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Variation in the Human Dentition: Some Past Advances and Future Opportunities
1 School of Dentistry, The University of Adelaide, Adelaide, South Australia, 5005; Correspondence: * corresponding author, grant.townsend{at}adelaide.edu.au
Key Words: teeth • genes • phenotypes • twins • sex chromosomes INTRODUCTION The purpose of this article is to share with the dental research community the milestones and creative insights that make dental research what it is today. We have been involved in dental research for some 40 years and have been fortunate enough to see astounding advances in the field of craniofacial biology. Each of us has been influenced by different mentors during our careers, and we have pursued different but complementary research initiatives. Now, an exciting new international collaboration is under way, involving the unique materials available in Adelaide and Oulu and innovative 2D and 3D imaging techniques for data acquisition in Liverpool. Together, we are developing new study designs, recording new dental phenotypes, and applying novel etiological modeling methods, utilizing association and linkage approaches. In this paper, we review some key influences and achievements that have led to our present collaboration, set out plans for the future, and offer to collaborate with others. THE AUSTRALIAN CONNECTION The School of Dentistry at the University of Adelaide has a long and distinguished history of research in the fields of dental anthropology and human growth, dating back to T, Draper Campbell, whose monograph "Dentition and Palate of the Australian Aboriginal" remains a classic text (Campbell, 1925). Regular visits to the Aboriginal settlement of Yuendumu, located northwest of Alice Springs, Australia, took place from the 1950s to the 1970s. Supported by a grant from the National Institute of Dental Research, United States Public Health Service, Murray Barrett and Tasman Brown assumed leadership roles in a longitudinal growth study of the Aboriginal children from around 6 to 18 years of age. The growth records collected during field trips to Yuendumu continue to provide a unique resource for dental scientists and anthropologists interested in studying facial and dental development in a group of Aboriginal people with only limited exposure to European customs and living conditions. There are over 1700 sets of dental casts for over 450 individuals in the Adelaide collection, together with genealogical and other growth records, including stature and weight measurements. In 1970, Townsend, a third-year dental student, accompanied Barrett and Brown on one of their annual field trips to Yuendumu, leading to an honors degree and a PhD thesis on the genetic basis of tooth size, under Brown’s supervision. The realization that collections of high-quality growth records derived from well-designed longitudinal growth studies, like the one at Yuendumu, could provide such an invaluable resource over so many years led Townsend and colleagues to commence studies of dentofacial morphology and development in Australian twins in the 1980s (Townsend et al., 2006). There are now over 1000 pairs of twins enrolled in the Australian twin studies, with three different cohorts represented. In analyses of data derived from the twins, advantage has been taken of the major developments in multivariate genetic modeling methods (Neale and Cardon, 1992). The ability to isolate DNA from buccal cells, as well as blood, has also facilitated zygosity determination. Genetic studies have shown that additive genetic contributions to phenotypic variation differ for different dental features, being strongest for tooth emergence, dental crown size, and Carabelli trait, but weaker for intercuspal distances and occlusal traits such as anterior overbite and overjet (Hughes et al., 2007). In addition to applying the traditional twin model to dental data, the Adelaide group has also analyzed data from opposite-sex dizygotic twins (Dempsey et al., 1999). The monozygotic co-twin design has been used to highlight the apparent role of epigenetic influences on dental development, including the expression of missing and extra teeth. THE FINNISH CONNECTION Alvesalo studied dentistry at the University of Turku, Finland, and following a 1963 summer spent as a dental assistant on Hailuoto, an island close to Oulu in Northern Finland, he suggested to his mentor, Kalevi Koski, that Hailuoto would be an excellent location to collect dental records for genetic purposes. In 1966, he examined 669 Hailuoto islanders out of a population of 1265. Extensive records were obtained, and genealogies were constructed by geneticist Petter Portin. Alvesalo’s 1971 thesis, "The influence of sex chromosome genes on tooth size in man", was based on a correlative study of cousins and siblings. It was concluded that the Y chromosome apparently affected tooth crown size, but that its effect differed from that of the X chromosome. Alvesalo also proposed that observed sexual dimorphism in tooth crown size was connected to the influence of the Y chromosome (Alvesalo, 1971). These findings were the impetus for Alvesalo to commence the large-scale Kvantti project in Finland, involving individuals with sex chromosome anomalies and also their close relatives. To date, 314 patients and 371 relatives have been examined, with records including karyotypes, dental casts, panoramic and lateral head radiographs, bitewing radiographs, special enamel radiographs, facial