
two sperm and are no more closely related
genetically than brothers and sisters. Hence they are
sometimes referred to as fraternal twins. Dizygotic
twins are dichorionic and diamniotic although they
can have a single fused placenta if implantation
occurs at closely adjacent sites.

The classical twin approach for separating the effects
of nature and nurture involves comparing identical
(monozygous) and non-identical (dizygous) twins.
Differences between monozygous (MZ) twin pairs
reflect environmental factors, whereas differences
between dizygous (DZ) twin pairs are due to both
genetic and environmental factors.
Therefore, greater similarities between MZ twin pairs
compared with DZ twin pairs can be interpreted as
reflecting genetic influences on the feature(s) being
studied.
SIGNIFICANCE OF TWIN STUDIES

Apart from comparisons of monozygous and dizygous
twins, there are other twin models that provide
insights into the contributions of genetic and
environmental factors to observed variability. The
monozygous co-twin model involves comparisons
of monozygous twins where each member of a pair
has been exposed to different environmental
effects. For example, identical twins might be
treated with different appliances to correct similar
malocclusions and the outcomes compared.
Monozygous twins are assumed to have identical
genotypes, so their offspring are genetically related
as half-sibs but are socially first cousins. A nested
analysis of variance similar to that used in analysing
data from half and full-sibling litters in animal
studies can be applied to provide estimates of
genetic and environmental effects.

Genetic influence on tooth number size,
morphology,position
Various developmental dental disorders, which are under the
influence of genes, include
Disorders in tooth morphogenesis.
Amelogenesis imperfecta (AI): this is a group of genetically
heterogeneous disorders affecting enamel formation.
It is clinically heterogeneous in that hypoplastic, hypocalcified
and hypomaturation forms have been described and
genetically heterogeneous with families exhibiting autosomal
dominant, autosomal recessive and X-linked inheritance.
In humans, two amelogenes, AMGX and AMGY, have been
cloned and mapped to the X and Y chromosomes,
respectively (Lau et al., 1989) and in 1997 MacDougall et al.
mapped the ameloblastin gene within the critical region for
autosomal dominant AI at chromosome 4q21. It is likely,
however, that mutations in several genes may be involved in
the aetiology of different forms of autosomally inherited AI

Dentinogenesis imperfecta (DI): this is autosomal and occurs in
approximately 1:8000 live births.
It presents with brownish discoloration of the teeth, crowns
susceptible to rapid attrition, fragile roots and pulp chamber
obliteration due to abnormal continuous production of dentine
matrix (Shields, 1973).
DI also presents a number of sub-types, one of which is coupled
with osteogenesis imperfecta in which there is an alteration in
type 1 collagen genes.
Most patients with this type of dentinogenesis imperfecta have
mutations and deletions for amino acid substitutions in genes
with encode for sub-units of type 1 collagen (Bonadio et al.,
1990). The structural defects in the collagen type 1 molecules
affects the extra cellular matrix formation, resulting in the
pathogenesis of DI.

Hypodontia
The congenital absence of teeth may be referred to as hypodontia, when
one or several teeth are missing, or anodontia when there is a
complete absence of one or both dentitions. Features include,
1. More common in permanent than primary dentition
2. Absence of primary teeth associated with absence of permanent
successors
3. May be associated with other developmental anomalies
• Grahnen (1956) in his familial and twin studies revealed the
hereditary nature of hypodontia and concluded that in children with
missing teeth, up to half of their siblings or parents also had missing
teeth.
• Osborne et al (1958) in his twin studies have shown that tooth
crown dimensions are strongly determined by heredity. The
molecular genetics of tooth morphogenesis with the homeostatic
Hox 7 and Hox 8 (now referred as Msx-1 and Msx-2) genes are
being responsible for stability in dental patterning.

Clinical evidence suggests that congenital absence of teeth and
reduction in tooth size are associated e.g., hypodontia and
hypoplasia of maxillary lateral incisors frequently present
simultaneously. Numerous pedigrees have been published
linking the two characteristics and implying that they are
different expressions of the same disorder.
• Gruneberg (1965) suggested that a tooth germ must reach
a critical size during a particular stage of development or the
structure will regress, and Suaraz and Spence (1974)
showed that hypodontia and reduction in tooth size are in fact
controlled by the same or related gene loci. It is apparent from
all the evidence in this respect that tooth size fits the polygenic
multifactorial threshold model.
• Markovic (1982) found a high rate of concordance for
hypodontia in monozygous twin pairs, while zygous twin pairs
he observed discordant. These and other previous studies
concluded that a single autosomal dominant gene could
explain the mode of transmission with incomplete penetrance.

