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4 Trends O RTHO T RIBUNE | A PRIL 2008 Genetic, epigenetic and environmental influences on
4 Trends O RTHO T RIBUNE | A PRIL 2008 Genetic, epigenetic and environmental influences on

Genetic, epigenetic and environmental influences on dental development

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there is a group of “dental genes” that not only influences the size and shape of teeth but also the expres- sion of missing or extra teeth. In other words, there are both pleiotropic genetic effects operating on the human dentition and spatial and/or temporal variations in local epigenetic events during odontogen- esis that lead to distinct phenotypic differences in the dentition, even in genetically identical twin pairs.

Fig. 2. MZ co-twins showing different expressions of missing, tapering and small maxillary lateral incisors.
Fig. 2. MZ co-twins showing different
expressions of missing, tapering and small
maxillary lateral incisors.

on assumptions that may not always be valid. There is a simpler research model involving twins that can also be employed by practising dentists. This model is referred to as the MZ co-twin design and it essentially involves studying pairs of MZ twins who may have different habits, receive different treatments, or dif- fer in expression for one or more features of interest. Because each MZ pair is matched for sex, age and genetic make-up, the co-twins pro- vide an extremely valuable research model. For example, just one pair of MZ twins displaying differences in their dentitions offers a great oppor- tunity to explore the underlying bio- logical processes of tooth formation. Given that MZ twin pairs almost always share the same genes, any differences observed between the members of an MZ pair are assumed to be due to differences in environ- mental effects between the co-twins or to the way in which their genes are expressed, that is, epigenetic effects. The MZ pairs described in this article have a very high proba- bility of being genetically identical based on DNA analysis. Further-

Fig. 3. MZ co-twins showing different expression of missing and small maxillary lateral inci- sors.
Fig. 3. MZ co-twins showing different expression of missing and small maxillary lateral inci-
sors. Twin A displays agenesis of the maxillary right lateral incisor and a small maxillary left
lateral incisor, whereas Twin B has two small maxillary lateral incisors. The mandibular pre-
molars had been extracted for orthodontic reasons.
Fig. 4. MZ co-twins showing different expression of missing and tapering maxillary lateral incisors. Twin
Fig. 4. MZ co-twins showing different expression of missing and tapering maxillary lateral
incisors. Twin A displays bilateral agenesis of the maxillary lateral incisors, whereas Twin B has
a tapering maxillary right lateral incisor and a missing maxillary left lateral incisor.

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We agree completely with Profes- sor Carels that studies of twins have contributed greatly to our under- standing of the role of genetic and environmental influences on dental development. However, the tradi- tional twin approach involving com- parisons between monozygotic (MZ) and dizygotic (DZ) twin pairs requires large samples and is based

more, there is no evidence in their records of major differences in envi- ronmental influences, either pre- natally or post-natally. Therefore, the differences between these co-twins could have been caused by epigenetic differences in the control of their DNA and/or by relatively minor variations in local environ- mental conditions during the process of odontogenesis.

Fig. 5. MZ co-twins showing different expressions of missing lower second pre- molars and third
Fig. 5. MZ co-twins showing different
expressions of missing lower second pre-
molars and third molar development.

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We have found many examples of MZ twin pairs who show quite marked differences in tooth size and an example of one pair who show marked differences in the size of their upper right central incisors is provid- ed (Fig. 1). The crowns of these teeth differ in mesiodistal size between the co-twins by 0.5 mm, the measure- ment in Twin A being 7.9 mm and that in Twin B being 8.4 mm. Given that the error of measurement for dental crown diameters is around 0.1 to 0.2 mm, the discrepancy observed represents a “real” difference in the size of these teeth. Around 5% of nearly 200 MZ pairs examined as part of our studies have shown size differences in upper central incisors that are at least as large, or larger, as that shown in the example.

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We have also found many exam- ples of MZ twin pairs who show dif- ferences in the expression of miss- ing teeth, both in terms of number and location. Panoramic radio- graphs of a pair of MZ twins aged 14 years are provided (Fig. 2). Twin A has a missing maxillary right lateral incisor and a tapering maxillary left lateral incisor (arrowed), whereas Twin B has two small maxillary lat- eral incisors (arrowed). Several other examples of different expres- sion of missing, tapering and small lateral incisors in MZ twin pairs have been observed in our studies (Figs. 3, 4), supporting the idea that there is a strong relationship between these features (Townsend et al., 1995). The panoramic radiographs of another pair of MZ twins aged 12.5 years highlight the fact that dental development can differ quite marked- ly between MZ co-twins (Fig. 5). Twin A has a missing lower right second premolar (arrowed), whereas the corresponding tooth is

present in Twin B (arrowed). There is also no evidence of the lower right third molar in Twin A but the corresponding tooth is present in Twin B (arrowed). The upper third molars are evident in Twin A (arrowed) but not in Twin B (arrowed).

