XXX10.

1177/0022034519845674Journal de Investigación Dental La Era del Genoma y la Medicina Dental

artículo de investigación 2019

JDR Centennial Series

Revista de Investigación Dental
2019, Vol. 98(9) 949-955
La era del genoma y
© International & American Associations
for Dental Research 2019

Dental Medicine
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/0022034519845674
journals.sagepub.com/home/jdr

1,2
K. Divaris

Abstract
Understanding the “code of life” and mapping the human genome have been monumental and era-defining scientific landmarks—
analogous to setting foot on the moon. The last century has been characterized by exponential advances in our understanding of
the biological and specifically molecular basis of health and disease. The early part of the 20th century was marked by
fundamental theoretical and scientific advances in understanding heredity, the identification of the DNA molecule and genes, and
the elucidation of the central dogma of biology. The second half was characterized by experimental and increasingly molecular
investigations, including clinical and population applications. The completion of the Human Genome Project in 2003 and the
continuous technological advances have democratized access to this information and the ability to generate health and disease
association data; however, the realization of genomic and precision medicine, to practically improve people’s health, has lagged.
The oral health domain has made great strides and substantially benefited from the last century of advances in genetics and
genomics. Observations regarding a hereditary component of dental caries were reported as early as the 1920s. Subsequent
breakthroughs were made in the discovery of genetic causes of rare diseases, such as ectodermal dysplasias, orofacial clefts, and
other craniofacial and dental anomalies. More recently, genome-wide investigations have been conducted and reported for several
diseases and traits, including periodontal disease, dental caries, tooth agenesis, cancers of the head and neck, orofacial pain,
temporomandibular disorders, and craniofacial morphometrics. Gene therapies and gene editing with CRISPR/Cas represent the
latest frontier surpassed in the era of genomic medicine. Amid rapid genomics progress, several challenges and opportunities lie
ahead. Importantly, systematic efforts supported by implementation science are needed to realize the full potential of genomics,
including the improvement of public and practitioner genomics literacy, the promotion of individual and population oral health, and
the reduction of disparities.

Keywords: genomics, genetics, dental caries, periodontal diseases, dentistry, precision medicine
achieve-ments and key contributions in the
domain of oral and cranio-facial health
genomics.
A Brief History of the Human Genome
Discovery and Exploration
Exploring the origins and boundaries of the observable uni-
verse, discovering the elementary particles that make up our
world, deciphering the human genome—there have been few
human achievements of such magnitude and ambition.
Understanding the “code of life” and mapping the human
genome have been 2 of these monumental and era-defining
sci-entific landmarks, analogous to setting foot on the moon.
While the origins of theories on heredity can be referenced to
ancient philosophers, including Hippocrates and Aristotle,
Mendel’s (1865) work on pea plants, conducted >2,000 years
later, is considered the foundation of most contemporary
work on biology and genetics. The last century has been
character-ized by unprecedented and exponential advances in
our under-standing of the biological, hereditary, and
specifically molecular basis of health and disease. This article
reviews the progress and landmark events in the study of the
human genome during the last century and summarizes the
First Part of the 21st Century: Heritability,
Chromosomes, and Genes
By the beginning of the 21st century, it was already understood that cells are the
fundamental units of life, largely owing to Schwann’s “cell theory” in the mid-
19th century. In the early 20th century, Wilhelm Johannsen (2014) defined and
pio-neered the use of the terms genotype, phenotype, and gene, and independent
work by Walter Sutton and Theodor Boveri sup-ported the notion that
chromosomes carry the genetic material. Around the same time, research done
by European scientists, including Hugo De Vries, Erich von Tschermak and Carl
Erich

1
Department of Pediatric Dentistry, School of Dentistry, University of North
Carolina–Chapel Hill, Chapel Hill, NC, USA
2
Department of Epidemiology, Gillings School of Global Health, University of North
Carolina–Chapel Hill, Chapel Hill, NC, USA

