Genetics and Heredity / Orthodontic Courses by Indian Dental Academy

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CONTENTS
Introduction
History
Principles of genetics
Molecular basis and biology of
genetics
Tools for molecular biology
Human genome project
Modes of inheritance
Genetic abnormalities
Genetic risk assessment
Genetic counseling
Bioethics
Conclusion
References

Genetics:
The branch of science concerned with
the means and consequences of
transmission and generation of the
components of biological inheritance .
Heredity :
The transmission of characters from
parent to offspring by information
encoded in the parental germ cells .
HISTORY
Gregor Mendel is considered
the Father of genetics. He
selected seven contrasting
character in garden peas. He
enunciated the principles of
heredity :
1.The law of uniformity.
2.The law of segregation of
alleles.
3.The law of independent
assortment.

Galton (1875) initiated
the idea of polygenic
inheritance.
Garrod (1902)
Landsteiner[1900]
discovered ABO blood
groups.
Hardy and Weinberg
population genetics.
Watson and crick
Discovered the double
helix model of DNA

Principles of genetics

Chromosomes and DNA replication
1. Organization of DNA into chromosomes .
Human genome
Principle :Method of things operation.
The ultimate source, origin or cause of something.

2.Replication of DNA and mitosis
3. Assortment and segregation of genes
during meiosis.

Regulation of gene expression

Transcription
Post transcriptional modifications
m-RNA processing
Translation
Post translational modifications

Cloning, nucleic acid hybridization and
DNA sequencing
Cloning : creation of a recombinant DNA
molecule that can be propagated indefinitely.

Nucleic acid hybridization : It is a
fundamental principle in molecular biology that
takes advantage of the fact that the two
complementary strands of nucleic acid bind or
hybridize to one another with very high
specificity.
DNA sequencing : A chemical process
known as dideoxy-sequencing allows the
identification of the exact nucleotide sequence
of a piece of DNA.
Mutations : A mutation can be defined as any change
in the primary nucleotide sequence of DNA regardless
of its functional consequences.

Point mutations : Involve single nucleotides.
Transitions : Substitutions, if a purine is replaced
by another purine.
Transversions : Changes from purine to
pyramidine or vice versa.
Missense mutation : DNA sequence change
occurs in coding region and alters an amino acid.

Molecular basis and biology of
genetics
DNA structure and function :
DNA is made up of deoxyribose-
phosphate backbone and a series of
purine: adenine (A) and guanine (G)
pyrimidine: thymidine (T) and cystine (C)
bases of nucleic acid.
Complementarity allows the transmission of
genetic information from DNA RNA protein.

It is possible to arrange the 4 bases into 64
different triplet codons (4
3
). By arranging the
codons in different combinations and in various
lengths, it is possible to generate the tremendous
diversity of primary protein structure.

Nucleoside: a compound of a sugar with a
purine or pyramidine base by way of an
N glycosyl link.

Nucleotide: a combination of a purine or
pyramidine, one sugar and a phosphate
group.

Genes
A gene is a portion of DNA that contains the
codes for polypeptide sequence.
Genes vary greatly in size : most of them
extend over 20-40 kbp.
Exons : portion of genes that are eventually spliced
together to form mRNA.
Introns : spacing regions between the exons that
are spliced out of precursor RNAs during RNA
processing.
The regulatory regions in genes most commonly
involve sequences upstream (5) of the transcription
start site. The upstream regulatory genes are also
referred to as promoters.

Transcriptional termination signals reside down
stream (3) of a gene.

5 3
Direction of transcription of genetic information

Key regulatory elements. Eg. globin and
immunoglobin genes

Chromosomes :

