Genetics - Seminar

8/6/2019 Genetics - Seminar

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G E N E T I C S

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.

DEVELOPMENT OF GENETICS:-

LAMARCK: Inheritance of acquired characteristics.

DARWIN: Origin of the species (1859).- Natural selection.- Survival of the fittest.

M ENDEL : Experiments on garden pea (1865) (Pisum Satium).F1 - 1 st filial generation.

F2 - Second generation, after self pollination of F 1.

Dominant and recessive characters.F2 - 3:1; no transitional forms.F3 - 1:2:1.

P UNNETT’S SQUARE: Male Genetics

T t

T TT TtFemale Genetics

t Tt tt

Parent Genetics Tt x TtProgeny

T t T t

TT Tt Tt tt TT Tt Tt tt1 : 2 : 1

3tall : 1 dwarf.

Homozygous : TTHetozygous : Tt

Dominant: character which is manifested. (T)Recessive : Character which is not manifested. (t)

Alleles: (Allelo Morphs)Genes responsible for contrasting characters.



Eg: - T and t

Genotype : Genetic constitution of an individual.

Phenotype: Appearance of an individual resulting from interaction of environment on genotype.

Three Laws:1. UNIT INHERITANCE:

Characteristics of the parents, though they might not be expressed in the first-gen.offspring, could reappear quite unchanged in a later generation.

2. SEGREGATION:The 2 members of a single pair of genes are never found in the same gamete, but always

segregate and pass to different gametes.

3. INDEPENDANT ASSORTMENT:There is random recombination of the paternal and maternal chromosomes in the

gametes.

CHROMOSOMAL THEORY OF INHERITANCE : 1903 Walter S.Sutton and Theodor Soveri.

DROSOPHILA : Fruit fly (1905).- Can be bred in the lab with case.- Female produces thousands of eggs in her life time; 20-25 generations 1 year.- Drosophila Melanogaster, has only 4 pairs of chromosomes, each pair with a distinctive

appearance.- Chromosomes in salivary glands of larvae are 100 times larger than those in other cells.

GARROD: 1901

- Inborn errors of metabolism.- Biochemical genetics.

“ One gene – one enzyme” hypothesis - Beadle and Tatum (1941).

CLASSIFICATION OF GENETIC DISORDERS:1. SINGLE – GENE DISORDERS:-

- Mutant Genes. (1 Chromosome of a pair or both chromosomes).- Rare, 1 in 2000 Pedigree pattern.

2. CHROMOSOME DISORDERS:-- Excess or deficiency of whole chromosome or chromosome segments.

Eg: Down’s Syndrome. (Chr. 21).- Common, 7 per 1000.

3. MULTIFACTORIAL INHERITANCE:- Combination of small variations, producing a serious defect.- Environmental factors.- No pedigree, but recur in families.

INDICATIONS FOR GENETIC ETIOLOGY: (NEEL AND SCHULL – 1954).- Occurrence of the disease in definite proportions in individuals related by descent, when

environmental causes can be ruled out.- Failure to appear in unrelated lines (Spouses, in-laws).



- Characteristic onset age and course in the absence of known precipitation factors.- Greater concordance in monozygotic than dizygotic twins.- Presence in the patient of a characteristic phenotype, incl. mental retardation, and a

demonstrable chromosomal abnormality with or without family history.

CHROMOSOMAL BASIS OF HEREDITY:-Karyotype- Chromosome constitution with respect to number and morphology.Locus – Position of the gene on the chromosome.LINKED OR SYNTENIC GENES: Genes, having their loci on the same chromosome.GENOME: fULL dna CONTENT OF THE CHROMOSOME SET.ALLELES:GENOTYPE;PHENOTYPE:HUMANS: 46 chromosomes; 23 pairs, 22 autosomes, 1 pair sex chromosomes.Diploid : Somatic cells: 2nHaploid: Ganetics : n.

CHROMOSOME:

- Metacentric- Submetacentric

Diagram - Acrocentric- Telocentric

Denver classification - 1960. 7 Chromosome groups : A to G Karyotyping.

Staining Methods:Q banding: Quinacrine mustard staining, under fluorescence microscopy. Bright + dim bands.

G banding: Trypsin – denatures protein.Giemsa staining.Dark + Light banding.