Corresponding Author:
K. Divaris, Department of Pediatric Dentistry, School of Dentistry, University of
North Carolina–Chapel Hill, Koury Oral Health Sciences Building, Chapel Hill,
NC 27599-7450, USA. Email: Kimon_Divaris@unc.edu
950
Figure 1. X-ray diffraction images of fibrous DNA used to theorize and support the double-helix structure by Watson and Crick in 1953
(reprinted with permission).
Correns affirmed and repopularized Mendel’s work on genet-
ics and inheritance, although most of its mechanistic aspects
remained elusive.
Building on this momentum, Thomas Hunt Morgan’s (1919,
1926) experimental work, in collaboration with Alfred Henry
Sturtevant, Calvin Blackman Bridges, and Herman Joseph Muller,
provided the much-needed first scientific evidence for hereditary
transmission mechanisms explaining Mendel’s theory, including the
fact that chromosomes carry genes. Importantly, Sturtevant’s (1913)
graduate work under the supervision of Morgan demon-strated that
genes can be arranged onto a linear map on a chromo-some. In sum,
Morgan’s scientific and conceptual contributions set the stage for
subsequent genetics research and initiated a new wave in
experimental and evolutionary biology.
For the next 2 decades, the building blocks for the discovery
of structure and function of the genome were incrementally set.
In 1933, Jean Brachet suggested that DNA is found in the cell
nucleus. Seven years later, setting the stage for the central dogma
of biology, Beadle and Tatum (1941) proposed the “one gene–
one enzyme” hypothesis, and in 1944, Oswald Avery (Avery et
al. 1944) suggested that DNA is a “transforming principle.” In
1950, Erwin Chargaff reported that adenine: thymine and
cytosine:guanine ratios are equal while the balance of A-T and C-
G ratios varies among species, and he went on to suggest that
DNA “could very well serve as one of the agents, or possibly the
agent, concerned with the transmission of inherited properties.”
Second Part of the 21st Century:
DNA and the “Code of Life”
In 1953, James Watson and Francis Crick, aided by observations
made by Rosalind Franklin and Maurice Wilkins, publish their
seminal work on the double-helix structure of the DNA mole-
cule (Fig. 1). Less than a decade later, Nirenberg and Matthaei
(1961) started to unravel the genetic code by reporting that a
synthetic triplet of DNA polynucleotide letters (a UUU codon)
could direct protein synthesis and encode a polyphenylalanine
protein. Subsequently, Nirenberg went on to report the “code of
life,” the nucleotide sequences encoding amino acids (Bernfield
Journal of Dental Research 98(9)
and Nirenberg 1965)—an achievement for which he was awarded
the Nobel Prize in Physiology and Medicine in 1968. Further
advances were catalyzed by the rapid development of techniques
and technologies for DNA sequencing pioneered by Frederick
Sanger in 1977 (Sanger et al. 1977) and subsequently the
development of polymerase chain reaction by Kary Mullis (Saiki
et al. 1988). In the 1960s, a pioneer in the field, Victor
McKusick, developed a catalog of Mendelian traits and disor-
ders, entitled Mendelian Inheritance in Man (McKusick 2016).
Today, the online evolution of the catalogue (OMIM) is the ref-
erence, authoritative compendium of human genes and genetic
phenotypes. Meanwhile, genetic discoveries with immediate
clinical relevance began to emerge. Trisomy 21 was linked to
Down syndrome (Lejeune et al. 1959), while Huntington’s dis-
ease was mapped to chromosome 4 (Gusella et al. 1983) and
attributed to a specific trinucleotide repeat (Andrew et al. 1993).
The New Era: Three Decades of Genomics
The term genomics made a bold debut in an editorial by
Victor McKusick and Frank Ruddle (1987), published in the
first issue of the eponymous journal Genomics. Shortly after,
one of the most ambitious undertakings ever was launched:
the Human Genome Project—a $2.7 billion, 15-y project
carried out by an unprecedented collaboration of several US-
based and international public and private institutions (Collins
et al. 2003). The first draft of the human genome was
announced in 2001, and a finished sequence was achieved in
2003 (International Human Genome Sequencing Consortium
2004). The completion of this milestone was quickly followed
by intense discourse by multiple stakeholders regarding its
rele-vance to health care and the ways that it was expected to
change the practice of medicine (i.e., “genomic medicine”;
Strasser 2003; Green et al. 2011).
The completion of the Human Genome Project has given
birth to several other large projects that extend or build on it,
including the HapMap (International HapMap Consortium
2003), ENCODE (ENCODE Project Consortium 2012), 1000
Genomes Project Consortium (2015), and the Haplotype
The Era of the Genome and Dental Medicine 951

Reference Consortium (McCarthy et al. 2016).

Although most of the genome’s function
genetic material 1900
remains unknown, epigenetics is now under-
Studies of heritability 1910
stood as a key mechanism of DNA regulation Understanding that 1920 Hereditary component of dental caries suggested
chromosomes carry genes

(Felsenfeld and Groudine 2003). In parallel, the

1930
DNA is found in cell nucleus

Human Microbiome Project (Turnbaugh et al.

