Genetics in Ortho
Genetics in Ortho
Genetics in Ortho
ORTHODONTICS
CONTENTS
• Introduction
• Nature versus nurture
• Basic definitions
• Heritability of dentofacial
• Structure of DNA. phenotypes
• From genes to proteins • Class II malocclusion
• Types of genetic effects and mode of • Class III malocclusion
inheritance • Hypodontia
• Regulation of gene expression • Ectopic eruption
• Signal transduction • Bilateral symmetry
• Craniofacial development • Exteral apical root
• Molecular regulation of development of resorption.
face • Craniofacial defects
• Signaling and growth factors • Cleft lip and palate
• Genetic control of craniofacial • Concepts of hereditary and
embryogenesis genetics in orthodontics
• Theories of growth control • Conclusion
• Heritability and its estimation • Bibliography
• Twin studies
• Familial study
INTRODUCTION
• Just before a cell undergoes division,the chromatin condenses to form discrete dark
staining bodies called chromosomes.
• The centromere defines primary constriction of the chromosome and divides the
chromosome into a short arm and along arm.
• It represent the smaller physical and functional units of inheritance that reside in
specific sites(loci)in the genome and are transmitted from parent to offsping.
• The genome contains the entire genetic content of a set of chromosome present
within a cell or an organism.
• The two sides are composed of sugar and phosphate components,held together by phosphodiester bond.
• Projecting from each side at regular intervals are the nitrogenous bases.
• Base projecting from one side is bound to the base from other side by weak hydrogen bonds.
• The information contained in DNA must be transported to the cytoplasm and then
used to dictate the composition of proteins.
• The DNA code is transcribed into messenger RNA,which then leaves the nucleus to be
translated into proteins.
• The type of RNA produced by the transcription process is termed messenger RNA(mRNA).
• To initiate mRNA transcription, RNA polymerase II binds to a promoter site on the DNA.
Gene Splicing
• The primary mRNA transcript is exactly complementary to the base sequence of the DNA template.
• Only after gene splicing,mature transcript move out of the nucleus into the cytoplasm.
• It interacts with molecules of tRNA which are cloverleaf-shaped RNA strands of about 80
nucleotides.
• Each tRNA molecule has a site at the 3’ end for the attachment of a specific amino acid by a covalent
bond.
• At the opposite end of the cloverleaf is a sequence of three nucleotides called the anticodon.
• The tRNA molecule picks up the aminoacid that is complementary to the anticodon sequence.
• Cytoplasmic site of protein synthesis is the ribosome,which consists of equal parts of enzymatic
proteins and ribosomal RNA(rRNA).
• The function of rRNA is to help bind mRNA and tRNA to the ribosome.
• When both the members of a pair of alleles are identical,the individual is homozygous for
that locus.
• When the two alleles at a specific locus are different,the individual is heterozygous for that
locus.
Autosomal dominant and recessive traits
• If having only one particular allele of the two alleles on a homologous pair of
autosomes(heterozygosity) is sufficient to lead to the production of the trait,the effect is
autosomal dominant.
• If production of the trait does not occur with only one particular allele of the two alleles on
an autosome,but does occur when both alleles are same(homozygosity),the effect is
autosomal recessive.
Variable expressivity
• Although in each individual the trait is present,it may vary in its severity or
expression.
• The association of two or more traits together more often than what would
be expected by chance defines a syndrome.
Environmental Modifying
factors genes
Protein
Proteins
Phenotype
Autosomal recessive traits
• Concept of gene carrier is used with autosomal recessive trait.
• Females who are heterozygous for the gene associated with the X linked
recessive phenotype may show some expression of the phenotype because
most of the genes on one of the X chromosomes in the female normally
get inactivated by a process called lyonisation.
• Polygenic term inferred the effect of multiple genes and enviromental factors on the
phenotype.
• A change in the phenotype depends on the result of the genetic and environmental
factors present at a given time.
• Gene regulation refers to the cellular control of the amount and timing of
changes in the appearance of the functional product of gene.
• Activators bind to switch a gene on and repressors bind to shut off a gene.
• Initiating the signal for gene regulation is achieved through the binding of some ligand to
a receptor.
• The receptors which are located both on the outside of the cell and on the inside of the
cell spanning the plasma membrane of the cell are called transmembrane receptors.
• Growth factors stimulate cell proliferation and differentiation by acting through specific
receptors on responsive cells.
• Growth factors play analogous roles in embryogenesis,in the immune system,and during
inflammation and wound repair.
• The early development of a primitive streak(a rapidly proliferating elongating mass of cells
in the embryonic germ disk)demarcates initial distinction of embryonic tissues.
• A gene,Lim-1,for organisation of the primitive streak and for the development of entire
head.
Craniofacial development-Geoffrey.H.Sperber.
Craniofacial development
Neural crest cells
• It is a transient component of the ectoderm,is located in between the neural tube and epidermis of
an embryo during neural tube formation.
• It is a highly pleuripotent cell population which plays critical role in the development of vertebrate
head.
• Neural crest cells migrates extensively throughout the embryo in four overlapping
domains(cephalic,trunk,sacral and cardiac).