R banding: Heat pretreatment.Then Giemsa staining. dark and light bands, reverse of G and Q bands.

C banding: Centromere + Constitutive heterochromatin – secondary constriction and distalsegment of long arm of the Y chromosme.

NOR Staining: Ammoniacal silver, stains meucleolar organizing regions – stalks of satellites.

Diagram

MEDICAL APPLICATIONS OF CHROMOSOME ANALYSIS:1. Clinical Diagnosis.2. Linkage and Mapping.3. Polymorphisms.4. Chromosomes and Neoplasia.5. Reproductive Problems.6. Prenatal Diagnosis.



STRUCTURE OF HUMAN CLOBIN GENE:-Diagram

TRANSCRIPTION AND TRANSLATION:-The process, whereby information is transmitted from DNA to messenger RNA is called

transcription.

Diagram

The process by which m RNA is translated into protein in co-operation with tRNA iscalled translation.Diagram

FINE STRUCTURE OF CHROMOSOMES:Diagram

Three types of chromatin:- Euchromatin- Centromeric heterochromatin- Intercalary heterochromatin.

RECOMBINANAT DNA TECHNOLOGY:Analysis of specific sequences of DNA by cutting DNA at specific sites.

- Restriction endonucleases in bacteria.It is a nucleic acid-clearing enzyme that acts upon DNA, cutting it into fraqments

at a specific sequence (restriction site).

Methods for sequencing DNA fragments by using restriction endonucleases – Walter Gilbert and Frederick Sanger (1980)

Principles (Steps):-- Restriction enzyme cutting – DNA fragments.- Recombination/Incorporation into suitable vector.- Transformation of a host organism (E.Coli)- cloming of host in culture medium/- Selection of clones with relevant DNA fragment.

Vectors:Carrier of the foreign DNA fragment.1. Plasmids:-

circular chromosomal elements in bacteria that replicate independantly of the bacterial chromosome. Carry restriction sites.Resistance to particular antibioties.

- Bacteriophages:- Viruses which infect bacteria.



- Cosmid:- A plasmid which has only he minimum vectr DNA present to allowinsertion of largest possible foreign DNA fragment.

Southern blatting:- Edwin Southern (1975)Analysis of DNA cleaved by restriction enzymes.

- Radioactive labelled probe.Diagram

RESTRICTION FRAGMENT LENGTH POLYMORPHISMS (RFLP S)Sites at which DNA fragment was altered so that cleavage was no longer possible.

- RFLP S/ RFLV S/DNA markers.- Inherited as mendelian codominant markers.- Uses:- Human gene mapping, Analysis of genetic disorders, prenatal diagnosis

preclinical identification.

MUTATION:-Change in the sequence of genomic DNA.1. Single base substitutions:- Point mutation.2. Deletions3. Insertions- Chain termination mutations:- Terminal coden mutation.- Splice mutations:- Change in excision of introns and splicing of exons.- Mutations in regulatory sequences:- Change in DNA sequence in CAT box

and/or TATA box. Reduced transcription.

DiagramCHROMOSOMAL ABERRATIONS

Classification:-- Numerical or structural- Only autosomes, sex chromosomes or both.- all body cells involved, or two or more cell lines, one or more of which are

abnormal (mosaicism).

I ABERRATIONS OF CHROMOSOMENUMBER:-

Processes involved:-- Non disjunction:- Failure of paired chromosomes or sister chromatids to disjoin

at anaphase either in mitosis or meiosis I or II.- Anaphase lag:- In anaphase of mitosis, when one or both daughter chromosomes

lag behind and fail to reach either pole.1. Euploidy:-

2n = 46n = 23.

Any no. that is an exact multiple of n.3n = triploid – failure of maturn division in gametes



4n = tetraploid – failure of cleavage division in 3yqote.

- POLYPLOIDY:-3n,4n, Nos. greater than 2n.

-ANEUPLOIDY:-Any no not an exact multiple of n.2n + 1 :- trisomic (down’s syn)2n – 1 :- Monosomic2n + 1 + 1 :- double trisomic, 2 different additional chromosomes.