“one gene-one enzyme” 1940
2007) has spearheaded the study of microbial DNA suggested as the agent Hereditary component of dentinogenesis imperfecta,

dentin dysplasia, enamel hypoplasia, tooth agenesis,

concerned with transmission

1950
genomics and its role in human health and of inherited properties Ehlers-Danlos syndrome and ankyloglossia suggested

disease. Trisomy 21 linked to Down Syndrome 1960 Genetic basis of 3rd molar agenesis
demonstrated

Discovery of double-helix DNA structure

At present, technological advances have Hereditary component of periodontal

Genetic code identi ed 1970 diseases suggested

made it possible to sequence an entire human
DNA (Sanger) sequencing

genome (i.e., whole genome sequencing) in a 1980 Genetic analyses of orofacial clefts
Huntington's disease mapped to chromosome 4

matter of days and at a cost of ~$1,000. AMELX identi ed as cause of

Development of polymerase chain reaction X-linked amelogenesis imperfecta

Consequently, several investigations have been 1990

Genomics term emerges

CFTR linked with enamel defects

undertaken during the last 10 y seeking to iden- Human genome project launches

PAX9 linked to palatogenesis

tify genomic markers (i.e., single markers, First draft of the human genome 2000 and tooth organ development

often referred to as single-nucleotide polymor- Human genome project completed

phisms) associated with rare and common dis- HapMap project First GWAS of periodontal disease
2010
eases or traits. Currently, an impressive number 1000 genomes project First GWAS of dental caries

of associations between genomic regions and Report of in utero EDA replacement

Haplotype Reference Consortium

TOPMed Consortium therapy for X-linked anhidrotic

health traits have been reported (MacArthur et ectodermal dysplasia including

>24,000 unique variant-trait associations in GWAS catalogue 2020 tooth development e–ects
al. 2017)—as of September 1, 2016, there were

>24,000 unique single-nucleotide polymor-

phism–trait associations reported from genome- Figure 2. Timeline of genome research (left side) and oral health–specific landmark
wide association studies. In contrast, only 59 evolvements and illustrative reports (right side) since 1900.
genetic polymorphisms are considered report-
able (to research participants) according to the American
College of Medical Genetics and Genomics (Kalia et al. 2017).
It is uncommon for genome-wide association studies or whole
genome sequencing results to be immediately actionable, espe-
cially in the context of common complex diseases with sub-
stantial environmental or behavioral components; however,
these studies continue to generate valuable insights and novel
discoveries in the etiology of several important human diseases
(Manolio et al. 2009). At the same time, ethical, legal, social,
and diversity issues have been long recognized in genomics
research, and the US National Institutes of Health has embarked
on a bold strategy and research program to tackle some of these
challenges (Sankar and Parker 2017). Ultimately, the advent of
precision medicine (Collins and Varmus 2015) is expected to
improve health via a more precise accounting for individual
variability via (but not limited to) genomics.