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Not only have we observed differ- ences of expression of missing teeth in MZ twin pairs, there are also examples of different expression of extra teeth in our samples. For example, panoramic radiographs of

a pair of MZ twins aged 9.5 years

show different expressions of super- numerary teeth (Fig. 6). Twin A has one mesiodens (arrowed), whereas Twin B has two (arrowed). Futher- more, the development of the unerupted teeth is more advanced in Twin B than Twin A. The examples shown of missing and extra teeth in our twin samples are not rare. Of 24 MZ pairs who were selected from our records because they showed at least one

missing lateral incisor or second premolar, 21 pairs showed differ- ences in the number or position of the affected teeth between co-twins.

A similar pattern emerged for super-

numerary teeth. Of nine MZ twin pairs who showed evidence of mesiodentes, eight pairs were dis- cordant for the number of supernu- meraries (Townsend et al., 2005a,b).

Fig. 6. MZ co-twins showing different expressions of supernumerary teeth.
Fig. 6. MZ co-twins showing different
expressions of supernumerary teeth.

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It is generally assumed that the genetic information controlling the development of bilateral structures, such as teeth, is the same on both sides. However, teeth rarely display complete symmetry in their mor- phology or their development. Asymmetrical expression of fea- tures can be either random in its expression, so-called fluctuating asymmetry, or favour one side over the other, so-called directional

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O RTHO T RIBUNE | A PRIL 2008 Trends 5 asymmetry. By examining the pat- terns
O RTHO T RIBUNE | A PRIL 2008 Trends 5 asymmetry. By examining the pat- terns

asymmetry. By examining the pat- terns and degrees of expression of asymmetry between contra-lateral teeth, it is possible to obtain further insights into the roles of genetic, epi- genetic and environmental influ- ences on dental development (Kha- laf et al., 2005a). One particularly interesting expression of asymmetry that can be observed in MZ twin pairs is the phenomenon of mirror imaging, where one twin “mirrors” the other for one or more features. Figure 7 shows panoramic radiographs of a pair of MZ male twins, aged 15 years, who show mirror-imaging for hypodontia of the lower second pre- molars. The left premolar is missing in Twin A (arrowed), whereas the right premolar is missing in Twin B (arrowed). In addition, a developing lower right third molar is evident in Twin A (arrowed) but not in Twin B (arrowed). The biological basis of mirror imaging is still not well understood, although it apparently reflects an underlying alteration in the determination of body symmetry at an early stage of development.

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The examples provided in this article and in other studies we have performed support the view that, even though there is a relatively strong genetic basis to missing or extra teeth, the number or position of affected teeth can be influenced by epigenetic factors. The exact nature of these influences is still unclear but they do not need to be due to differences in methylation of DNA or acetylation of histones. Rather, we suggest that they may reflect different responses of odonto- genic cells to minor variations in the spatial and temporal expression of local signalling molecules passing between cells during development. In other words, we are proposing that “disturbances” in epigenetic events at the local level during tooth formation can lead to quite major differences in the final appearance of the dentitions of MZ co-twins. A multi-factorial model linking tooth size and number has been pro- posed to account for the different patterns of expression of missing and extra, and also large and small teeth observed in males and females (Brook, 1984; Brook et al., 2002; McKeown et al., 2002; Khalaf et al., 2005b). The relatives of individuals with missing or extra teeth have been found to be more likely to also display missing or extra teeth, supporting the concept of an under- lying genetic predisposition to hypodontia or supernumerary teeth. We believe that such a multifactorial model, with multiple genetic and environmental influences, provides the best explanation for our observa- tions involving missing and extra teeth in MZ twin pairs. With the superimposition of thresholds on this underlying distribution, it is pos- sible to explain the relationship between tooth size and the presence or absence of teeth. Below a certain threshold for tooth size, missing

teeth will occur, and the prevalence of missing teeth is greater in females who have smaller teeth, on average, than males. At the other extreme of the distribution, with increasing tooth size, another threshold is reached above which extra teeth will occur. The prevalence of extra teeth is greater in males who have larger teeth, on average, than females (Fig 8.).