-HETEOPLOID:-Including euplaid aneuploid. Any no that deviates from n and 2n.Diagram

II. ABERRATIONSOF CHROMOSOME STRUCTURE:-Clastogens (breaking agents):- Ionizing radiations- Viral infections.- Chemicals.- Stable or instable- Stable types of aberrations:-

Pass unaltered through cell divisions.1. DELETION:-Diagram

2. DUPLICATIONS:-Sister chromatid exchange at X forms double sized dicentrix ring in mitosis.

3. INVERSION:-- Paracentric :- Beside centromere.- Pericentric :- Around the centromere.

Paracentric PericentricDiagram

4. TRANSLOCATION- Reciprocal:-

Exchange of blocks of chromatin between 2 nonhmologous chromosomes.- Robertsonian:-

2 acrocentric chromosomes which fuse at centromere and lose their heterochromatic short arms.

- Insertion:- rare non reciprocal translocation.three breaks.



Segment removed from, chromosome, inserted into broken region of non-homologous chromosome.

Insochromosmes:Division of centromere of chromosome – sequarates 2 arms rather than chromatics.

Diagram

Mosaicism:-If non disjunction occurs at an early cleavage division of the zygote rather thangametogenesis, an individual with 2 or more cell lines with different chromosome nos. is

produced.

Mosaics:2 cell lines with different karyotypes, derived from a single zygote.

Causes of aberrations:-- Late maternal age.- Genes predisposing to non disjunction- Autoimmune disease- Radiation- Viruses, teratogens.- Chromosomal abnormality.

PATTERNS OF SINGLE GENE INHERITANCE:4 basic paterns:-

Dominant DominantAutosomal X-linked

Recessive Recessive.

AUTOSOMAL INHERITANCE:-

- Autosomal Dominant:- Criteria:-

1. The trait appears in every generation with no skipping.Exception:- New mutant failure of penetrations, variability of expression.

2. Any child of affected person has 50% risk of inheriting the trait.3. Unaffected family members do not. tranomit the trait. exception: failure of

penetration.4. The occurrence and transmission are not influenced by sex.

Co dominance – Both alleies of a pair are fully expressed in heterozygotes.Intermediate inheritance – eterozygate is different from both homozygotes. Reducedseverity.



Multiple alleles:- When, at a single locus, more than 2 alternative alleles exist in a population they are called multiple alleles.

AUTOSOMAL RECESSIVE INHERITANCE:- Expressed only in homozygotes, who have received the recessive gene from both

parents.- Already, affected child has to be presentin the family for study.- Consanguineous marriages- Genetic isolates.

Criteria:-1. Trait characteristically appears only in sibs, not in their parents, off springs or

other relatives.2. On average, 1/4 th of the sibs of proband are affected.3. Parents of affected child may be consanguineous4. Males and females are equally likely to be affected.

X-LINKED INHERITANCE:-

X-linked – holandric inheritance.

X-LINKED RECESSIVE INHERITANCE:- Expressed by all males who carry the gene, but only by homogygous females.

Criteria:-1. Incidence is higher in males than in females.2. Trait is passed from an affected man, through all his daughters to on average, half

their sons.3. trait is transmitted three carrier females.4. Carriers show variable expression of trait.

X-LINKED DOMINANT INHERITANCE:--Twice as common in females than males.Criteia:-

1. Affected males have no normal daughters and no affected sons.2. Affected heterozygons females transmit the condition to half their children of

either sex/ Affected homozygons females transmit it to all their children.3. Affected females are more common, but have variable expression; heterozygotes.

VARIATION IN GENE EXPRESSION;-- PENETRANCE AND EXPRESSIVITY;-Penetrance – Gene’s likelihood to being expressed at all.Expressivity – Degree of expression (mild, moderate severe). (Reduced, penetrance) (Variableexpressively)- PLEIOTROPY:One gene, more than one effect, gene- polypeptide synthesis - many consequences.Multiple phenotypic effects produced by a single gene or gene pair mutation.

Genetic haterogenety:-Several genes, one effect.



Mutations at different loci or different mutations at same locus, independantly producing thesame trait or traits that are difficult to distinguish clinically.

- Anticipation: -Apparent worsening and earlier onset age of a disease in successive generations.

- Gene interaction:-o Interaction of allelic genes.o Interaction of non-allelic genes.o Genetic background.

MULTIFACTORIAL INHERITANCE

A multifactorial trait is defined as one that is determined by a combination of factors,genetic and possibly also non genetic, each with only a minor effect.