photographs, intra-oral photographs, measures of oral health, and anthropometric measurements. It has been found that the sex chromosomes have modifying effects not only on tooth crown size, but also on tooth shape, structure, and root size, as well as influencing craniofacial form and body size and shape (Alvesalo et al., 1975; Alvesalo, 1997; Lahdesmaki and Alvesalo, 2004). The Kvantti results also showed that the Y chromosome promotes both dentin and enamel growth, whereas the effect of the X chromosome seems to be limited to enamel (Alvesalo and Tammisalo, 1981; Alvesalo, 1985; Alvesalo et al., 1991). These differential effects of the X and Y chromosomes on cell function and proliferation, especially that of the Y chromosome on cell proliferation, may be related to the sexual dimorphism observed in tooth number, average crown and root size, crown morphology, and, assuming genetic pleiotropy, other somatic features such as statural growth and sex ratio at birth (Alvesalo, 1997). Numerous questions arise regarding the manner and extent of this influence of the Y chromosome on growth (Alvesalo, 1997). In 1972, Alvesalo was invited to participate in the research project "Genetic-odontometric study of pre- and neonatal growth", led by Richard H. Osborne, which formed part of a larger project conducted by the National Institute of Neurological Disorder and Stroke in the USA. Dental casts and intra-oral photographs were collected from over 2000 children, including about 200 pairs of twins. In 1988, after his retirement, Osborne shipped all the dental records and medical information to Alvesalo. Analyses performed subsequently at Oulu indicated that mothers’ smoking leads to a reduction in tooth size of their children (Heikkinen et al., 1992), and that preterm children’s teeth are also smaller in size, but the eruption of their permanent teeth is advanced (Harila-Kaera et al., 2003). THE ENGLISH CONNECTION Brook was an undergraduate at Guy’s Hospital, where Jeff Osborn’s teaching and research in dental anatomy were a particular inspiration. After qualifying, Brook performed clinical research on the normal and anomalous development of the dentition, leading to a thesis on the prevalence, clinical features, associations, and etiology of dental anomalies of number, size, and shape, by means of a large epidemiological and family study at Eastman Dental Hospital, London. He constructed an etiological model for anomalies of number and size which could be tested statistically (Brook, 1984). This multifactorial model is based on a continuous scale, related to tooth number and size, with thresholds. Position of an individual on the scale depends on a combination of the additive effect of numerous genetic and environmental factors. Within this background, a single gene of major effect, a chromosomal anomaly, or a major environmental insult may greatly influence an individual’s position on the scale, taking him or her beyond a threshold with the development of an anomaly. This model stimulated a series of hypotheses that have been subsequently tested, first with hand measurements and subsequently with 2D image analysis. The studies confirmed the presence of sex differences in tooth size, of smaller teeth and reduced form in hypodontia, but larger teeth and altered form when supernumeraries are present. Studies of a large sample of Romano-British skulls from Pounbury, Dorset, England have shown the same underlying patterns, yet with smaller tooth sizes and higher prevalences of hypodontia compared with those in the modern British population, possibly associated with major environmental stressors such as poor nutrition, chronic lead ingestion, and recurrent infections (Brook and Johns, 1995). As an example of a single gene of major effect in the multifactorial etiological model, mutations of PAX 9 associated with hypodontia have been described (Das et al., 2003). Subsequent studies in one of these families have confirmed the effect of this mutation on tooth size as well as tooth number. In the etiology of enamel defects, an epidemiological and family study of enamel defects in London schoolchildren identified both genetic and environmental factors. Studies of X-linked amelogenesis imperfecta identified different mutations in AMELX, and recently, a large X-chromosomal deletion associated with microphthalmia, linear skin defects, and amelogenesis imperfecta has been described (Hobson et al., 2008). Major environmental factors—including recurrent infections, excess lead ingestion, and poor nutrition—may have been involved in the much higher frequency of hypoplastic enamel defects found in Romano-Britons compared with a modern British population. These findings are compatible with Brook’s proposed multifactorial etiology model for enamel defects (Brook, 1999). A further ongoing area of development has been new methodologies to improve clinical phenotyping, thereby enabling differences between and among individuals to be quantified more accurately to enhance etiological studies. There have been contributions to new diagnostic clinical indices for anomalies (Brook et al., 2001) and the development and validation of 2D image analysis and 3D laser scanning techniques. Another ongoing theme involves multidisciplinary collaboration, with examples including input from statisticians to describe the complexity of tooth shape (Robinson et al., 2002), and to explain the distribution of hypodontia around the arch, including the relationships of tooth position and type. A NEW