J Dent Res Updates 2014 Dec;1(1):29-35 Genetics & Orthodontics

Review article

Genetics and orthodontics: digging secrets of the pastVerma VK, Panda S, Sachan A, Singh K, Rai A

ABSTRACT: This paper reviews the changing concepts of genetics in the field of orthodontics from pastto present. Orthodontists in past were mainly concerned with the correction of malocclusion by movingteeth into an ideal occlusal relationship, but the inception of the concept of growth modification hasprovoked a controversial area of interest and activity in orthodontic fraternity. Like every biologicallybased clinical discipline, there was a significant lag time between the discoveries in the emerging field ofgenetics and incorporation of these discoveries into concepts. A rapid advance in the field of genetics hasprovided new insight into craniofacial development and has led to a better understanding of the subject.Advancements are so rapid, that only by keeping our eyes steady on what went before; we can progresswith intelligence and confidence.

Key words: History; Genetics; Orthodontics; Theories; Experiments; Occlusal.

PIONEERS IN THE FIELD OFGENETICS

“The heritages of the past are the seeds thatbring forth the harvest of the future.”

It has been more than 50,000 years when Homosapiens first appeared on this planet, ever sincethen we have been curious about the matters ofinheritance. It is this never ending desire toknow our existence that has led to variedadvancements in the field of genetics.

Genetics in simple words is a field of biologicalscience which deals with the mechanisms ofheredity. The first name that comes to our mindwhen we talk about history of genetics is GregorMendel. His contributions to the field ofgenetics cannot be overstated but it is veryinteresting to know that history of geneticsbegan with Hippocrates. In his theory heconcluded the inheritance of acquired characterswith the view that each part of the bodyproduces something which is then somehowcollected in the “semen” and these form thematerial basis of heredity, as they develop intothe characters of the offspring; hencebaldheaded fathers will have baldheaded sons.1

Aristotle criticized this hypothesis for thefollowing reasons, (1) Individuals sometimesresemble remote ancestors rather than theirimmediate parents, (2) Peculiarities of hair and

nails, and even of gait and other habits ofmovement, may reappear in offspring, and thatthese are difficult to interpret in terms of simpleform of the hypothesis, (3) Characters not yetpresent in an individual may also be inherited,(4) The effects of mutilations or loss of parts,both in animals and plants, are often notinherited. His general conclusion was that whatare inherited are not characters themselves inany sense but only the potentiality of producingthem.2

It was in the 17th century, when Dutch scientistslike Leeuwenhoek and De Graaf recognized theexistence of sperm and ova, thus explaining howfemales could also transmit characteristics to heroffspring.

The quest to understand sexual reproduction andits mechanism in animals and plants led tovaried investigatory studies by the botanist andzoologist of that time. Most satisfactory generalaccount of the state of knowledge at that timewas found in Darwin’s discussion in TheVariation in Animals and Plants underDomestication (1868).3

Charles Darwin recognized two more or lessdistinct types of variations– those that came tobe known as continuous and discontinuous,respectively. He concluded that crossing has aunifying effect. Since hybrids are generallyintermediate between their parents, crossing

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tends to keep population uniform, whileinbreeding leads to differences betweenpopulations.

Much of our knowledge of laws of genetics andmode of inheritance is due to the outstandingwork of Gregor Johann Mendel. In the summerof 1854, Mendel grew thirty – four strains ofpeas; he tested them for constancy in 1855. In1856 he began the series of experiments that ledto his paper, which was read to the BrunnSociety for Natural History in 1865 and waspublished in their proceedings in 1866. Despitethe efforts his conclusions remained unnoticedfor many decades.4