Eg:- - Stature.- Total fingerprint ridge count- Intelligence.

Correlation Co-efficient:- Inheritance in families.Genes in common: - Genes inherited from a common ancestral source.

Relatives:- 1 st degree, 2 nd degree.

Heritability:-Proportion of total phenotypic variance of a trait that is caused by additive geneticvariance.

Contribution of additive genetic factors-G.

Contribution of environment within the family – BContribution of random environmental factors – E

Heritability (h 2) = GG+B+E

THRESHOLD TRAITS:- Normal and abnormal separated by threshold.

Criteria for multifactorial inheritance:-- Correlation between relatives is proportional to the genes in common.

- If mating is random, environmental differences are unimportant and if genes areadditive, mean for offspring is midway between parental value and populationmean.

- If a threshold trait is more frequent in one sex than the other, recurrence risk ishigher for relatives of patients of the less susceptible sex.

- Population frequency = P, risk for 1 st deg. relative is √P. Lower the P, greater therelative increase in risk for sibs.

- Recurrence risk is higher when more than one member of family is affected.



- Increase severity, increase recurrence risk.- Risk to relatives is lower for 2 nd degree than 1 st degree relatives.- Concordance rate in MZ and DZ twins:-

MZ > twice of DZ ≠ simple dominantMZ > twice times of DZ # simple recessive.

- Multifactorial.- Parental consanguinity – multiple factors with additive effects, if recessiveinheritance can be ruled out.

LINKAGE AND MAPPING:-Genes on same chromosome – Systemic Gene close together on the same chromosometend to be inherited together – linked.

A B in couplingA b in repulsion.

Detection: - Observing simultaneous transmission of non-allelic genes through successivegenerations of families.

GENE MAPPING:- Actual assignment of genes to specific chromosomal locations.- Family studies- Chromosome analysis- Somatic cell studies- Molecular technology- Recombinant DNA- Trisomy mapping



RECENT ADVANCES IN GENETICS AND MOLECULAR BIOLOGY:

CRANOFACIAL DEVELOPMENT IN THE EMBRYO:-

MALOCCLUSION

Genetic Epigenetic

Population studies:- Family and twin studiesGenetic factors - Etiology of malocclusion.Environmental factors – Differences between parents and children, siblings, monozygotictwins.

Facial development in the embryo:-Prechordal plate- 14 th day of 1.4.life cranial end of embryo.

Neural crest cells – ectomesenchymal cells.Interaction with extra-cellular matrix and adjacent epithelia – neural, skeletal connectivetisue.

Neural crest cell migration and localization in bronchial arches:-Craniofacial morphogenesis and patterning – HOMEOBOX GENES.

CELL ADHESION MOLECULES:-- Cadherins- Integrins Glycoproteins on external surface of cell- Immunoglobulins membranes.- Proteoglycans

Cell adhesion molecules;-Role in embryo genesis:-

- Migration of cells by attachment to one another.- Elevation of palatal shelves (syndecan)- Fusion of palatal shelves – N cadherin (nasal, oral epithelium and mesenchyme).- Tooth formation Lbud, cap stage interaction of epithelium and mesenchyme)

Syndecan.

HOMEOBOX GENES:-Genes, which are highly conserved thoughout evolutionof diverse organisms.

Homeobox - A 60 – amino acid encoding DNA sequence; specific regionof 180nucleotide base pairs in all genes.Amino acid sequence – homeodomain.

First studied in Drosophila melanogaster.



Homeosis - Bateson(Genetirist)Body parts are transformed into indetifiable but inappropriate structures. Homeotictransformation in Drosophila. Groups of genes were identified, involved in normalspecification of regional identity within the Drosophila embryo.

Assign distinct spatial identities to cells in diff. regions along the fly’s AP aris.

Homeobox genes - Regulatory genes.- Homeobox containing genes encode DNA binding proteins that regulate gene

expression and control various aspects of morphogenesis and cell differentiation.- Control the function of other genes by either up regulating or down regulating

their expression; by a regulatory gene product – protein with a specific DNA binding activity.