COLLABORATIVE INITIATIVE The 6th International Symposium on Dental Morphology, held in Reykjavik, Iceland, in 1983, provided an opportunity for Townsend and Alvesalo to meet in person for the first time. A long-term collaboration developed that was re-energized and re-focused when Alan Brook, organizer of the 12th International Symposium on Dental Morphology in Sheffield in 2001, proposed the establishment of a three-way international research collaboration. Brook’s subsequent appointment at the University of Liverpool, the establishment of the International Collaborating Centre in Oro-facial Genetics and Development with Brook as Director, and the support of the University in appointing Alvesalo and Townsend to limited-term professorships and as Associate Directors of the International Collaborating Centre are now enabling these plans to come to fruition. Collections of dental casts and other growth records such as those housed in Adelaide and Oulu are unique and are unlikely ever to be replicated for other human groups. Enormous improvements in computing power and the development of 2D and 3D imaging techniques are opening up new opportunities for revisiting many research questions that were posed in the past but remained unresolved due to limitations in the quality and quantity of data that could be derived and analyzed. THE FUTURE Genome-wide association studies are now possible, enabling the identification of genes associated with common human diseases and disorders of complex etiology. It is now feasible to apply genetic linkage and association analyses to dental phenotypes, with data from twins and their relatives being particularly valuable (Boomsma et al., 2002). Rather than being limited to simple 2D measurements of dental crown and arch dimensions—for example, maximum mesiodistal and buccolingual crown diameters—we can now capture the occlusal surfaces of teeth in 3D digital form, generate surface contours, and compare images mathematically. Scanning micro-tomography permits the examination of other aspects of the dental tissues, including enamel and dentin. These new technologies open up new opportunities to address key basic biological and clinically important research questions. Developments in molecular biology are providing a much clearer picture of the processes involved in odontogenesis, including how crown shape is determined, as well as why certain teeth develop in certain regions of the oral cavity. Signals from the primary enamel knot are instructive for the formation of secondary enamel knots, which represent the sites of future cusp tips, and the arrangement of cusps is determined by a balance of the inductive and repressive signaling molecules produced by the knots (Miletich and Sharpe, 2003). In fact, development of cusps seems to involve repeated activation of the same set of developmental genes, with the precise location of the cusps being determined by a cascade of epigenetic events, rather than being under strict genetic control (Jernvall and Thesleff, 2000). While the original morphogenetic field theory was a useful rule-of-thumb to describe patterns of variation observed within the dentition, recent molecular studies have led to the description of an odontogenic homeobox code to explain dental development in terms of differential gene expression. Mitsiadis and Smith (2006) proposed that the field, clone, and homeobox code models could all be incorporated into a single model to explain dental patterning, so that these three models should be viewed as complementary rather than contradictory. This unifying view can be extended into the clinical setting with the use of findings on dental patterning in individuals with missing and extra teeth. After an international workshop and symposium on normal and abnormal development of the dentition in November, 2007, with a group of researchers joining the International Collaborating Centre network, we agreed to share resources and expertise to enable some key research questions to be explored. These include:
The amino acid sequences of the X and Y amelogenin genes (AMELX, AMELY) seem to differ to some extent, and the transcriptional products of the X and Y chromosomes are both quantitatively and qualitatively different. The Y chromosome locus encodes a functional protein, even though its level of expression is only 10% of that of the locus on the X chromosome. We recognize that there are other centers of excellence also involved in this fascinating and rapidly developing area of research. Our hope is that this review will encourage further productive collaborations in addressing the many important research questions in craniofacial and dental development. ACKNOWLEDGMENTS We express our sincere appreciation to all of the participants who have agreed to take part in our studies to date, and to all of our colleagues for their support and contributions over the years. We also thank the various funding bodies that have supported our research, including the National Health and Medical Research Council of Australia, the Australian Dental Research Foundation, The Academy of Finland, The University of Turku Foundation, Emil Aaltonen Foundation, The Wellcome Trust, The Royal Society of Medicine, and Biotechnology and Biological Sciences Research Council. Received for publication December 12, 2007. Revision received June 26, 2008. Accepted for publication June 27, 2008. REFERENCES
Journal of Dental Research, Vol. 87, No. 9,
802-805 (2008)
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