It was only after 35 years that Mendel’s workwas rediscovered by joint efforts of Correns, DeVries, Tschermak. The period between thepublication of Mendel’s paper and its rescue in1900 was dominated by the development of thetheory of evolution and its implications. Therewere, however, several real advances whichhelped to make Mendel’s result acceptable.Amongst such advances were the knowledge ofcytological details of fertilization and celldivision, increasing emphasis on the importanceof discontinuous variation and germplasm theoryby Weismann. Weismann concluded that thecytoplasm found with germ cells is composed of“determinants” that transmit traits from parentsto offspring and germplasm is not affected bythe life experiences of the parents, which was aclear contradiction of the ideas of Lamarckism(i.e., inheritance of acquired characteristics).5

Significant contribution was also made by Pierrede Maupertuis, who studied hereditary traitssuch as extra digits (polydactyly) and lack ofpigmentation (albinism), and showed frompedigree studies that these two conditions wereinherited in different ways. John Daltonobserved inheritance pattern in patients withcolor blindness and hemophilia. Color blindnessis still sometimes referred to as Daltonism.3

Bateson was most active proponent of Mendel’swork and he introduced many of now-familiarterms- such as genetics, for the subject itself;zygote, for the individual that develops from thefertilized egg, as well as for the fertilized eggitself; homozygote, heterozygote, and

allelomorph. Bateson usually used the wordfactor, which was later termed gene byJohannsen.6

Among this period, a quite different approach tostudy of heredity was developed by FrancisGalton, cousin of Darwin, considered the fatherof Eugenics. He carried out various breedingexperiments with animals.

Galton introduced the classic ‘Twin method’, amethodology that studies twins and attempts todifferentiate between genetic and environmentaleffects on the manifestation of a trait. This isusually done by comparing monozygotic(identical) and dizygotic (fraternal) twins. It isassumed that identical twins have the samechromosomal DNA and the two are geneticallyidentical so any difference between them shouldbe solely the result of environmental influence.7

The other classic method of estimating theinfluence of heredity is to study the familymembers, observing similarities and differencesbetween mother-child, father-child, sibling pairs,since they share similar (50% of their genes incommon on average) genetic background. Incase of a strong genetic influence the trait ofinterest is usually more common in certainfamilies compared with the general population.8

CONCEPTS OF CRANIOFACIAL GROWTH,ORTHODONTICS, AND GENETICS

Mathematical laws of inheritance of trait couldbe appreciated after the rediscovery of Mendel’sexperiments but the knowledge about of natureof gene, mechanism of gene action and itscontrol was largely unknown. Orthodontistswere practically interested in the postnatalcraniofacial growth and the possibilities ofmodifying it. As a result many theories ofcraniofacial growth was proposed andinvestigated by variety of methods.

Major concern in the middle of the 20th centurywas the role of unique structures- such assutures, cranial base, synchondroses, andmandibular condyle in craniofacial growth.Early research of postnatal development focusedon nature of bone growth.

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Influenced by the experiments of Sir JohnHunter (1771), first general theory ofcraniofacial growth- the Remodeling Theory wasproposed by Brash. He concluded that: 1) bonegrows by apposition at surfaces; 2) growth ofmaxilla and mandible is characterized bydeposition at posterior surface; 3) calvarialgrowth occurs via ectocranial deposition andendocranial resorption.9

By the end of first half of 20th century, Brodie(1941) gave his Genetic Theory of craniofacialgrowth, which stated that the persistent patternof facial configuration is under genetic controland genes determine the overall growth control.Thus the primary role of orthodontist was totreat a malocclusion by moving teeth into a moreharmonious position relative to the facial type;facial growth could not be affected byorthodontic treatment.10

Later in 1940s Weinmann and Sicher proposedthe Sutural Theory, which considered sutures asan active area of bone growth and stated that theexpansive proliferative growth of suturalconnective tissue force the bones of the vaultand circummaxillary complex apart.

James H. Scott and Melvin Moss were notconvinced with the Sutural Theory. Scott in1950s, through his descriptive histologicalanalysis postulated the Nasal Septum Theory andstated that sutures are merely secondary andcompensatory sites of bone formation andgrowth. The essential primary element directingcraniofacial growth is the cartilages within thecranial base, particularly nasal septal cartilage.11

All these theories generally assumed thatcraniofacial growth is largely inherited,intrinsically regulated, predetermined andimmutable. Major question that still remainedunanswered was about “where do heredity andgenes act, what is the mode of its action andcontrol.”