- Alteration of MRNA expression or transcriptional activity.- Recombinant DNA – probes.- Hox Genes :- Best studied homeobox genes – clustered homeobox gene.

o

Expressed along AP axis, with segmental differences in their expression.o Transmitted to corresponding arches by neural crest cell migration. Non Hox Genes:- Scattered throughout genome.Hox genes - Hox A, Hox B, Hox C, Hox D – Clusters on diff. chromosomes.Spatial colinearity – within each cluster, the gene sequence along the chromosome is inthe same order as their expression along the long axis of the embryo.

DiagramHox Genes in craniofacial development:-Msx 1,2 - Muscle Segment.D1x – distal less

Otx – orthodonticalGsc – GoosecoidShn - sonic hedgehog.

Hox genes – proteins – RNA transcription factors – malecular events in morphogenesis – other genes – genes (on loff).

Regulatory proteins:-- Growth factor family- Steroid / Hyroid/Retinoic acid super family.

Functions of Hox genes-- H,F patterning- Induction- Programmed cell death- Epitherial mesenchymal interaction.

Regulatory malecules in the mesenclyme:-- Fibablast growth factor (FGF)



- Epidermal Growth Factor (EGF)- Transforming growth factor and α (TGF α )- Transforming growth factors β (TGF β )- Bone morphogenetics proteins (BMP)

Vehicles through which homeobox gene information is expressed in Co-ordination of cellmigration and subsequent cell interactions.

BRANCHIAL HOX CODE

Hox Genes in craniofacial development:-Msx 1,2 – Muscle segment.D1x – distal lessOtx – OrthodonticalGSC - Goosecoid

Shn – Sonic hedgehog.

Hox genes – proteins – RNA transcription factors.

Molecular events in morphogenesis other genes genes (on/off)

Regulatory proteins:-- Growth factor family- Steriod/Thyroid/Retinoic acid super family.

Function of Hox genes.

- H,F, patterning- Induction- Programmed cell death- Epithelial mesenchymal interaction.

Molecular genetics in oral and Cranio facial dysmorphology:-

Animal studies:-- Hemofacial microsomia – neural crest involvement.- Treacher Collins syndrome – Ratinoic acid administration.- Craniosynostosis- Apart, crouzon syndromes - Mutation in fibralorast growth factor (FGF) genes.- Clsidocronical dysplasia- Tooth development:-

Msx-1 and Msx –2 – epithelial mesendrymal interaction.o Tooth morpliogenesis.o Developmental position.o Dentinogensis.



- Clidocranial dysostosis.

Hyperdontia (supernumerary teeth):- No simple mendelian inheritance. But seen in twins.

- Ectodermal dysplasia

- Cleft lip, jaw palate- Down’s sign.

Anodontia:- Msx 1 (Mackenzie,et al – 1992) Cap,Bud,Bell stage.

Satokata and mass (1994) Agenesis in mice due to absence of Msx 1.

- Transposition of teeth:-Maxillary canine with 1 st premolar or lat-incisor.Genetic + multifactorial inheritance.Studies in siblings – Peek et al-1993.

- Submerged pirmary molars;-Concordance in Monozyjons twins-Genetics.

- Mineralization of teeth;-- Amelogenesis Imperfecta (A1);-

o Clinically heterogeneous.o Genetically herogeneous –

Autosomal dominantAutosomal recessive.X-linked.

Amelogenes:- AMGX,AMGY

Ameloblastin gene.- Anterior open bite:- Witkop et al.

o Decrease alveolar growth due to tongue thrusting.o Genetic anomaly in CF develop :- Rowkey, Hill, Winter.

through stem cells in neural crest.- Dentinogenesis Imperfecta (D1):-

o autosomal dominant.Type I – D1 with osteogenesis imperfecta Mutation:- Deletion for amino acidsubstitution in genes, which encode for type 1 collagen extra cellular matrix formation.

- DENTAL MALOCCLUSION:- Tooth position – rotations, displacements and buccal segment relation, overjet,

overbite, crowding – Environmental factors.- Arch width, arch length – Genetic (Craniofacial, bone based dimensions).

Maternal effects – environmental contribution to intersi similarities.Lundstrom – twins.Chung and Niswander – Pairs of siblings in Hawai.



Genetic component:-Overjet>overbite>molar relationship.

- Skeletal Malocclusion:Lundstrom – 40% of dental and facial variation leading to malocclusions – hereditaryfactors.