• Vastardis (Nature Genetics 1996) studied the cause
for selective tooth agenesis in human, where missense
mutation occurred in the MSX-1 homeodomain. This occurs
as a consequence of replacement of arginine with proline
protein (Arg196Pro mutation) in the homoedomain of MSX-
1. Tooth agenesis was reported in a family with a ser 105
stop mutation of MXS-1 gene.
• Dermaut and Smith (AJO1997) studied the prevalence
of tooth agenesis correlated with jaw relationship and dental
crowding in 185 patients and found that,
1. Hypodontia occurred more often in girls than in boys.
2. The upper lateral incisors and lower premolars were the
most frequently missing teeth.
3. Class I skeletal relationships were found more often in
patients with agenesis than in patients without missing teeth
and are associated with deep-bite growth patterns.

• Research work by Cobourne (BJO 1999) on families
affected with hypodontia has revealed that it is transmitted as
an autosomal dominant disorder with variable expressivity and
incomplete penetrance. Missing maxillary laterals and
mandibular second premolars have been associated with
defects in MSX-1and MXS-2 genes.
• Van den Boogard et al (Nature Genetics 2000)
observed a genetic aberration in a Dutch family with tooth
agenesis. A stop codon in MSX-1 mutation was identified
implying the involvement of this gene in tooth agenesis.
• Nieminen (Eu J of Human Genetics 2001) found that, a
non-sense mutation in the PAX-9 gene was associated with
molar tooth agenesis in a Finnish family. The A340T
transversion creates a stop codon at lysine 114, and truncates
the coded PAX-9 protein at the end of the DNA-binding paired
box. The tooth agenesis phenotype involved all permanent
second and third molar and most of the first molars.

• Lidral (JDR 2002) concluded that a mutation in MSX-1 gene
in chromosome 4 has been identified as the causative factor for
oligodontia involving the absence of all second premolar and
third molar. Missing first molar and second molars have been
linked with a substitution mutation of MSX-1 gene.
• With the help of molecular genetics techniques, Peck and
Peck (AJO 2002) assessed a family exhibiting an autosomal
dominant trait of missing second premolar and third molars. The
affected chromosome was isolated to be in a chromosome 4p
and many genes were considered to be responsible for this
tooth agenesis. A point mutation was detected in the MSX 1
gene in all affected family. Also mutation of PAX-9 transcription
factors has been observed in familial tooth agenesis and also in
missing mandibular second premolars and central incisors.

ECTOPIC ERUPTION AND TRANSPOSITION OF
CANINES
Various studies in the past have indicated a genetic tendency for
ectopic maxillary canines.
• Zilberman et al (1990) and Peck et al (1994) concluded
that palatally ectopic canines were an inherited trait, being one
of the anomalies in a complex of genetically related dental
disturbances often occurring with missing teeth, tooth size
reduction, and other ectopically positioned teeth.
• Previous studies by Mossey et al (1994) have also shown an
association between ectopic-maxillary canine and Class II div 2
malocclusion, a genetically inherited trait.
• Peck et al (1997) classified a number of different types of
tooth transposition in both maxillary and mandibular arches, with
maxillary canine/first premolar class position being the most
common.

They also provided strong evidence of a significant
genetic component in the cause of this most common
type of transposition in that there was
• A familial occurrence
• Bilateral occurrence in a high percentage of cases
• Female predominance and a difference in different
ethnic groups
An increased frequency of associated dental anomalies;
tooth agenesis and peg-shaped maxillary lateral
incisors were also reported.
Neubuser et al (1995) found that PAX-9
transcription factor is associated the genetic
mechanism for tooth displacement anomalies, such
as palatally displaced canines and canine
transposition.