Advances in Genomics and

Dental Medicine
Genetics Insights for Dental and
Craniofacial Health Traits and Conditions
There have been great strides and early reports on the heritable
nature of oral and craniofacial traits, parallel to other systemic
conditions and traits (Fig. 2). Observations regarding a heredi-
tary component of dental caries were reported as early as in the
1920s (Kappes 1928; Bunting 1934; Klein and Palmer 1940;
Hunt et al. 1944). In a key paper while at the National Institute of
Dental Research, Carl Witkop, who later edited the book
Genetics and Dental Health, presented an overview of dental
Figure 3. Proportion of discordant (in terms of dental caries) pairs of
first permanent molar teeth among monozygotic and dizygotic twins,
used by Mansbridge in 1959 to support the joint environmental and
genetic contributions to dental caries (reprinted with permission).
hereditary diseases, including dentinogenesis imperfecta, den-
tin dysplasia, enamel hypoplasia, tooth agenesis, Ehlers-
Danlos, ankyloglossia, and dental caries (Witkop 1958).
Mansbridge (1959) reported on the joint contribution of
environment and genetics to dental caries among a group of
952
224 Scottish twins. Similar to previous investigators, he found
that discordance in dental caries experience (e.g., as measured in
first permanent molars; Fig. 3) was less in monozygous than
dizygous twins. On the basis of these observations, he went on to
suggest that environmental and genetic factors are both important
for caries development. A few years later, Garn et al. (1963)
reported on the genetic basis of third molar agenesis and the
associated size reduction of remaining teeth, while Goodman
(1965) discussed the genetic contribution of dento-facial
development in general. Gorlin et al. (1967) conducted a
literature review and concluded that although a genetic contri-
bution to periodontal disease is plausible and likely, it was not
possible to be confirmed from the available data and the inher-ent
complexity and multifactorial etiology of the disease. Some of
these issues, relevant to and affecting the outcomes of genomic
studies of caries and periodontal disease, remain today. In 1984,
Marazita and colleagues reported on genetic findings for
orofacial clefting from an analysis of a large sam-ple of Danish
kindreds.
In more recent contributions, Lagerström et al. (1991)
iden-tified a deletion in the amelogenin gene as causative for
X-linked amelogenesis imperfecta. Wright et al. (1996)
reported that the CFTR cystic fibrosis–causing mutation also
caused enamel defects. In 1997, Kornman and colleagues
reported on an association between an interleukin 1 beta
genotype and periodontal disease.
The discovery of the role of PAX9 in tooth organ develop-
ment (Stockton et al. 2000) and palatogenesis (Lan et al. 2004) in
the early 21st century, aside from providing novel mechanistic
insights into signaling pathways at play, set the stage for the sub-
sequent development of effective, molecularly based therapies.
This was accomplished in the context of X-linked hypohidrotic
ectodermal dysplasia, which is known to result in oligodontia.
Schneider et al. (2018) recently reported the successful in utero
protein replacement therapy with recombinant ectodysplasin in 3
embryos: at ages 14 to 22 mo, the 3 infants had shown clinical
improvements and demonstrated more-than-expected tooth buds.
In parallel, Jia et al. (2017) demonstrated that anti-ecto-dysplasin
receptor agonist antibody therapy was effective in resolving
palate defects in PAX9-deficient mice. Enzyme-replacement
therapy has also been recently used for the treat-ment of
hypophosphatasia, showing improved clinical outcomes in
human trials (Whyte et al. 2012) and reduction of associated
dental, specifically enamel, defects in mice (Yadav et al. 2012).
Numerous other investigations undertaken during the last
century have led to discoveries of the genetic causes of rare
diseases, such as ectodermal dysplasias, orofacial clefts, and
other craniofacial and dental anomalies. A detailed and
insight-ful overview of genetics and genomics developments
as they relate to oral and craniofacial health research was
published by Slavkin (2012). Along the same lines, Vieira et
al. (2014) offered an excellent review of human genomics
research spe-cifically in dental caries, and Schaefer (2018)
and Morelli et al. (2019) recently reported comprehensive
reviews on the genet-ics of periodontal disease and tooth
morbidity (i.e., dental car-ies and tooth loss).
Journal of Dental Research 98(9)
The Genomics Era
More recently, genome-wide association studies have enabled
interrogation of large proportions of the variation in the human
genome (as opposed to candidate-gene studies)—they have been
conducted and reported for several oral and craniofacial diseases
and traits, including periodontal disease (Schaefer et al. 2010;
Divaris et al. 2013; Teumer et al. 2013), adult (Wang et al. 2012;
Zeng et al. 2014; Morrison et al. 2016) and child-hood
(Ballantine et al. 2018; Haworth et al. 2018) dental caries, tooth