Corrucini - much lower.

Class II Div. 1 Familial, polygenic + environmental.class II Div 2

100% concordance in monozygotic twins90% discordance in dizygotic twins. Markovi 1992.

Therefore stronger genetic component – Autosomal dominant with incomplete penetrance, and variable expressivity.+ Multifactorial.

Class III malocclusion:-Hapsburg Jaw – Autosomal dominantStrohmayer – 1937.

Familial tendency:- autosomal dominant or recessive with variable expressivity and penetrance.

Environmental factors:- Enlarged tonsils, nasal blockage, congenital anatomic defectshormonal disturbances endocrine imbalances posture, trauma.

Multifactorial polygenic, with different modes of transmission in different families or different populations.

- Vertical jaw proportions:-Ant.open bite – Blacks Inherent facial morphology.Deept bite - whites.

Posture – environmental factor.

Soft tissue morphology:-Van der Linden (1966) – balance between external and internal functional matrices.

Class II div 1 – Short upper lip, low lip level with flacid lip tone – proclination of Uincisors.

Class II Div. 2 – High lip level.External matrix - genetically determined.Internal matrix – tongue posture.



( Genetic + Environmental).

- MALFORMATION SYNDROMES:-- Associated with mandibular deficiency:

- Pierre Robin anomalad:o

Heterogeneous : Stickler syndrome is autosomal dominant.- Treacher collins syndrome:-o autosomal dominant.

- Nager acrofacial dysostosis:-o Autosomal recessive.

- Hemifacial microsomia :- (Goldenhar Syn).Sporadic, few familial – autosomal dominant or recessive.

- Associated with mandibular prognathism.- Basal cell nevus syn. (Gorlin’s Syn)

o autosomal dominant.- Klinefelter syn:-

o XXY Karyotype, XXXY and XXXXY can also occur.- Marfan syn:-

Autosomal dominant- Osteogenesis imperferta:-

autosomal dominant, etiologically heterogeneous.- Waurdenburg syn:-

o Autosomal dominate.- Associated with mandibular prognathism:-

- Basal cell nevus syn. (Gorlin’s syn.)o Autosomal dominant.

- Klinefelter syn:-o XXY traryotype, XXXY and XXXXY can also occur.

- Marfan syn:-o Autosomal dominant.

- Osteogenesis imperferta:-o Autosomal dominant, etiologically heterogeneous.

- Warden burg syn:-o autosomal dominant.

- Associated with facial asymnctry:-- Hemifacial microsomia.- Neurofibromatosis:-

o Autosomal dominant.- Associated Structures:-

o Hereditary anomalies of soft tissues:- Ankyloglossia.High labial fremim attachments. –

Role of Epigenetic Factors:-Genetics + Environmental factors,



Genetic information in bones,nerves, muscles and macromuscular patterns. – Morphogenesis. (Basic form, size location of CF structures incl. teeth).

Environmental factors:-Post natal development.

climate, nutrition, lifestyle, oral, dental pressure habits, mucles malformation, orthodontictreatment.

(Functional matrix theory – Moss).

- Multifactorial.

Hereditary

Acquired HereditaryMalocclusions. Malocclusions.

Environment

AGGRAVATION

Accumulation

Hereditary ExogenousFactors Influence

Compensation

Camouflage

Treatment palliative or surgical, in case of a pirmary genetic cause of malocclusion.

Treatment – environmental etiology – interceptive orthodontics – permit the face togrow according to fundamental genetic pattern with minimal obstruction fromenvironmental influences, habit and adverse functional factors.

Future research: -

- Lack of research- Blunt tools.- Limited knowledge of genetic mechanisms.- More longitudinal studies.



- Computer based analysis of spatial changes during craniofacial morphogenesis.- Diagnostic techniques in molecular genetics; identify morphogenes or genetic

markers; selective manipulation of homeobox genes responsible for initiation of tooth formation and patterning.

Clinical Implications: -Orthodontic correction:-Altering the phenotypic expression of a particular morphogenetic pattern.

Degree depends upon: -- Relative contribution of each factor.- Extent to which skeletal pattern can be influenced by orthodontic and orthopaedic

appliances.- Increase genetic component – Worse is the prognosis.- Genetic determination of cranial form and lack of evidence of long-term influence

of orthopaedic appliances.