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To date, molecular studies in humans have concentrated mainly on locating the genes associated with missing teeth. As Carels has pointed out, mutations in two genes, MSX1 and PAX9, have been shown to be associated with familial cases of severe hypodontia (where many teeth are missing) and the pedigrees have been consistent with an autoso- mal dominant mode of inheritance

although showing variations in the number and position of teeth miss- ing. However, there are some 300 genes that appear to be involved in dental development and a number of them could be candidates for miss- ing teeth. Furthermore, the most common clinical presentation relat- ing to missing teeth is hypodontia where only a small number of teeth are missing. Given that there appears to be a link between the size and shape of teeth, and hypodontia or supernu- merary teeth, we propose that there is likely to be a group of “dental genes” that exert pleiotropic effects on all of these dental phenotypes, accounting for their observed co- variation. Just how many genes are involved remains to be seen, but it is possible that it may be a relatively small number. Support for this view is provided by a paper in Nature by

researchers from Finland (Kangas et al., 2004) showing that dental char- acters seem to be non-independent and that increasing the levels of expression of just one gene can lead to increases in cusp number, altered cusp shape and position, develop- ment of longitudinal crests on teeth, and increases in tooth number in experimental mice. Rather than a monogenic mode of inheritance, we believe that a multi- factorial model (with genetic, epige- netic and environmental influences) provides the best explanation for our observations involving hypodontia and supernumerary teeth in MZ twin pairs. Such a model, with superim- posed thresholds linking tooth size, morphology and number, enables us to explain why MZ co-twins, who

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posed thresholds linking tooth size, morphology and number, enables us to explain why MZ co-twins, who

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6 Trends O RTHO T RIBUNE | A PRIL 2008 OT page 5 have the same
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have the same genotypes, may dis- play different expressions of miss- ing, tapering and microdont inci- sors. Presumably these MZ twin pairs have a genetic predisposition for hypodontia that places them near the threshold for agenesis, but minor variations in local epigenetic events during odontogenesis may lead to different phenotypic expression between co-twins. A similar expla- nation may also account for the dis-

Fig. 7. MZ co-twins showing mirror-imaging for missing lower second premolars and differ- ent expressions
Fig. 7. MZ co-twins showing mirror-imaging
for missing lower second premolars and differ-
ent expressions of third molar development.

cordant patterns of missing premo- lars or supernumerary teeth within MZ co-twins. Presumably, these MZ twin pairs have a genetic make-up that places them near to a threshold for either missing or extra teeth, but variations in local epigenetic events during odontogenesis, probably relating to the spatial arrangement of cells or temporal events, deter- mine on which side of the threshold they fall. Molenaar’s concept of develop- mental systems with emergent self-

organizing properties is consistent with our current understanding of the molecular basis of tooth development. The various stages of odontogenesis, including initiation, morphogenesis and differentiation, result from a series of epithelial-mesenchymal interactions between oral epithelial and ecto-mesenchymal tissues that are facilitated by the exchange of var- ious signalling molecules. The work of Jernvall and colleagues in Helsinki has shown how the same genes are expressed and the same signalling molecules released in a reiterative fashion to produce each of the cusps of a molar tooth (Jernvall and Jung, 2000). In fact, these genes seem to be highly conserved in an evolutionary sense and once the process of odonto- genesis has been initiated, it tends to proceed as a continuous self-organiz- ing process as described by Molenaar and colleagues (Molenaar et al., 1993). Our studies of intra-coronal dimensions of molar teeth in twins are also consistent with the concept of a dynamically developing crown pattern during odontogenesis, linked to the formation of signalling centres referred to as enamel knots (Townsend et al., 2003). We suggest that variations in dental crown form between species probably result from regulation of a relatively small number of highly conserved genes that control tooth formation in verte- brates, whereas variations observed within a species, for example in humans, probably result from alter- ations in the timing of interactions between cells during odontogenesis, as well as the positions of cells rela- tive to each other. Using our broad definition of epi- genetics, both of these processes can

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About the authors

 
Professor Townsend has research interests in craniofacial biology and dental education. His research involv- ing

Professor Townsend has research interests in craniofacial biology and dental education. His research involv- ing twins has been supported by the National Health and

ing twins has been supported by the National Health and Professor Brook’s research interests are in

Professor Brook’s research interests are in craniofacial biology, particular- ly dental develop- ment. He is also currently the Royal Society of Medi-

Medical Research Council of Australia. He spent eight months during 2007-2008 on study leave in Liverpool working with Pro- fessor Brook and Professor Alvesalo from Finland to establish an International Collaborating Research Centre in Orofacial Genetics and Development.

cine Frohlich Visiting Professor to estab- lish collaborative international research links and is Clinical Principal Investiga- tor in a five-year Wellcome Programme Award on Biomineralisation.