FAMILY AND TWIN STUDIES FOR
HERITABILITY
OF DENTOFACIAL PHENOTYPESThe twin method, when appropriately applied, provides
geneticists with one of the most informative technique
available for analysis of complex genetic traits. Alternative
method for investigating the role of heredity in determining
craniofacial and dental morphology is by familial studies.
Heritability in such studies is normally expressed in terms of
parent/offspring correlation coefficients or correlation
coefficients with sibling pairs, of which twins are a special
kind.
The study of craniofacial relationship in twins has provided much
useful information concerning the role of heredity in
malocclusion. The procedure is based on the underlying
principle that observed differences within a pair of
monozygotic twins (whose genotype is identical) are due to
environment and those differences within a pair of dizygotic
twins (who share 50% of their total gene complement) are due
to both genotype and environment.

A comparison of the observed within-pair differences for
twins in the two categories should be provide a
measure of the degree to which monozygotic twins
are more alike than dizygotic twins. The larger this
differences between the two twin categories, the
greater the genetic difference effect on variability of
the trait.
This model implies the zygosity is accurately
determined and that environment effects are equal in
the two twin categories
The bulk of the evidence for the heritability of various
types of malocclusion arises from family and twin
studies.

CLASS II MALOCCLUSION
Class II Division I Malocclusion:
Extensive cephalometric studies have been carried out to
determine the heritability of certain craniofacial parameters in
class II division I malocclusion (Harris 1975).
These investigation have shown that in the class II patients, the
mandible is significantly more retruded than in class I patients,
with the body of the mandible length smaller and overall
mandibular length reduced.
These studies also showed a higher correlation between the
patient and his immediate family that data from random
pairings of unrelated siblings, thus supporting the concept of
polygenic inheritance for class II division I malocclusion

Class II Division 2 malocclusion
Class II division 2 is a distinct clinical entity and is a more
consistent collection of definable morphometric features
occurring simultaneously i.e., syndrome than the other
malocclusion types put forward by Angle in the early 1900’s.
Class II division-2 malocclusion along with characteristic skeletal
features is often accompanied by particular morphometric
dental feature also, such as a poorly developed cingulum on
the upper incisors and a characteristic crown angulation.
Markovic 1992 carried out a clinical and cephalometric study of
114 Class II division-2 malocclusions, 48 twin pairs and six
sets of triplets. Intra- and Inter- pair comparisons were made
to determine concordance-discordance rate for monozygotic
and dizygotic twins. Of the monozygotic twin pairs, 100%
demonstrated concordance for the Class II division-2
malocclusion, whilst almost 90% of the dizygotic twin pairs
were discordant. This is strong evidence for genetics as the
main etiological factor in the development of class II division2
malocclusion. www.indiandentalacademy.com

The studies point to incontestable genetics influences
probably autosomal dominant with incomplete
penetrance and variable expressivity. It could also
possibly be explained by a polygenic model with a
simultaneous expression of a number of genetically
determined morphological traits acting addictively,
rather than being the effect of a single controlling
gene for the entire occlusal malformation.
Aspects of skeletal and muscle morphology are
genetically determined and there is some recent
experiment evidence from a twin study
(Lauweryns et al 1995) indicating strong genetic
factors in certain aspects of masticatory muscle
behavior.

CLASS III MALOCCLUSION
Probably the 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
Hungarians/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.
This could be regarded as an exception and in itself, does not
provide sufficient information to predict the mode of inheritance
of mandibular prognathism.
• Suzuki (1961) studied 1362 persons from 243 Japanese
families and noted that, while the index cases and mandibular
prognathism; there was a significantly higher incidence of this
trait in other members of his family (34.4%) in comparison of
families of individuals with normal occlusion (7.5%).

Schulze and Weise (1965) also studied mandibular
prognathism in monozygotic and dizygotic twins. They
reported that concordance in monozygotic twins was six times
higher than among dizygotic twins.
Both of the above studies reported a polygenic hypothesis as the
primary cause for mandibular prognathism (Litton et al
1970).
A class III malocclusion resulting from a skeletal imbalance
between the maxillary and mandibular bases may result from
deficiency in maxillary growth, excessive mandibular growth,
or a combination of both. Various studies have also
highlighted the influence of a distinct cranial base morphology
with a more acute cranial base angle and shortened posterior
cranial base resulting in a more anterior position the gleniod
fossa, thus contributing to the mandibular prognathism (Ellis
and Mcnamara, 1984; Singh et al 1997).