This period also marked the beginning of thescience of Developmental Genetics. Inparticular, research by Waddington clearlyestablished the linkage between embryology andgenetics by proposing to think of genes asorganizers and “evocators” of development.12

In 1950, two major breakthroughs in geneticswere (1) discovery of double helical structure ofDNA by Watson and Crick and (2) the OperonTheory by Jacob and Monod.13 These providedan explanation for how genes and whole groupsof genes operate within common regulatorysequences that can be turned on and off tocontrol transcription of mRNA and geneexpression. This also provided a betterunderstanding of the mechanism ofdevelopment.

During 1950s and 1960s the major emphasis inorthodontics was on the specific location(s) ofthe “center(s)” at which the inherited traitsdetermining craniofacial growth and form wereactually expressed. Areas of growing skeletonthat exhibit “ tissue separating capabilities,”which included all craniofacial cartilages thatare primarily under the control of heredity, werereferred to as growth centers. Locations at whichactive skeletal growth occurs as a secondary,compensatory effect, lacking direct geneticinfluence were defined as growth sites.14

In early 1960s, Melvin Moss extending theconcept of van der Klauuw, proposed theFunctional Matrix Hypothesis of craniofacialdevelopment. This acted as a catalyst forfunctional paradigm, which emphasized theplasticity of development and growth ofcraniofacial skeleton. It also supportedconsideration of the use of dentofacialorthopedic techniques to correct a developingmalocclusion or facial deformity.15

Moss, in a revisitation of the Functional MatrixHypothesis and resolving synthesis of therelative roles of genomic and epigenetic(environmental) processes and mechanisms thatcause and control craniofacial growth anddevelopment, concluded both are necessary.Neither genetic nor epigenetic factors alone aresufficient, and only their integrated activitiesprovide the necessary and sufficient cause ofgrowth and development. Moss furtherconsidered genetic factors as intrinsic and priorcauses and epigenetic as extrinsic andproximate.11,17

In 1970s, Petrovic gave the Servosystem Theoryof craniofacial growth based on cell physiology

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and integrated biology, the major significance ofthis theory is that it emphasizes an approach tocraniofacial growth research dealing with theexpression of growth factors and signalingmolecules that are true gene productsinfluencing growth. It added that all craniofacialtissues are not alike in their ability to expressintrinsic growth potential and to respond tofunctional, epigenetic and extrinsic factors.16

Thus it was clear that the development ofcraniofacial region is complex and there is noHoly Grail of craniofacial biology- no singletheory of craniofacial growth.

FIELD AND CLONE THEORIES

The Servosystem Theory emphasized theimportance of genes and signaling molecules butthe basic mechanism of gene action and itspathway was unknown until new discoveriesunfolded the role of Neural Crest Cells andHomeobox genes.

It was postulated that different neural crest cellsmigrate to different specific parts of cranial faceand dentition and form different developmental/morphogenetic fields.18,26 Concept ofmorphogenetic fields originated from RossHarrison’s (1918) studies on newt forelimbdevelopment and was supported by Spermann’sembryological organizing centers.19,25 Weissreaffirmed the interpretative value of the fieldconcept.20,29

Opitz states that processes indevelopmental fields are self-organising,spatially coordinated and ordered,epimorphically hierarchial, temporarilysynchronized, epigenetically interactive,developmentally constrained, andphylogenetically conserved.21,26