Higher eukaryotes have their
genomic packages
chromosomes, separated from
the general cytoplasm by
nuclear envelope.
histones.
Heterochromatin : These regions
tend to be super coiled around
histones in condensed regions.
Euchromatin : Most the DNA
regions, those coding for
proteins are relatively
uncondensed during interphase
and constitute the euchromatin.
Transcription and
translation
Transcription
Post transcription
modification
m-RNA processing
Translation
Post translation
modification
Stop codons :
UAA,UAG,UGA
Transcriptional control
Translation
Tools for molecular biology
1) Restriction enzymes :
Genomic DNA can be cut into a number of
fragments by enzymes called restriction
enzymes which are obtained from bacteria.
Eg. : Enzyme EcoRI.
2) Gel electrophoresis :
As DNA is negatively charged molecule, the
genomic DNA that has been digested with a
restriction enzyme can be separated
according to size and charge by
electrophoresing DNA through gel
matrix.
Pulsed field gel electrophoresis.
3) Southern blotting and DNA probes :
Southern blotting allows the visualization
of individual DNA fragments.
DNA probes are useful to indicate where
the fragment of interest lies.
4) Northern blotting and western
blotting :
Northern blotting is used to visualize RNA
fragments on to membrane.
Western blotting is used to visualize
proteins.
Southern
blotting
and
DNA probes.
5) Polymerase
chain reaction :

Minute amounts of
DNA can be
amplified over a
million times within
a few hours using
this invitro
technique
6) DNA cloning
Recombinant
DNA technique,
showing
incorporation of
foreign DNA into
plasmid.
Ampicillin
resistant genes
can be used to
distinguish
transformed E.
coli cells
7) DNA libraries
These are pools of isolated and cloned DNA
sequences that form a permanent resource for
further experiments.

2 types of libraries :
Genomic libraries -contains almost every
sequence in the genome.
cDNA libraries - contain sequences
derived from all mRNAs expressed in that
tissue.

8) DNA sequencing :
Used to identify the exact nucleotide sequence
of a piece of DNA.
The human genome project :

The HGP was initiated in the mid
1980s to characterize the human
genome, culminating in a
complete DNA sequence.
Main goals of HGP include :
Creation of genetic maps
Development of physical maps
Determination of the complete
human DNA sequence.
Genetic map
Physical map
HGP was completed in June
2000.
Modes of inheritance :

An inherited trait may depend on a single gene pair
or on the cumulative effect of a large number of
genes.
The former is called Mendelian or unit factor
inheritance. The latter is called polygenic inheritance.
Mendelian inheritance
Autosomal inheritance
Autosomal dominant
Autosomal recessive
When the two members of an allelic pair are
identical, they are said to be homozygous and when
they are unlike each other the combination is said
to be heterozygous.
A trait is said to constitute the phenotype of an
individual, while the allelic pair of genes determining
the trait constitute the genotype for that trait.
Sex-linked inheritance :
Inheritance through the genes carried on sex
chromosomes X and Y.
X-linked inheritance :
A male has only one representative of any X-linked
gene a hence is said to be hemizygous rather than
homozygous or heterozygous.
X-linked recessive : eg. Hemophilia.
X-linked dominant. Eg. Vit. D Resistant rickets, Xg
blood group.
Y-linked inheritance :
holandric inheritance (because only in males)
Eg. Hairy ears.
Polygenic inheritance (multifactorial)
GENETIC ABNORMALITIES

Cherubism :
Occurs as an autosomal dominant disorder
and with 100% penetrance in males and 50
to 75% penetrance in females, with 2:1 male
predominance.
Marked fullness of the jaws.
Ectopic eruption, severe malocclusion.

Permanent teeth may be missing or
malformed as the developing tooth follicles are
displaced.
Osteogenesis imperfecta :
Caused by mutations that cause a quantitative
defect in production of type I collagen.
OI is the probably the most common inherited
bone disease.
OI type I : autosomal dominant, most common.
OI type II : autosomal recessive, most severe.
OI type III : both AD and AR.
OI type IV : AD.
Classically this condition includes fragile
bones, blue sclerae, ligamentous laxity, hearing
loss and dentinogenesis imperfecta.
Primary teeth are more severely affected than
the permanent teeth.
Crowns are described as shortened and bell
shaped with cervical constriction.
Cleidocranial dysplasia :

Inherited as AD with high penetrance with wide
variability in expression.
A gene for this disorder has
been mapped to
chromosome 6p21.
Maxillary hypoplasia gives the mandible a
relatively prognathic appearance.
Palate is narrow and high arched.
Increased incidence of submucosal clefts and
complete or partial clefts of the palate involving the
hard and soft tissues.
Non union of symphysis of mandible.
Unerupted supernumerary teeth.
Crouzons syndrome
(Craniofacial dysostosis) :