• Ectomesenchymal neural crest cells interact with epithelial and mesodermal population present
within the arches,leading to the formation of craniofacial bone,cartilage and connective tissue.
• These structures are the frontonasal process,the medial and lateral nasal
process,the maxillary and mandibular process.
• All these facial process are covered by the ectoderm beneath which lies
mesoderm.
• Mesenchyme of the upper face comes from the neural crest cells from the
forebrain and midbrain areas while mandible from neural crest cells of
midbrain and hindbrain region.
• Growth of all these processes results from interactions between the overlying ectoderm
and underlying mesoderm.FGF-8 and Shh stimulate the growth of mesenchyme.
• The medial region of mandibular process responds to FGF-2 and FGF-4 local epithelial
signals and stimulates the growth of the underlying mesenchyme.
• These signals are mediated by bone morphogenetic proteins Bmp-4 and Bmp-7 which are
produced in the lateral regions of the mandibular process.
• Dlx-1 and Dlx-2 expressed most proximally in the mandibular process;Dlx-5 and Dlx-6
more proximal;Dlx-3 and Dlx -7 most distally.
• Genes that have a homeobox are called homeobox genes and form homeobox gene family.
• Regarded as master gene of the head and face controlling patterning,induction,programmed cell
death,and epithelial mesenchymal interaction during the development of the craniofacial complex.
Craniofacial development-Geoffrey.H.Sperber
Genetic control of craniofacial embryogenesis
• The genetic control of craniofacial embryogenesis is via Hox genes which are responsible
for controlling morphogenesis of the regions of head and neck.
• Other homeobox containing genes which are expressed in the maxillary and mandibular
arches,and developing facial primordial are Msx-1,Msx-2.Dlx1-6,and Barx-1.
• Members of the Msx gene family,esp Msx-1 and Msx-2 are predominantly expressed in
the neural crest derived mesenchyme of the developing facial prominences.
• The major difference in theories is the location at which genetic control is expressed.
• The first theory implies that genetic control is expressed directly at the level of bone;its locus should be the
periosteum
• Second or cartilage theory suggests the genetic control is expressed in cartilage while bone responds
passively being displaced
• Third theory assumes that genetic control is mediated to a large extend outside the skeletal system and that
growth of both bone and cartilage is controlled epigenetically occuring only in response to signal from other
tissues.
• The scientific study of human twins began in the 1870s when Sir Francis Galton
published articles arguing that heredity is a strong factor than environment.
• Any differences between them should be solely the result of environmental influences.
• Dizygotic twins occur when two eggs are released at the same time and fertilised by
different spermatozoa.
• They are not more similar than ordinary siblings,except that they share the same
intrauterine and family environment.
• Difficult to establish zygosity and confirm the environments is same for both members of twin pair.
• Significance
• Well done twin studies-best way to evaluate heritability.
• Using twins with siblings as controls,Hudhes et al heriditary component for variation in spacing and
tooth position within the dental arches was 69% to 89%.It was 53% for overbite and only 28%for
overjet(greater environmental component than crowding,spacing/overbite).
• Dietary changes in modern societies, with increased consumption of soft, energy-rich food, has
resulted in less interproximal wear between the teeth.
• A soft diet may also result in underdevelopment of the jaws and a lack of arch space, leading to
crowding.
• According to this hypothesis, hard diet requires vigorous mastication, stimulating the growth of
facial bones, particularly in the transverse dimension of the maxilla and mandible.
• Experimental studies have shown that dietary consistency and masticatory activity affect not
only the masticatory muscles, but also many aspects of bone growth, including bone size and
mass, internal bone structure, and craniofacial size and morphology.
Malocclusions
• A malocclusion should be regarded as a developmental condition and does not represent
a single entity.
• Although in certain cases specific factors and pathologies can be identified as the cause
of a malocclusion; in the majority, the aetiology is less clear.
• In each individual there is a close interaction between genetics and the environment
during development and growth of both the jaws and dentition; it is at this interface that
the aetiology of malocclusion lies .
• Recently, mouse studies showed that long-range transcriptional enhancers regulate the
expression of genes near and far during craniofacial development, resulting in subtle
differences in craniofacial shape.
Orthodontics Craniofacial Research 2015 April;18(01):-Genetics of the dentofacial variation in human malocclusion.
• Genes implicated in bone (TGFB3, LTBP, IGF1, ENPP1) cartilage
development (Matrilin-1 and COL2A1), muscle function
(MYO1H and DUSP6) and tooth morphogenesis (EDA, XEDAR,
and BMP2), influence jaw and tooth size discrepancies.
Orthodontics Craniofacial Research 2015 April;18(01):-Genetics of the dentofacial variation in human malocclusion.
Contemporary Orthodontics 5th edition-William.R.Proffitt.
Textbook of craniofacial growth-Sridhar Premkumar
Class III malocclusion
• Mandibular prognathism referred as Hapsburg jaw.
• Although it is said to be multifactorial, in majority of cases it appears
to have autosomal dominant inheritance with incomplete penetrance
and investigators concluded there is a major gene that influences the expression
• Class III malocclusion features affect multiple craniofacial structures, appear early in
development, worsen with age.