Butler’s Field Theory states that mammaliandentition can be divided into severaldevelopmental fields, which include molar/premolar field, the canine field and the incisorfield. Within each developmental field, there is akey tooth, which is more stable developmentallyand on either side of this key tooth, theremaining teeth within the field becomeprogressively less stable. Within molar/

premolar field, maximum variability will be seenfor the third molars, second molars can alsoshow variations, second premolars are morecommonly affected than the first premolars.Within incisor field, the maximum variabilitywill be seen for lateral incisors and within thecanine field, maxillary canines are commonlyimpacted or ectopically erupted.21-23

Inger Kjaer described the developmental fieldsin human cranium and in the dentition. Differentfields included the occipital and cervical spinefield, theka field, frontonasal field, maxillaryfield, palatal field, and the mandibular field.13

Spranger et al concluded that an intrinsic,nondisruptive disturbance of a developmentalfield will lead to a field defect.26,27

Osborn proposed the Clone Model, stating that asingle clone of pre-programmed cells leads tothe development of all the teeth within aparticular class. Most recent work invokes areaction-diffusion model in the region of apresumptive tooth, where activators induceplacode formation while negative regulators arehigher in interplacodal regions, which preventstooth formation and, thus, accounts for orderlyspacing of teeth.28,29

EXPERIMENTAL STUDIES IN THE FIELD OFORTHODONTICS

During 1930s, Professor Stockard conducted themost influential animal breeding experiment bycrossbreeding dogs. His experiments indicatedoccurrence of dramatic malocclusion in hiscrossbred dogs, more from jaw discrepanciesthan from tooth size-jaw size imbalances. Thusit was concluded that independent inheritance offacial characteristics could be a major cause ofmalocclusion and increased outbreeding resultsin rapid increase in malocclusion accompanyingurbanization. However, these experimentsturned out to be misleading because manybreeds of small dogs used in these experimentscarry the gene for achondroplasia, resulting inunderdeveloped midface.30

Much of the 20th century, focused on two majorpossibilities for the production of malocclusionby inherited characteristics. The first would bean inherited disproportion between the size and

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shape of the upper and lower jaws, causingimproper occlusal relationships. The secondwould be an inherited disproportion between thesize of teeth and the size of the jaws, resulting incrowding or spacing.31

Primitive human populations in whichmalocclusion are less frequent than in moderngroups are characterized by genetic isolation anduniformity. Thus it was concluded that the greatincrease in outbreeding that occurred as humanpopulations grew and became more mobile wasthe major explanation for the increase inmalocclusion in recent centuries.31

In 1971, Chung et al carried out a study inHawaii, to examine the result of out breeding inhuman population. He concluded that the mostlikely explanation for the increasedmalocclusion seen in “civilization” is changedenvironment, such as food and airway effects, asthe children of racial crosses are at no increasedrisk of malocclusion. In addition, the increase inmalocclusion in populations recently moved intoan industrialized lifestyle is too quick to be theresult of genetic change.17,32

In 1975, Niswander noted that the frequency ofmalocclusion is decreased among siblings ofindex cases with normal occlusion, whereas thesiblings of index cases with malocclusion tend tohave the same type of malocclusion moreoften.33

In 1975, Harris et al showed that the craniofacialskeletal patterns of the children with skeletalclass II malocclusion are heritable and that ahigh resemblance to the skeletal patterns occursin their siblings with normal occlusion. It wasconcluded that the genetic basis for thisresemblance is polygenic, and family skeletalpatterns were used as predictors for thetreatment prognosis of the child with a class IImalocclusion.34

In 1983, Lavelle CL studied mandibular shape inmouse fed on hard and soft diet and showed thatdifference in shape of mandibular condyle was“slightly greater” among four different inbredstrains of mice on a hard diet than on a soft dietfor 6 weeks. It was concluded that the geneticbackground of an individual can influence the

response to environmental factors thus when theenvironment changed sufficiently, the responsewas different among animals with differentgenotypes that was not evident before theenvironmental change.35

King et al, in regards to human beings said thatthe substantive measures of intersib similarityfor occlusal traits reflect similar responses toenvironmental factors common to both siblings.Malocclusions appear to be acquired, but thefundamental genetic control of craniofacial formoften diverts siblings into comparablephysiologic responses leading to development ofsimilar malocclusions.36