Various models have been suggested, such as autosomal
dominant with incomplete penetrance (Stiles and
Luke1953), simple recessive (Downs 1928), variable both
in expressivity and penetrance with differences in different
racial populations (Kraus et al 1959).
Litton et al (1970) carried out an analysis of the literature to
that date and also analyzed a group of probands, siblings and
parents with Class III malocclusion, and analyzed the results
in an effort to determine a possible mode of transmission.
Both autosomal dominant and autosomal recessive transmission
were ruled out and there was no association with gender
(male or female).
The polygenic multifactorial threshold model put forward by
Edward et al 1960, however, did fit the data and
accordingly proposed a polygenic model with a threshold for
expression to explain familial distribution, and the prevalence
both within general population and in siblings of affected
persons

Soft tissues do not generally play a part in the etiology of Class III
malocclusion, and in fact there is a tendency for lip and tongue
pressure to compensate for a skeletal Class III discrepancy by
retroclining lower incisors and proclining upper incisors.
Polygenic inheritance implies that there is scope for
environmental modification and many familial and twin studies
bear this out.
Watnick (1972) studied 35 pairs of monozygotic and 35 pairs of
dizygotic like-sexed twins using lateral cephalometry. He
concluded that the analysis of unit areas with the craniofacial
complex represents local growth sites and revealed different
modes of control within the same bone.
Certain areas, such as the lingual symphysis, lateral surface of
the ramus and frontal curvature of the mandible are
predominantly under genetic control. Other areas, such as the
antegonial notch, are predominantly affected by environmental
factors.

Hughes and Moore 1942 suggested that the
mandible and maxilla are under separate influence
of genetics control, and that certain portions of
individual bones, such as the ramus, body, and
symphysis of the mandible are under different
genetic and environmental influences.
Nakasima and Nakata (AJO 1982) assessed
the craniofacial morphologic differences between
parents of Class II patients and parents of Class III
patients, as well as parent-offspring correlations,
and the genetic and environmental components of
variation within the craniofacial complex in these
malocclusions.
,

The results showed that
The parents of Class II patients had a convex profile
with a distoclusion type of denture pattern, while the
parents of Class III patients had a concave profile
with a mesioclusion type of denture pattern. This
suggests that both Class II and Class III
malocclusions have a genetic basis.
The skeletal pattern was more directly related to
genetic factors.
Parent-offspring correlation data were in good
agreement with the expected level under the
polygenic model of inheritance.

HERITABILITY OF LOCAL
OCCLUSAL VARIABLES
• It has been thoroughly documented that measurements of the
skeletal craniofacial complex have moderate to high heritability,
while measures of the dento-alveolar portions of the jaws i.e.,
tooth position and dental relationships are given much less
attention in the literature.
• Because of the adaptability of the dentoalveolar region when
subjected to environmental factors, local malocclusions are
primarily acquired and would be expected to have low
heritablities
• In an analysis of the nature versus nurture in malocclusion
Lundstrom (1984) concluded that the genetic contribution to
anomalies of tooth position and jaw relationship overall is only
40%, with a greater genetic influence on the skeletal pattern
than on the dental features.

• Lundstrom (1984) studied 50 pairs of monozygotic and 50 pairs
of dizygotic twins and concluded that heredity played a significant
role in determining, among other factors, width and length of the
dental arch, crowding and spacing of the teeth and degree of
overbite.
• A study by Hu et al (1992) also reported familial similarity in
dental arch form and tooth position.
• In a recent study by King et al (1993), initial treatment records of
104 adolescent sibling pairs, all whom subsequently received
orthodontic treatment, were examined. Heritability estimates for
occlusal variations such as rotations, crossbites and displacements
were significantly higher than in a comparable series of adolescents
with naturally good occurring occlusions. The explanation offered
was that a genetically influenced facial types and growth patterns of
the siblings are likely to respond to environment factors e.g., chronic
mouth breathing and reduced masticatory stress similar fashions.
• It is also important to remember the soft tissue morphology and
behaviour have a genetic component and they have a significant
influence on the dentoalveolar morphology.