agenesis (Jonsson et al. 2018), orofacial clefts (Marazita et al.
2009; Dixon et al. 2011), cancers of the head and neck (Lesseur
et al. 2016), orofacial pain and temporomandibular disorders
(Sanders et al. 2017; Smith et al. 2018), and facial shape (Claes
et al. 2018). Above and beyond the discovery of novel genomic
contributions to these conditions, information that has been
generated from this line of research and its aggre-gation in the
context of large-scale collaborative consortia has enabled the
application of novel methodological approaches for the
investigation of causal effects (e.g., Mendelian randomiza-tion;
Shungin et al. 2015) and the study of oral systemic disease
connections via derivation of genetic correlations between oral
and systemic traits (Shungin 2018).
The Future: Translation of Genomics Knowledge to
Genome Editing and Molecular Therapies
The available information on phenotype-genotype associations
will continue to increase, likely at an accelerated pace. There is
an opportunity for the oral health community and dentistry to
accelerate their pace on both the discovery and education fronts.
With saliva being an accessible, easy-to-collect medium enabling
genomic studies and with routine dental visits occur-ring at
regular intervals, oral health professionals are in an advantageous
position. Importantly, the realization that the human microbiome
is key player for health (Cho and Blaser 2012), essentially
functioning as an organ that is influenced by factors both
environmental and innate, further increases the value of
potentially sampling or monitoring the oral microbi-ome via
meta- (i.e., microbial) genomics. For these and more reasons, the
dental and allied health education communities should be on the
forefront of genomics education. Meanwhile, direct-to-consumer
genetic and genomics testing services are a reality, exerting
positive pressure to both the professional and educational aspects
of dentistry.
Importantly, gene therapies and gene editing with clustered
regularly interspaced short palindromic repeats (CRISPR) /
CRISPR-associated nucleases (CRISPR/Cas) systems repre-sent
the latest frontier surpassed in the era of genomic medicine
(Cong et al. 2013; Allen et al. 2019). Personalized (or, rather,
precision) cancer treatment, targeted pharmacotherapies, and
prenatal testing and interventions are currently some of the most
active areas for genomics applications. The opportunity for the
oral and craniofacial domain is enormous and extends beyond the
acceleration of mechanistic, biological research (Fig. 4). Potential
applications include the development of
The Era of the Genome and Dental Medicine
Figure 4. Illustration of applications of the clustered, regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated
nucleases (CRISPR/Cas) system in oral and craniofacial biology, as reported by Yu et al. 2019 (reprinted with permission). iPSCs,
induced pluripotent stem cell; MSCs, mesenchymal stem cells.
precise molecular therapies, tissue engineering and
craniofacial defect restoration, and microbiome- and
pharmacotherapy-related interventions (Yu et al. 2018).
Our Responsibility: Improving Individual and
Population Oral Health via Advances in Genomics
In this era of rapid genomics developments and expanding
applications, several challenges and opportunities lie ahead.
First, and based on the experience of the Human Genome
Project, maintaining a truly collaborative spirit is key for the
acceleration and translation of scientific discovery.
International cross-disciplinary collaborations and intentional
team science approaches, as embodied by Trans-Omics for
Precision Medicine (Brody et al. 2017) and Gene-Lifestyle
Interactions in Dental Endpoints (Shungin et al. 2019), are
ideal vehicles for advancing the field. At the same time, oral
health endpoints and clinical data collection have yet to be
included in the pro-tocol of bold large-scale genomics efforts
such as the All of Us research program (Sankar and Parker
2017). The oral health community and its stakeholders must
remain at the discussion table and advocate for the inclusion
of oral health as a funda-mental element of precision health
and care (versus strictly precision medicine).
953
The improvement of individual and population health via the
emerging genomics discoveries and knowledge base is a major
opportunity, but it is also faced with numerous chal-lenges—
arguably, an implementation science approach is needed to
realize the full potential of genomics and precision health care
(National Academies of Sciences, Engineering, and Medicine
2016; Roberts et al. 2017). Improving the genomics literacy of
current and future oral health professionals should be a priority,
and efforts in this direction can be made while discoveries are
being made, in all levels of oral health educa-tion. Community
engagement is another major direction of necessary action—in
terms of increasing the diversity and rep-resentativeness of
genomics results but also for illuminating gaps and opportunities
in our translational program. There is a growing ethical