In 1991, Harris and Johnson, from hislongitudinal sib analysis, concluded that theheritability of craniofacial (skeletal)characteristics was relatively high but that ofdental (occlusal) characteristics was low. For theskeletal characteristics, the heritability estimatesincreased with increasing age; for dentalcharacteristics, the heritability estimatesdecreased, indicating an increasingenvironmental contribution to the dentalvariation.18,37

Conclusion: Discoveries about the nature ofgenome and of specific action of genes inregulation of craniofacial growth are continuingat an unparallel pace through The HumanGenome Project and Genome-Wide AssociationStudies. It is not far when we will be able toidentify the specific factors that causecraniofacial dysmorphogenesis, and the locationof genes for these factors on the chromosome. Acentral question in this millennium is: how thesediscoveries will directly affect concepts andapproaches to the treatment, how can thegenomic and epigenetic factors be engineeredand introduced into the treatment of anindividual at appropriate time and in appropriatemeasure in order to produce a biologicallymeaningful and clinically efficacious effect.

Authors affiliation: 1. Vinay Kumar Verma,MDS, Prof. & Head, 2. Sujit Panda, MDS,Professor, 3. Avesh Sachan, MDS, Reader, 4.Singh K, MDS, Senior Lecturer, 5. Anshu Rai,PG student, Department of Orthodontics, RamaDental College, Kanpur, Uttar Pradesh, India.

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REFERENCES

1. Liu Y. Like father like son. A freshreview of the inheritance of acquiredcharacteristics. EMBO Reports.2007;8(9):798-803.

2. Sturtevant AH. Chapter 1: BeforeMendel, A History of Genetics. ColdSpring Harbor Laboratory Press.2001;1-8.

3. Darwin C. The Variation of Animalsand Plants under Domestication.London, UK: John Murray. 1868.

4. Sandler I. Development. Mendel’slegacy to genetics. Genetics.2000;154(1):7-11.

5. Lenay C. Hugo De Vries: from thetheory of intracellular pangenesis to therediscovery of Mendel. C R Acad SciIII. 2000;323(12):1053-60.

6. Bateson P. William Bateson: A biologistahead of his time. J Genet. 2002;81:49-58.

7. Bulmer M. Commentary: FrancisGaltonand the twin method. Int JEpidemiol. 2012;41(4):911-3.

8. Proffit WR, Fields HW, Sarver DM.Contemporary Orthodontics. 5th edition.Saint Louis: Mosby. 2013;131-3.

9. Brash JC. Some problems in the growthand developmental mechanics of bone.Edinburgh Med Jour. 1934;41(5)305-87.

10. Carlson DS. Growth modification: frommolecules to mandibles. Department ofBiomedical Sciences and Center forCraniofacial Research and Diagnosis,Baylor College of Dentistry, TexasA&M University System Health ScienceCenter

11. Carlson DS, Theories of CraniofacialGrowth in the Postgenomic Era, SeminOrthod. 2005;11:172-83.

12. Waddington CH. Genes as evocators indevelopment. Growth (Suppl 1).1939:37-44.

13. Jacob F, Monod J: Elements ofregulatory circuits in bacteria, in HarrisRJC (ed): Biological Organization at theCellular and Subcellular Level.London,Academic Press. 1963;1-24.

14. Baume LJ: Principles of cephalofacialdevelopment revealed by experimentalbiology. Am J Orthod. 1961;47:881-901.

15. Moss ML: The functional matrix, inKraus B, Reidel R (eds): Vistas inOrthodontics. Philadelphia, Lea &Febiger. 1962;85-98.

16. Petrovic A: Control of postnatal growthof secondary cartilages of the mandibleby mechanisms regulating occlusion.Cybernetic model. Trans Eur OrthodSoc. 1974;69-75.