Bolton's ratio
Bulent Baydas et al (EJO 2005) :
Sample size = 106 FM and 78 M.
These were patients and their siblings who reported for
orthodontic treatment.
Bolton's ratio has a high heritability in siblings of same
gender, in siblings of different gender ,the anterior
and overall ratios did not show any heritability.

GENETIC FACTORS AND
EXTERNAL
APICAL ROOT RESORPTIONAnalysis of the genetic basis for variable response to treatment
has been applied to the specific adverse outcome sometimes
associated with orthodontic treatment called external apical
root resorption (EARR).
The degree and severity of EARR associated with orthodontic
treatment is multifactorial, involving host and environmental
factors. An association of EARR exists, in those who have not
received orthodontic treatment, with missing teeth, increased
periodontal probing depths, and reduced crestal bone heights.
Individuals with bruxism, chronic nailbiting, and anterior open
bites with concomitant tongue thrust also may show an
increased extent of EARR before orthodontic treatment
Genetic variation accounts for 50% to 64% of the variation in
EARR of the maxillary Incisors.

Variation in the interleukin-lb gene (IL-1B) in orthodontically
treated individuals accounts for 15% of the variation in EARR.
Persons in the orthodontically treated sample who were
homozygous for IL-1B allele "1" were estimated to be 5.6
times more likely to experience EARR of 2 mm or more than
those who were heterozygous or homozygous for allele "2.
Iwasaki et al found individual differences in a ratio of IL-l b to IL-l
RA (receptor antagonist) cytokines in crevicular fluid that
correlated with individual differences in canine retraction using
identical force
Although the relation to genetic markers was not undertaken, this
study indicates a variable individual response to orthodontic
force that may be mediated at least in part by IL-l b and IL-l
RA cytokines.
This supports the hypothesis that bone modeling mediated, at
least in part, by IL-l b as an individual response to orthodontic
force can be a factor in EARR

Further testing of another candidate gene using
nonparametric sibling pair linkage analysis with the
DNA microsatellite marker D18S64 (tightly linked to
the gene TNFRSFllA) identified evidence of linkage
of EARR affecting the maxillary central incisor
This indicates that the TNFRSFllA with EARR.The
TNFRSFllA gene codes for the protein RANK, part
of the osteoclast activation pathway.

GENOMICS AND OROFACIAL CLEFTS
• Orofacial clefts, the most common craniofacial
malformation ranks second among all the craniofacial
anomalies, among all the congenital malformation
affecting human.
These include,
• Cleft lip and Cleft palate
Cleft lip with or without cleft palate
Cleft palate only
• Median clefts
• Alveolar clefts
• Facial clefts
• Etiology of orofacial clefts appears to be complex
with involvement of genetic, environmental and
tetragenic factors complicating the process

CLEFT LIP AND CLEFT PALATE
Etiological factors:
1. Monogenic or single gene disorder
2. Polygenic or multifactorial inheritance
3. Chromosomal abnormalities
4. Familial
5. Sex predominance
6. Racial incidence

Monogenic or single gene disorders
Approximately half of the recongnized syndromes associated
with cleft lip and palate are due to single gene disorders with
equal distribution between autosomal dominant and
autosomal recessive. Single gene defect may give rise to
Mendelian pattern of inheritance, either of isolated cleft lip
(palate) or in multiple malformations associated with cleft lip
with or without cleft palate.
Polygenic or multifactorial inheritance
Several genes, each with a relatively small effect, act in concert
with poorly defined environmental triggering mechanisms
leading to the expression of the abnormality. Thus, such
cases show a slight familial tendency but do not confirm to
simple Mendelian inheritance patterns.
Chromosomal abnormalities
Chromosomal abnormalities account for 18% of the clefting
syndromes and would invariably be associated with other
malformations, delayed development and poor prognosis.
Chromosomal abnormalities notably trisomy D and also less
frequently trisomy E, may cause multiple malformations
including cleft lip (palate).