AD with complete penetrance and variable
expressivity.
Mutation in the fibroblast growth factor receptor
2 gene (FGFR2) which maps to chromosome
10q25-q26, cause this syndrome.
Shallow orbits are the most common feature.
Frog like facies. Midface hypoplasia and
exopthalmos are striking.
Mandibular prognathism with nose resembling
parrots beak.
Maxillary hypoplasia, high arched palate.
Bilateral posterior lingual cross bites.
Anterior open bite.
Treacher Collins syndrome
(mandibulofacial dysostosis) :
AD with high degree of penetrance but variable
expressivity.
Mutation in a gene of unknown function referred to
as treacle which maps for 5q 32 33.1 are
responsible.
Facial appearance is characteristic and is often
described as bird like or fish like.
Includes various degrees of hypoplasia of the
mandible, maxilla, zygomatic process of
temporal bone, external and middle ear.
Oral finding include cleft palate, macrostomia,
high arched palate, dental malocclusion
consisting of apertognathia and widely
separated and displaced teeth.
The peculiar broad and concave nature of the
inferior border of the mandible is characteristic.

Pierre Robin syndrome :

Fetal malposition and interposition of the tongue
between the palatal shelves is probable etiology.
Severe micrognathia and mandibular hypoplasia.
U shaped cleft palate is common.
Glossoptosis
High arched palate sometimes.
Down syndrome
(Trisomy 21) :

Incidence 1 in 600-700.
Most cases of trisomy 21 are caused by non
disjunction, resulting in an extra chromosome.
Skull is brachycephalic with flat occiput and
prominent forehead.
Frontal, sphenoid sinuses absent and maxillary
sinus is hypoplastic.
Fissured tongue, Macroglossia.
Open mouth posture
Palatal width and length are significantly
decreased, bifid uvula, cleft lip and palate.
Delayed eruptions, hypodontia, microdontia,
crown root malformations.
Occlusal disharmonies, posterior crossbites,
apertognathia, severe anterior teeth crowding.
Hemifacial atrophy :

Progressive unilateral atrophy of the face.
Tongue, lips and salivary glands may show
hemiatrophy.
Developing teeth may show incomplete root
development and delayed eruption.
Cleft lip and palate :

Majority of cases of cleft lip or cleft palate or both
can be explained by the multifactorial threshold
hypothesis (polygenic inheritance).
Abnormalities of tooth number, size, morphology,
calcification and eruption.
Prevalence of hypodontia increase with severity.
Tooth formation often delayed and enamel
hypoplasia, microdontia or macrodontia and fused
teeth are seen frequently.
Macroglossia :

Down syndrome
Hunter syndrome
Hurler syndrome
Maroteaux lamy
syndrome
Microglossia :

Oromandibular
limb hypogenesis
spectrum.
Moebius
sequence.
Freeman Sheldon
syndrome
Amelogenesis imperfecta :

AI represents a group of hereditary defects of
enamel unassociated with any other generalized
defects.
Types :
Hypoplastic mainly AD.
Hypocalcified AD & AR.
Hypomaturation AD & AR.
Dentinogenesis imperfecta :

The association between
DI and OI is well
recognized although each
condition may occur
independently
Type I AD generally.
Both DI and OI present
Type II Never occurs
with OI. Autosomal
dominant.
Type III Brandywine
type. Same clinical
appearance of teeth as
types 1 and 2 but it may
also show multiple pulp
exposures in deciduous
teeth.
Genetic risk assessment :
One of the most important aspects of genetic
counseling is the provision of a risk figure.

Probability / probability of recurrence (P) :
Probability of an outcome can be defined as the
number or more correctly, the proportion of times it
occurs in a large series of events.

Probability is indicated as a proportion of 1.

Probability theory :
Laws of addition and multiplication

Bayes theorem :
It provides a very valuable method
for determining the overall probability
of an event or outcome, such as carrier
status by considering all initial
possibilities, eg. carrier or non carrier
and then modifying or conditioning
these by incorporating information.