17. Graber L.W, Vanarsdall R.L, KatherineW.L. Orthodontics Current Principlesand Techniques. 5th edition.Philadelphia: Mosby. 2012;145-47.

18. Le Douarin NM. The neural crest in theneck and other parts of the body. BirthDefects. 1975;11(7):19–50.

19. Spemann H. Embryonic developmentand induction. New Haven: YaleUniversity Press. 1938.

20. Weiss KM. Duplication with variation:metameric logic in evolution from genesto morphology. Yrbk Phys Anthropol.1990;33:1–24.

21. J. M. Opitz, Development: clinical andevolutionary considerations. Am J MedGenet, Part A. 2007;143(24):2853–61.

22. Phulari B.S, orthodontics principles andpractice, first edition, pg 144-45.

23. Butler PM. Studies of the mammaliandentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B1939;109:1–36.

24. Butler PM. What happened to the fieldtheory. Dental morphology. Sheffield:Sheffield Academic Press Ltd. 2001;3–12.

25. Eddy M, De Robertis, Elaine AM, KENWY. Gradient fields and homeoboxgenes. Development. 1991;112:669-78.

26. Kjær I. Dental Approach to CraniofacialSyndromes: How Can DevelopmentalFields Show Us a NewWay toUnderstand Pathogenesis?. InternationalJournal of Dentistry. 2012;145749:1-10.

27. Spranger J, Benirschke K, Hall JG.Errors of morphogenesis: concepts andterms. Recommendations of an

34

J Dent Res Updates 2014 Dec;1(1):29-35 Genetics & Orthodontics

international working group. Journal ofPediatrics. 1982;100(1):160–65.

28. Osborn JW. Morphogenetic gradients:fields versus clones. In: Butler PM,Joysey KA, editors. Development,function and evolution of teeth. London:Academic Press; 1978;171–201.

29. Townsend G, Harris EF, Lesot H,Clauss F, Brook A. Morphogeneticfields within the human dentition: Anew, clinically relevant synthesis of anold concept. Archives of oral biology.2009;54:34–44.

30. Stockard CK, Johnson AL. Genetic andEndocrine basis for differences in Formand Behaviour. Philadelphia: The WistarInstitute of Anatomy and Biology. 1941.

31. Corrucini RS. An epidemiologicaltransition in dental occlusion in worldpopulation. Am J Orthod.1984;86(5):419-26.

32. Chung CS, Niswander JD. Genetic andepidemiological studies of oralcharacteristics in Hawaii’sschoolchildren: V. Sibling correlationsin occlusion traits. J Dent Res.1975;54(2):324-329.

33. Niswander JD. Genetics of commondental disorders. Dent Clin North Am.1975;19(1):197-206.

34. Harris JE, Kowalski CJ, Watnick SJ.Intrafamilial dentofacial associations forclass II, Division 1 probands. Am JOrthod. 1975;67(5):563-70.

35. Lavelle CL. Study of mandibular shapein mouse. Acta Anat. 1983;117(4):314-20.

36. King L, Harris EF, Tolley EA.Heritability of cephalometric andocclusal variables as assessed fromsiblings with overt malocclusions. Am JOrthod Dentofac Orthop.1983;104(2):121-31.

37. Harris EF, Johnson MG. Heritability ofcraniometric and occlusal variables: alongitudinal sib analysis. Am J OrthodDentofac Orthop. 1991;99(3):258-68.

Corresponding Author:Anshu Rai, Postgraduate studentDepartment of Orthodontics andDentofacial Orthopedics,Rama Dental CollegeKanpur, Uttar Pradesh, IndiaE-mail: contactanshu.rai@gmail.com

How to cite this article: Verma VK, Panda S, Sachan A, Singh K, Rai A. Genetics andorthodontics: digging secrets of the past. J Dent Res Updates 2014 Dec;1(1):29-35

Sources of support: Nil Conflict of Interest: None declared

Sources of support: Nil Conflict of Interset: None declared

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