Familial
Fogh-Anderson’s family studies showed that siblings of patient
with cleft lip had increased frequency of cleft lip and cleft
palate, but no increased frequency of cleft palate alone.
Siblings of patients with cleft palate had increased frequency
of cleft palate, but not CL and CP.
Sex predominance
More males are born with cleft lip and cleft palate than females
and more females than males have cleft palate alone.
Racial incidence
The incidence of cleft lip and cleft palate is greatest in the
Mongoloid population being greater than that in the Caucasian
population, which is in turn greater than in the Negroid
population. In contrast, the racial differences for cleft palate or
not significant.

Over 300 syndromes are known to have clefting of the lip or
palate as an associated feature Some of the syndromes
associated with CLP are,
• Pierre Robin syndrome
• CLP-ectodermal dysplasia syndrome (CLPED-1)
• Ectrodactyly, ectodermal dysplasia, orofacial cleft (EEC
syndrome)
In addition to syndromic CLP, progress has also been made in
elucidating the genetic mechanisms behind several
syndromic causes of isolated CP. Some of the syndromes
associated with CP are,
• Mandibulofacial dysostosis (Treacher Collins syndrome)
• Holoprosencephaly, type-3
• Stickler syndrome

CRANIOFACIAL SYNDROMES
A syndrome is recognised to represent multiple
malformations occuring in embryonically non-
contiguous areas. more than 40 syndromes known to
include malocclusion as one of their features.
Some of the syndromes with dental importance are,
 Crouzons syndrome
 Aperts syndrome
 Treacher Collins syndrome
 Pfeiffer syndrome
 Craniofacial microsomia
 Williams Syndrome

CROUZONS SYNDROME
It is a frequent form of craniofacial dysostosis.
It is characterized by multiple anomalies of the
craniofacial skeleton with an autosomal
dominance inheritance pattern
Genetic etiology:
Caused by multiple mutations in the fibroblast
growth factor receptor2 gene (FGFR2). Mutation
in Tyrosine kinase receptor, at Ig II – Ig III domain
Chromosome and region: 10q 253-q26

Clinical features:
They are limited to the head
and neck region in contrast
to other craniosynostosis
syndrome in which hand,
feet involvement or both are
common.
Forehead is often high and
prominent
There is hypertelorism,
strabismus, midface
hypoplasia, a prominent
beaked nose, high arched
palate, mandibular
prognathism and dental
malocclusion. www.indiandentalacademy.com

TREACHER COLLINS SYNDROMETREACHER COLLINS SYNDROME
Treacher collins syndrome is characterized by
bilaterally symmetrical abnormalities of structures
within the first and second branchial arches.
It is inherited as autosomal dominant trait.
Genetic etiology:
Treacher collins syndrome occurs as result of mutation
of Treacle gene (TCOF1 gene) located in
chromosome 5q 32 – q 33.1. TCOF1 encodes a
protein that is 1411 amino acids in length and has
been named ‘treacle

Clinical features:
The facial appearance is
downward slanting
palpaberal fissures,
depressed zygoma,
displastic ears and receding
chin.
Zygomatic arches may be
absent but more often are
symmetrically
underdeveloped.

WILLIAMS SYNDROME (EJO2004)
Williams syndrome is a genetic desorder caused by a
hemizygose micro deletion of chromosome
7(7q11.23) affecting multiple organ system
WS first reported by william(1961)Bverine(1962)
independently.
Clinical features are ;
Cardiac anomalies
Mental retardation
Distinctive facial features and dental abnormalities

CONCLUSION
WE ARE IN A POSITION TO PREDICT ABNORMALITIES
EVEN BEFORE ANY SYMPTOMS AND SIGNS ARISE, ENABLING
US TO EFFICIENTLY ADDRESS AND TREAT THE PROBLEM.
MORE PRECISE RESEARCH TOOLS AND METHODS
ARE REQUIRED TO IMPROVE KNOWLEDGE AND
UNDERSTANDING, WHICH IN TURN IS A PREREQUISITE TO
THE APPRECIATION OF THE POTENTIAL FOR GENETIC
AND/OR ENVIRONMENTAL MANIPULATION IN ORTHODONTIC
THERAPY.
ORTHODONTIC DIAGNOSIS AND TREATMENT
PLANNING MAY WELL TAKE ON A COMPLETELY NEW
MEANING AS WE MOVE INTO THE FUTURE OF GENETICS.

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