• A recent study in 292 Caucasian adults which accounted for 81% of the phenotypic variation
recorded.
• About 54% of the variation was explained by the anterior–posterior (AP) position of the
mandible compared to the cranial base, the size of the maxillomandibular horizontal
discrepancy, and the lower incisor AP position.
Orthodontics Craniofacial Research 2015 April;18(01):-Genetics of the dentofacial variation in human malocclusion.
• Positive correlations for mandibular prognathism include genes EPB41, MATN1,
SSX2IP, and PLXNA, Also positive associations have been found for genes COL2A1,
MYO1H, TGFB3, and LTBP2.
• Studies show that variants within DUSP6 could account for Class III malocclusion
due to maxillary hypoplasia subsequent to premature fusion of maxillary sutures.
Orthodontics Craniofacial Research 2015 April;18(01):-Genetics of the dentofacial variation in human malocclusion.
HYPODONTIA
• Occur without a family history or as a part of a syndrome.
• As food habits are more defined with change to selective pressure during chewing,there is
concominant reduction in tooth volume in the respective fields of incisors,premolars and molars.
• Therefore hypodontia involving third molars second premolars,lateral incisors are more
commonButler’s field theory.
• Palatally placed ectopic canines are an inherited trait often occuring with missing
teeth,tooth size reduction and other ectopically placed tooth.
• More males are born with cleft lip and palate and more
females have cleft palate alone.
• Genes and loci associated with oral clefts (IRF6, 8q24, SNAI1,
MSX1, ABCA4-ARHGAP29, and MAFB) were found to be associated
with normal facial variation and facial features within the cleft
phenotypic spectrum.
• Orthodontic Era(1900-1930)
• Edward angle and his followers believed in what he referred to as “nature’s plan” for
the normal function and form of the occlusal plane.
• Abnormal growth of the jaws leading to malocclusion and dentofacial deformity is not
inherited directly ,but results from abnormal function caused by ‘perverted’
behavioural habits and other external environmental conditions.
American Journal of Orthodontics and Dentofacial Orthopedics 2015 Dec 148(6):-Evolving concepts of
hereditary and genetics.
• Angle asserted that orthodontic appliances can ‘unpervert’ forces on the
developing jaw and thereby stimulate normal growth of occlusal arches.
• Calvin Case relied on accepted scientific beliefs of the time about hereditary to
assert that the skeletal structures of the face and occlusal arches are inherited in
the final size and form through what he referred as biologic laws-meant Darwin’s
concept of pangenesis.
• American Journal of Orthodontics and Dentofacial Orthopedics 2015 Dec 148(6):-Evolving concepts of hereditary and
genetics.
Hereditary versus environment era(1930-1970)
• M.F Guyer provided the first discussion of Mendalian inheritance and use of the term
“genetics” in the AJO-DO in 1924.
• Theoretic basis for increased interest in the principles of hereditary and their potential
relevance for understanding malocclusion was summarized by Salzmann.
• Virtually all of these studies tended to support hereditary determines the size and shape
of the jaws in both normal and abnormal development and growth
American Journal of Orthodontics and Dentofacial Orthopedics 2015 Dec 148(6):-Evolving concepts of hereditary
and genetics.
• By 1940s,hereditary factors are considered first in importance and local
environmental fators second in the process of growth and development.
Heritability era(1970-2000)
• The National Institute of Dental Research organised 2 workshops to review
the contemporary status of orthodontic research on the role of genetics in
malocclusion and occlusal variation.
American Journal of Orthodontics and Dentofacial Orthopedics 2015 Dec 148(6):-Evolving concepts of
hereditary and genetics.
• By mid 1980s,significant methodological problems in contemporary studies of
heritability overall had become apparent to several researchers.
• The greatest progress took place in the identification of the genes for
craniofacial dysmorphologies,including growth factors and transcription
factors controlling morphogenesis and growth of craniofacial
tissues,candidate gene for midfacial deformities and genes affecting growth
of the condylar cartilage of the mandible both normally and during
treatment.
American Journal of Orthodontics and Dentofacial Orthopedics 2015 Dec 148(6):-Evolving concepts of
hereditary and genetics.
CONCLUSION
• The interactions of genetic and environmental factors may account for the variability in expression of
malocclusion.
• The etiological complexity lies not only in unpredictable expression, but also in the wide spectrum of
dentofacial variation present in affected individuals.
• This complexity explains in part why most treatment approaches for malocclusion are directed to the
symptoms rather than to etiology.
• However, despite this complexity, the study of malocclusion etiology is fundamental to understanding
the biology underlying craniofacial growth and dental relations.
• Understanding the biology will aid progress toward effective treatment, prevention, thereby
decreasing the burden of this condition
Orthodontics Craniofacial Research 2015 April 18(01):-Genetics of the dentofacial variation in human
malocclusion.
American Journal of Orthodontics and Dentofacial Orthopedics 2015 Dec 148(6):-Evolving concepts of
hereditary and genetics.
Craniofacial development-Geoffrey.H.Sperber