TWINS IN MEDICAL GENETICS:Galton –(1875) Importance of twin studies for comparisonof the effects of ‘nature’ and‘nurture’.

Two types of twins:-- Monozygotic (identical).- Dizygolic (fraternal).

Monozygotic twins – Arise from a single fertilised ovum, the zygote, which divides intotwo embryos at an early developmental stage (within 1 st 14 day after fertilization).

- Like – sexed.- Identical genotypes.

Dizygotic twins – two ova are fertilized by two separate sperms.- Different genotypes.- Half of D2 twins are not of same.

DETERMINATIONOF ZYGOSITY:-- Placenta and fetal membranes.

o Inner, delicate amnionOuter, thicker clarion

o Monochorionic or dichorionic (can be secondarily fused)o Monochorionic.

MonoamnioticDiamniotic.

Arrangement of placentas and fetal membranes in twins:-Diagram



- Protein enzyme analyses- Histocompatibility- Blood investigation

o Boold groups.o PTC (phenyl thicarbamide) taste sensitivity serological tests.o Dermatoglyphics.

Paterns of ridged skin of the digits, palms and soles.- Fingerpsimts.- Ridgecount (Total ridge count)- Palm patterns.- Sole patterns.

Gernal features :- Sex, facial features, eye colour, hair colour, body build etc.,

Twin studies in Orthodontics:-- Heritability of diseases, malformations, biometric traits.- Heritability of craniofacial and dental characteristics.

- Relative contribution of heridity and environment to observed variation in variousfeatures (Sir Francis Golton – 1887).- Siemens (1924) – Polysymptomatic similarity test.- Determination of zygosity:-

Shiffand Verscheer (1933) – MZ – similar blood groups.Becker (1977) :- used various tests.

- Heritability and genetic influence of various malocclusions.o Lundstrom (1988) - cephalometric studyo Harris and Johnson(1991) –

Craniofacial skeletal dimensions. and tooth based occlusalvariables. Craniometrics variables – high Heritability occlusal

variables – low genetic contributions.- Manfredi, et al – (1997) –

o Genetic Vs environmental factors affecting Heritability of craniofacialfeatures.

o Vertical variables – strong genetic control.o Heritability – More anterior than posterior expression.

Mandibular shape more than size – Genetic Lower 3 rd of face – strong genetic control.

Importance of Twin Studies:-Galton (1875) – ‘Nature’ Vs ‘Nurture’. Comparison of monozygotic and dizygotictwins:-

- Variance of quantitative traits.o Genetico Environmental.

- Heritability of diseases, malformations and biometric traits.- Genetic variance estimates.

o Additive vairance



Individual alleleso Dominance variance

Homologous alleleso Epistatic variance

Combinations of nonhomologous loci- MZ and DZ twins:-

o Witin – pair VoAmong – twin-pair

o Co-habitational effect :- (Garn et al)Sharingthe same environmentMZ>DZ>Sibs

o Same maternal environmentPre and Post natal conditionsDietChildhood illnessesSocio-economic status etc.,

o Offsprings of MZ twins – half sibs.

Twin Studies in Orthodontics:-L undstrom - Occlusal variables in MZ and DZ twins.Overjet – 75% heritabilityArch width different, buccal segment relation,Overbite – Decrease heritability.

Corruccini, Potter (AJO,1980)-Genetic variance and heritability for arch and occlusal traits in 60 twins (11-20years) 40traits, dental stone casts used.

Results:-1. Arch size:-

Length > breadth.Size:- 27% gentic, 73% environ.

2. Overjet and Upper and Lower arch length discrepancy:-Decrease variance, DZ>MZ

3. Buccal segment relation and side to side asymmetry:- No. Significant heritability.

4. Overbite:-Increase variance among MZ

5. Cross-bite and arch breadth discrepancy :-High haritability.(Environmental co-variance for MZ>DZ).

6. Tooth rotations and displacement:- No significant heritability

Conclusions:-Increase environmental component of variance in occlusion.



- William K.Lobb (AO, 1987):-- Variation within CF skeletons of MZ and dZ twins in terms of shapre and spatial

arrangement of component parts.- Relating to occlusion.