responsibility for the dissemination of genom-ics knowledge and
the increase in genomics research diversity. Genomics
information can and will be used to keep people healthier and
improve their lives—and with it, there remain the responsibilities
to do no harm and reduce health inequalities.
Author Contributions
K. Divaris, contributed to conception, design, data acquisition,
analysis, and interpretation, drafted and critically revised the
man-uscript. The author gave final approval and agrees to be
account-able for all aspects of the work.
954
Acknowledgments
I would like to thank Kaitlin Jones for her assistance in
compiling the sources and literature used to produce this article
and Zannie Gunn for her assistance in the production of artwork.
The author acknowledges support from a grant from the National
Institutes of Health/National Institute of Dental and Craniofacial
Research U01DE025046. The author declares no potential
conflicts of inter-est with respect to the authorship and/or
publication of this article.
References
1000 Genomes Project Consortium; Auton A, Brooks LD, Durbin RM,
Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean
GA, Abecasis GR, et al. 2015. A global reference for human genetic varia-
tion. Naturaleza. 526(7571):68-74.
Allen F, Crepaldi L, Alsinet C, Strong AJ, Kleshchevnikov V, De Angeli P,
Páleníková P, Khodak A, Kiselev V, Kosicki M, et al. 2019. Predicting the
mutations generated by repair of Cas9-induced double-strand breaks. Nat
Biotechnol. 37:64–72.
Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr
E, Squitieri F, Lin B, Kalchman MA, et al. 1993. The relationship between
trinucleotide (CAG) repeat length and clinical features of Huntington’s
dis-ease. Nat Genet. 4(4):398–403.
Avery OT, Macleod CM, McCarty M. 1944. Studies on the chemical nature of
the substance inducing transformation of pneumococcal types. J Exp Med.
79(2):137–158.
Ballantine JL, Carlson JC, Ferreira Zandoná AG, Agler C, Zeldin LP, Rozier
RG, Roberts MW, Basta PV, Luo J, Antonio-Obese ME, et al. 2018.
Exploring the genomic basis of early childhood caries: a pilot study. Int J
Paediatr Dent. 28(2):217–225.
Beadle GW, Tatum EL. 1941. Genetic control of biochemical reactions in
neu-rospora. Proc Natl Acad Sci U S A. 27(11):499–506.
Bernfield MR, Nirenberg MW. 1965. RNA codewords and protein synthesis:
the nucleotide sequences of multiple codewords for phenylalanine, serine,
leucine, and proline. Ciencia. 147(3657):479-484.
Brachet J. 1933. Recherches sur la synthese de l’acide thymonucleique pendant le
développement de l’œuf d’Oursin. Archives de Biologie. 44:519–576.
Brody JA, Morrison AC, Bis JC, O’Connell JR, Brown MR, Huffman JE,
Ames DC, Carroll A, Conomos MP, Gabriel S, et al. 2017. Analysis
commons, a team approach to discovery in a big-data environment for
genetic epidemi-ology. Nat Genet. 49(11):1560–1563.
Bunting RW. 1934. Bacteriological, chemical, and nutritional studies of dental car-
ies by the Michigan Research Group: a summary. J Dent Res. 14(2):97–105.
Chargaff E. 1950. Chemical specificity of nucleic acids and mechanism of
their enzymatic degradation. Experientia. 6(6):201–209.
Cho I, Blaser MJ. 2012. The human microbiome: at the interface of health and
disease. Nat Rev Genet. 13(4):260–270.
Claes P, Roosenboom J, White JD, Swigut T, Sero D, Li J, Lee MK, Zaidi A,
Mattern BC, Liebowitz C, et al. 2018. Genome-wide mapping of global-
to-local genetic effects on human facial shape. Nat Genet. 50(3):414–423.
Collins FS, Morgan M, Patrinos A. 2003. The Human Genome Project:
lessons from large-scale biology. Ciencia. 300(5617):286-290.
Collins FS, Varmus H. 2015. A new initiative on precision medicine. N Engl J
Med. 372(9):793–795.
Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang
W, Marraffini LA, et al. 2013. Multiplex genome engineering using
CRISPR/ Cas systems. Ciencia. 339(6121):819-823.
Divaris K, Monda KL, North KE, Olshan AF, Reynolds LM, Hsueh WC,
Lange EM, Moss K, Barros SP, Weyant RJ, et al. 2013. Exploring the
genetic basis of chronic periodontitis: a genome-wide association study.
Hum Mol Genet. 22(11):2312–2324.
Dixon MJ, Marazita ML, Beaty TH, Murray JC. 2011. Cleft lip and palate:
understanding genetic and environmental influences. Nat Rev Genet.
12(3):167–178.
ENCODE Project Consortium. 2012. An integrated encyclopedia of DNA ele-
ments in the human genome. Naturaleza. 489(7414):57-74.
Felsenfeld G, Groudine M. 2003. Controlling the double helix. Nature.
421(6921):448.
Garn SM, Lewis AB, Kerewsky RS. 1963. Third molar agenesis and size
reduc-tion of the remaining teeth. Naturaleza. 200(4905):488-489.
Goodman HO. 1965. Genetic parameters of dentofacial development. J Dent
Res. 44(1):174–184.
Journal of Dental Research 98(9)
Gorlin RJ, Stallard RE, Shapiro BL. 1967. Genetics and periodontal disease. J
Periodontol. 38(1): 5-10.
Green ED, Guyer MS; National Human Genome Research Institute.2011.
Charting a course for genomic medicine from base pairs to bedside. Nature.
470(7333):204–213.
Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE,
Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, et al. 1983. A poly-