Anterior information

Prior probability

Posterior
information

Conditional
probability

Joint probability

Relative
probability
Risks in multifactorial disorders :

One of the basic principles in the
multifactorial inheritance is that the risk of
recurrence in first degree relatives, siblings and
offspring, equals the square root of incidence
of the disease in the general population i.e. P
1/2
where P equals the general population
incidence.
The theoretical risks for 2nd and 3rd degree
relatives can be shown to approximate to P
3/4

and P
7/8
respectively.
Genetic counseling:
Patients with a great variety of diseases
and syndromes are now referred for
evaluation and counseling.
Genetic evaluation and counseling has
become team affair.
The traditional role of counselor is to
estimate P, the probability of recurrence.
Family physician is the most appropriate
person to do the counseling because he
know the family, its attitudes and
socioeconomic background better than a
consultant.
Evaluation of the patient :

The genetic evaluation of the family begins well before the
genetic counseling process.

Does the patient have a disease of clearly non genetic
origin, such as infection or birth trauma ?
Does the baby have a disease of clear genetic etiology,
such as haemophilia ?
If the patients disorder doesn't fall into either of the above
categories, does the patient have features that suggest a
syndrome ?
When a syndrome cannot be identified, one must consider
what further investigations are necessary. Is examination
of the chromosomes indicated ?
In any case, the family history should be screened for
clues to the possible genetic basis for babys problem.
Genetic counseling Aims :

Obtaining a full and careful history.
Establishing an accurate diagnosis.
Drawing a family free is essential.
Estimating the risk of a future
pregnancy being affected of carrying a
disorder.
Information giving
Continued support and follow up.
Genetic screening includes prenatal
diagnosis, carrier detection.
Bioethics in genetics
In no other area of biomedical research there
has been a greater concern for ethical issues
than in the field of human genetics.
Serious issues related to the participation of
human subjects in genetic research are raised
particularly when the intervention involves
rights of human embryo and subjects who are
not competent to give informed consent.
Recent experiments on cloning sheep and
mice have brought human cloning into the
realm of possibility, raising additional set of
ethical legal and social issues.
General guidelines :

Clinical research besides being subject to general
ethical considerations of protection from harm and
voluntaries of participation has following addition
considerations:
The harm may not only be physical but also
psychosocial.
Maintaining confidentially of research findings.
Genetic counseling is akin to therapy. Written
explanation about presentation and natural courses
of disease, interventions, etc has special place in
clinical research.
Genetic manipulations have consequences for
future, some of which are unknown. Hence, greater
care towards potential dangers is necessary.
Institutional ethical committee.
Prenatal diagnostic techniques act 1994.
Ethical issues :
Pedigree studies
Genetic screening :
Screened subjects are entitled to receive information in
a way that :
They can understand what is proposed to be
done.
They must be made aware of any substantial risk.
They must be given time to decide whether or not
they would like to participate or not.
Therapeutic trials including gene therapy :
Recombinant protein products
Gene therapy
Somatic cell gene therapy
Germ line therapy
Gene therapy for enhancing characters.
Eugenic genetic engineering.
DNA banking
DNA diagnosis
Pre morbid diagnosis in children.
Pre morbid diagnosis in adults.
DNA diagnosis in forensics.
Prenatal diagnosis
Assisted reproductive techniques
Cloning : Since its safety, success,
utility and ethical acceptability is not
yet established, research on cloning
with intent to produce an identical
human being as of today is prohibited.

REFERENCES :
Emerys elements of medical genetics.
Robert F. Mueller, Ian D. Young.
11th edition.

Kumar and Clark Clinical medicine.
Praveen Kumar
Michael Clark
5th edition.
Harrisons Principles of internal
medicine.
Volume 1, 5th edition.
Medical genetics
- Jorde, Carey
- 5
th
edition
Essentials of Human genetics
-Bhatnagar, Kothari, Mehta


Text book of oral pathology
- Shafer
- 4
th
edition

Indian council of medical research.
API textbook of medicine.
Siddharth N. Shah
7th edition.
Smiths Recognizable patterns of
human malformation.
Kenneth Lyons Jones.
5th edition.

Oral pathology Regezi and Sciubba.
- Clinical pathologic
correlations.
- 3rd edition.
Next seminar is by
Dr.Bhuvaneshwari
on
Hinge axis

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