30 pairs – MZ, 30pairs – DZ.Qualitative and Quantitative.Shape:-Individual components of maxilla, mandible, cranium and cranial base.

Spatial Arrangement:-Superimposition.

- Along SN plane- Along anatomic occlusal plane.

Intrapair and Interpair variation.Zinear and Angular variables:-

Conclusions:-- Intrapair variaton – MZ and DZ.

DZ>MZ.- Spatial arrangement of component parts:-

Test variation.- Shape of mandible and cranial base increase variability than maxilla or cranium.

Due to different in gonial angle and cranial base flexure.- Superimpositions:-

o Ant. cranial base:-Additive effect;- Increase variation in shape and position of mandible.

MZ>DZ.o Cranial base – Increase heritability.Gonial angel – Decrease heritability adjustable.

o CF skeleton represents a complex integrated balance between morphologicunits under strong genetic control and units which accomodate for variance within the system provide structural integrity for functionalocclusion.

o Malocclusion.o Compensatory mechanismo Modification.

- Harris andJohnson (Am.J.Orthod. Dentofac. Orthop. – 1991)

Longitudinal sib analysis.Relative contribution of heredity to relative contribution of heredity to expression of CFskeletal dimensions and tooth based occlusal variables.

Ages;- 4 years – Full deciduous.14years – early permanent.20 years – early adulthood.



Results;- Heritability estimates;-- Age 4 :-

Palatal > Craniofacial > occlusal.- Age 14:-

Craniofacial > Palatal > Occlusal.

- Age 20:-Craniofacial>Palatal = Occlusal.- Vertical CF variables> Horizontal.

Diagram.

Genetics + environmental.Co-Habitational effect.

Conclusions:-CF dimensions – Moderate heritability occlusal, tooth based parameters – low

heritability.Craniofacial similarities among family members and occlusal variation. Malocclusion – tooth malposition acquired.

- Manfredi, et al (Am J.Orthod. Dentofac. orthop. – 1997).

Evaluate genetic Vs. environmental factors affecting heritability of CF features.39 orthodontic Ceph. parameters.MZ,DZ and same sex singletons. (sibs).

- MZ vs DZ- MZ vs sibs.

Results:-- Skeletal parameters – Increase heritability- Vertical parameters:-

o Total anterior face height Increase heritability.o Lower anterior face height

- Upper skeletal parameters – Low heritability.- Shape of mandible increase genetic control than size.

- Mandibular corpus and ramus – Decrease heritability example Lower incisor toA-Pog line linear and angular – Increase heritability.- Cranial base;-

o MZ vs DZ – Decrease heritabilityo MZ vs sibs – Increase Heritability.

- Triangle of face similarity:-Triangle NaGoGn

Na GoGn



GoGnNa Increase habitability in MZ vs DZ or sibs.TAFH

Minimal chance to achieve a stable vertical modification.

Conclusions:-

Occlusal and Dentofacial structure: -Early twin studies – Lund Strom: -Genetic factors in malocclusion.

Environmental Influence:-Begg and Kesling – Australian Aborigines.Corruccini – Etruscan Cranial mat.

Corruccini, Sharma et al. :-Decrease genetic – Occlusal.Increase genetic – plaate, dental arch.

Lundstrom – Increase Heritability for facial height: facial depth.Maxillary to mandibular sella-apical base.

Dental characteristics:-Kraus and Furr – Lower 1 st premolar Crown dimensions – genetic, but different for M.D. and B.L. dimensions.

Odontometric asymmetry:-- Corruccini, sharma – Environmental influences on bilateral dental asymmetry.- Genetic component – Twinning process.- Mirror imaging – MZ- Nery and oka in MZ Down’s system.

Brown et at – MZ twin boys. Contradicted by potter and Nance.

Fusion malformations and asymmetry:-- Increase in relative frequency of same sexed twins among mothers of children

showing midline neurological defects and clubfoot deformities.Therefore Association between maternal factors for twinning and midlineneurological defects.

- Non-right handedness (NRH)o Neural tube defects.o Orofacial clefting.

Functional components:-Spatial arrangement of bones – Decrease Heritability.Therefore response to functional demands:

- Muscular activity.- Biggs et al – EMG activity of masseter and temporal is – Increase in MZ.

Heritability and mode of inheritance of functional components – Increase research.

Genetics - Seminar

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