morphic DNA marker genetically linked to Huntington’s disease.
Naturaleza. 306(5940):234-238.
Haworth S, Shungin D, van der Tas JT, Vucic S, Medina-Gomez C, Yakimov
V, Feenstra B, Shaffer JR, Lee MK, Standl M, et al. 2018. Consortium-
based genome-wide meta-analysis for childhood dental caries traits. Hum
Mol Genet. 27(17):3113–3127.
Hunt HR, Hoppert CA, Erwin WG. 1944. Inheritance of susceptibility to
caries in albino rats (Mus norvegicus). J Dent Res. 23(5):385–401.
International HapMap Consortium. 2003. The International HapMap Project.
Naturaleza. 426(6968):789-796.
International Human Genome Sequencing Consortium. 2004. Finishing the
euchromatic sequence of the human genome. Naturaleza. 431(7011):931-
945.
Jia S, Zhou J, Wee Y, Mikkola ML, Schneider P, D’Souza RN. 2017. Anti-
EDAR agonist antibody therapy resolves palate defects in Pax9(–/–) mice.
J Dent Res. 96(11):1282–1289.
Johannsen W. 2014. The genotype conception of heredity. Int J Epidemiol.
43(4):989–1000.
Jonsson L, Magnusson TE, Thordarson A, Jonsson T, Geller F, Feenstra B,
Melbye M, Nohr EA, Vucic S, Dhamo B, et al. 2018. Rare and common
variants conferring risk of tooth agenesis. J Dent Res. 97(5):515–522.
Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, Herman GE,
Hufnagel SB, Klein TE, Korf BR, et al. 2017. Recommendations for report-ing
of secondary findings in clinical exome and genome sequencing, 2016 update
(ACMG SF v2.0): a policy statement of the American College of Medical
Genetics and Genomics. Genet Med. 19(2):249–255.
Kappes LO. 1928. Factors in the decay of teeth. Am J Dis Children. 36(2):268–276.
Klein H, Palmer CE. 1940. Dental caries in brothers and sisters of immune and
susceptible children. Milbank Mem Fund Q. 18:67–82.
Kornman KS, Crane A, Wang HY, di Giovine FS, Newman MG, Pirk FW,
Wilson TG Jr, Higginbottom FL, Duff GW. 1997. The interleukin-1 geno-
type as a severity factor in adult periodontal disease. J Clin Periodontol.
24(1):72–77.
Lagerström M, Dahl N, Nakahori Y, Nakagome Y, Bäckman B, Landegren U,
Pettersson U. 1991. A deletion in the amelogenin gene (AMG) causes X-
linked amelogenesis imperfecta (AIH1). Genómica. 10(4):971-975.
Lan Y, Ovitt CE, Cho ES, Maltby KM, Wang Q, Jiang R. 2004. Odd-skipped
related 2 (Osr2) encodes a key intrinsic regulator of secondary palate
growth and morphogenesis. Desarrollo. 131(13):3207-3216.
Lejeune J, Gauthier M, Turpin R. 1959. Les chromosomes humains en culture
de tissus. Comptes Rendus Acad Sci. 248:602–603.
Lesseur C, Diergaarde B, Olshan AF, Wünsch-Filho V, Ness AR, Liu G,
Lacko M, Eluf-Neto J, Franceschi S, Lagiou P, et al. 2016. Genome-wide
associa-tion analyses identify new susceptibility loci for oral cavity and
pharyngeal cancer. Nat Genet. 48(12):1544–1550.
MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, Junkins H,
McMahon A, Milano A, Morales J, et al. 2017. The new NHGRI-EBI
Catalog of published genome-wide association studies (GWAS Catalog).
Nucleic Acids Res. 45(D1):D896–D901.
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ,
McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, et al. 2009.
Finding the missing heritability of complex diseases. Naturaleza.
461(7265):747-753.
Mansbridge JN. 1959. Heredity and dental caries. J Dent Res. 38(2):337–347.
Marazita ML, Lidral AC, Murray JC, Field LL, Maher BS, Goldstein McHenry T,
Cooper ME, Govil M, Daack-Hirsch S, Riley B, et al. 2009. Genome scan, fine-
mapping, and candidate gene analysis of non-syndromic cleft lip with or without
cleft palate reveals phenotype-specific differences in link-
age and association results. Hum Hered. 68(3):151–170.
Marazita ML, Spence MA, Melnick M. 1984. Genetic analysis of cleft lip with
or without cleft palate in Danish kindreds. Am J Med Genet. 19(1):9–18.
McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A, Kang HM,
Fuchsberger C, Danecek P, Sharp K, et al. 2016. A reference panel of 64,976
haplotypes for genotype imputation. Nat Genet. 48(10):1279–1283.
McKusick VA. 2006. A 60-year tale of spots, maps, and genes. Annu Rev
Genomics Hum Genet. 27:1–27.
McKusick VA, Ruddle FH. 1987. A new discipline, a new name, a new journal.
Genomics. 1:1–2.
Mendel G. 1865. Versuche Über Pflanzen-Hybriden. Verhandlungen des
natur-forschenden Vereines zu Brünn. 4(1865):3–47.
The Era of the Genome and Dental Medicine
Morelli T, Agler CS, Divaris K. 2019. Genomics of periodontal disease and
tooth morbidity. Periodontol 2000. In press.
Morgan TH. 1919. The physical basis of heredity. Philadelphia (PA): JB
Lipincott.
Morgan TH. 1926. The theory of the gene. New Haven (CT): Yale University
Press.
Morrison J, Laurie CC, Marazita ML, Sanders AE, Offenbacher S, Salazar CR,
Conomos MP, Thornton T, Jain D, Laurie CA, et al. 2016. Genome-wide
association study of dental caries in the Hispanic Communities Health
Study/Study of Latinos (HCHS/SOL). Hum Mol Genet. 25(4):807–816.
National Academies of Sciences, Engineering, and Medicine. 2016. Applying
an implementation science approach to genomic medicine: workshop sum-
mary. Washington (DC): National Academies Press.