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Contact

Grant Townsend, BDS, BScDent, PhD, DDSc, FICD, FADI Professor of Dental Science School of Dentistry University of Adelaide South Australia, 5005 Professor of Basic Dental Sciences School of Dental Sciences University of Liverpool UK, L69 3GN E-mail: grant.townsend@adelaide.edu.au

Alan Brook, BDS, LDS, MDS, FDS, ILTM Professor of Paediatric Dentistry Director, International Collaborating Research Centre in Orofacial Genetics and Development School of Dental Sciences University of Liverpool UK, L69 3GN Email: A.H.Brook@liv.ac.uk

Fig. 8. Multifactorial model with superimposed thresholds that explains the relationship between tooth size and
Fig. 8. Multifactorial model with superimposed thresholds that explains the relationship
between tooth size and missing or extra teeth in males and females. (Brook, 1984)

be considered to be examples of epigenetic control. In the case of variation between species the con- trol is likely to reside at the level of DNA, whereas in variation within a species the epigenetic influences are likely to occur at the local tissue level.

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Genome-wide association studies (GWAS) are currently being used to identify genes linked to various com- mon diseases, including coronary heart disease, hypertension, diabetes and arthritis. We plan to use a similar approach to identify the key genes involved in dental development. While the identification of key genes for dental development in humans will undoubtedly be a major step forward, there will still be much work to do. Merely identifying the genes will not necessarily mean that we will be able to explain fully how various dental anomalies arise in

individuals. This is where further exploration of epigenetic factors will be essential. Already researchers are beginning to study epigenetic bio- markers in an attempt to explain the reasons for observed differences between MZ twin pairs (Wong et al., 2007). At this stage, the focus is on try- ing to determine the extent of differ- ences in global genomic DNA methy- lation levels but it is likely that more specific analyses will be developed soon. Once these approaches aimed at the level of DNA are refined further, and our understanding of the nature of the epigenetic influences at a local tissue level improves, we should be able to provide a clearer picture of how genetic, epigenetic and environ- mental factors influence human den- tal development. With this knowl- edge, we will be in a better position to consider preventive and therapeutic approaches to many of the common developmental problems affecting the human dentition.

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References

1. Brook AH. A unifying aetiological explana-

Orthodont 2002;24:131–141. 9. Molenaar PCM, Boomsma DI, Machin G. A third source of developmental differences. Behav Genet 1993; 23:519–524. 10. Townsend GC, Rogers J, Richards L, Brown T. Agenesis of permanent maxillary lateral incisors in South Australian twins. Aust Dent J 1995;40:186–192.

tion for anomalies of tooth number and size. Archs Oral Biol 1984;29:373–378.

2. Brook AH, Elcock C, Al-Sharood MH, McKe- own HF, Khalaf K, Smith RN. Further studies

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a model for the etiology of anomalies of

tooth number and size in humans. Conn Tiss Res 2002; 43:289–295.

3. Carels C. The impact of genes on facial mor- phology. Ortho 2007;1:38–46.

11. Townsend GC, Richards LC, Hughes TE. Molar intercuspal dimensions: genetic input and phenotypic variation. J Dent Res

2003;82:350–355.

4. Jernvall J, Jung HS. Genotype, phenotype and developmental biology of molar tooth charac-

ters. Yrbk Phys Anthropol 2000;43:171–190.

 

5. Kangas AT, Evans AR, Thesleff I, Jernvall J. Nonindependence of mammalian dental characters. Nature 2004;432:211–214.

6. Khalaf K, Elcock C, Smith RN, Brook AH. Fluctuating dental asymmetry of multiple crown variables measured by an image analysis system. Arch Oral Biol

12. Townsend G, Hughes T and Richards L. The dentitions of monozygotic twin pairs:

focusing on the differences rather than the similarities. In: E. Zadzinska E. Current trends in dental morphology research. Ref- ereed proceedings, 13th International Sym- posium on Dental Morphology, University of Lodz, Poland, 2005a;337–352. 13. Townsend G, Richards L, Hughes T, Pinkerton S, Schwerdt W. Epigenetic influ- ences may explain dental differences in monozygotic twin pairs. Aust Dent J 2005b;50: 95–100. 14. Wong NC, Joo EJ, Weinrich B, Mossman D, Scott RJ, Morely R, Craig JM and Saffery R. Investigating epigenetic biomarkers underlying phenotypic discordance in monozygotic twins. Twin Res Hum Genet 2007;10 (Supplement): 58.

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7. Khalaf K, Robinson DL, Elcock C, Smith RN, Brook AH. Tooth size in patients with super- numerary teeth and a control group meas- ured by image analysis system. Arch Oral Biol 2005b;50:243–248.

8. McKeown HF, Robinson DL, Elcock C, Al-Sharood M, Brook AH. Tooth dimensions in hypodontia patients, their unaffected relatives and a control group measured with

a

new image analysis system. Europ J