Nirenberg MW, Matthaei JH. 1961. The dependence of cell-free protein syn-
thesis in E. coli upon naturally occurring or synthetic polyribonucleotides.
Proc Natl Acad Sci U S A. 47:1588–1602.
Roberts MC, Kennedy AE, Chambers DA, Khoury MJ. 2017. The current
state of implementation science in genomic medicine: opportunities for
improve-ment. Genet Med. 19(8):858–863.
Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB,
Erlich HA. 1988. Primer-directed enzymatic amplification of DNA with a
thermostable DNA polymerase. Ciencia. 239(4839):487-491.
Sanders AE, Jain D, Sofer T, Kerr KF, Laurie CC, Shaffer JR, Marazita ML,
Kaste LM, Slade GD, Fillingim RB, et al. 2017. GWAS identifies new
Loci for painful temporomandibular disorder: Hispanic Community
Health Study/Study of Latinos. J Dent Res. 96(3):277–284.
Sanger F, Nicklen S, Coulson AR. 1977. DNA sequencing with chain-
terminat-ing inhibitors. Proc Natl Acad Sci U S A. 74(12):5463–5467.
Sankar PL, Parker LS. 2017. The precision medicine initiative’s all of us
research program: an agenda for research on its ethical, legal, and social
issues. Genet Med. 19(7):743–750.
Schaefer AS. 2018. Genetics of periodontitis: discovery, biology, and clinical
impact. Periodontol. 78(1):162-173.
Schaefer AS, Richter GM, Nothnagel M, Manke T, Dommisch H, Jacobs G,
Arlt A, Rosenstiel P, Noack B, Groessner-Schreiber B, et al. 2010. A
genome-wide association study identifies GLT6D1 as a susceptibility
locus for periodontitis. Hum Mol Genet. 19(3):553–562.
Schneider H, Faschingbauer F, Schuepbach-Mallepell S, Körber I, Wohlfart S,
Dick A, Wahlbuhl M, Kowalczyk-Quintas C, Vigolo M, Kirby N, et al.
2018. Prenatal correction of X-linked hypohidrotic ectodermal dysplasia.
N Engl J Med. 378(17):1604–1610.
Shungin D. 2018. The Gene-Lifestyle Interactions and Dental Endpoints
(GLIDE)consortium: shared genetic contributions between oral and general
health using gwas in 506,667 adults. J Dent Res. 97 (Spec Iss B):1717.
Shungin D, Cornelis MC, Divaris K, Holtfreter B, Shaffer JR, Yu YH, Barros
SP, Beck JD, Biffar R, Boerwinkle EA, et al. 2015. Using genetics to test
the causal relationship of total adiposity and periodontitis: Mendelian
955
randomization analyses in the Gene-Lifestyle Interactions and Dental
Endpoints (GLIDE) consortium. Int J Epidemiol. 44(2):638–650.
Shungin D, Haworth D, Divaris K, Agler C, Kamatani Y, Lee MK, Grinde K,
Hindy G, Alaraudanjoki V, Pesonen P, et al. 2019. Genome-wide analy-sis
of dental caries and periodontal disease combining clinical and self-
reported data. Nat Comm. 10(1):2773.
Slavkin HC. 2012. The birth of a discipline: craniofacial biology. Newtown
(PA): Aegis Communications.
Smith SB, Parisien M, Bair E, Belfer I, Chabot-Doré AJ, Gris P, Khoury S,
Tansley S, Torosyan Y, Zaykin DV, et al. 2018. Genome-wide association
reveals contribution of MRAS to painful temporomandibular disorder in
males. Dolor. 160(3):579-591.
Stockton DW, Das P, Goldenberg M, D’Souza RN, Patel PI. 2000. Mutation
of PAX9 is associated with oligodontia. Nat Genet. 24(1):18–19.
Strasser BJ. 2003. Who cares about the double helix? Naturaleza.
422(6934):803-804. Sturtevant AH. 1913. The linear arrangement of six sex-
linked factors in Drosophila, as shown by their mode of association. J Exp
Zool. 14(1):43–59. Teumer A, Holtfreter B, Völker U, Petersmann A, Nauck
M, Biffar R, Völzke H, Kroemer HK, Meisel P, Homuth G, et al. 2013.
Genome-wide associa-tion study of chronic periodontitis in a general German
population. J Clin
Periodontol. 40 (11): 977-985.
Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI.
2007. The human microbiome project. Naturaleza. 449(7164):804-810.
Vieira AR, Modesto A, Marazita ML. 2014. Caries: review of human genetics
research. Caries Res. 48(5):491–506.
Wang X, Shaffer JR, Zeng Z, Begum F, Vieira AR, Noel J, Anjomshoaa I,
Cuenco KT, Lee MK, Beck J, et al. 2012. Genome-wide association scan
of dental caries in the permanent dentition. BMC Oral Health. 12:57.
Watson JD, Crick FH. 1953. Molecular structure of nucleic acids: a structure
for deoxyribose nucleic acid. Naturaleza. 171(4356):737-738.
Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert
D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, et al. 2012.
Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl
J Med. 366(10):904–913.
Witkop CJ Jr. 1958. Genetics and dentistry. Eugen Quart. 5:1:15–22.
Wright JT, Kiefer CL, Hall KI, Grubb BR. 1996. Abnormal enamel development
in a cystic fibrosis transgenic mouse model. J Dent Res. 75(4):966–973.
Yadav MC, de Oliveira RC, Foster BL, Fong H, Cory E, Narisawa S, Sah RL,
Somerman M, Whyte MP, Millán JL. 2012. Enzyme replacement pre-
vents enamel defects in hypophosphatasia mice. J Bone Miner Res. 27(8):
1722–1734.
Yu N, Yang J, Mishina Y, Giannobile WV. 2019. Genome editing: a new hori-
zon for oral and craniofacial research. J Dent Res. 98(1):36–45.
Zeng Z, Feingold E, Wang X, Weeks DE, Lee M, Cuenco DT, Broffitt B,
Weyant RJ, Crout R, McNeil DW, et al. 2014. Genome-wide association
study of primary dentition pit-and-fissure and smooth surface caries.
Caries Res. 48(4):330–338.