CENTENNIAL SPECIAL ARTICLE

Evolving concepts of heredity and genetics

in orthodontics
David S. Carlson
Dallas, Tex

The field of genetics emerged from the study of heredity early in the 20th century. Since that time, genetics has
progressed through a series of defined eras based on a number of major conceptual and technical advances.
Orthodontics also progressed through a series of conceptual stages over the past 100 years based in part on
the ongoing and often circular debate about the relative importance of heredity (nature) and the local environ-
ment (nurture) in the etiology and treatment of malocclusion and dentofacial deformities. During the past
20 years, significant advancements in understanding the genomic basis of craniofacial development and the
gene variants associated with dentofacial deformities have resulted in a convergence of the principles and con-
cepts in genetics and in orthodontics that will lead to significant advancement of orthodontic treatments. Funda-
mental concepts from genetics and applied translational research in orthodontics provide a foundation for a new
emphasis on precision orthodontics, which will establish a modern genomic basis for major improvements in the
treatment of malocclusion and dentofacial deformities as well as many other areas of concern to orthodontists
through the assessment of gene variants on a patient-by-patient basis. (Am J Orthod Dentofacial Orthop
2015;148:922-38)

Heredity orthodontics in the late 19th century, there has been

I am the family face: debate regarding the roles of heredity and the environ-
Flesh perishes, I live on, ment, euphemistically referred to as nature and nurture,
Projecting trait and trace as causes of malocclusion and dentofacial deformities.
Through time to times anon, Ideas regarding inheritance of malocclusion and dento-
And leaping from place to place facial deformities during the early years of orthodontics
Over oblivion. were understandably naïve; even leaders in the study of
The years-heired feature that can
heredity at that time lacked understanding of the princi-
In curve and voice and eye ples of inheritance. Nevertheless, those early concepts
Despise the human span established a foundation for opinions regarding the
Of durance—that is I; role of genetics in craniofacial growth as well as clinical
The eternal thing in man, treatment of malocclusion and dentofacial deformities
That heeds no call to die for the past century or more.
Thomas Hardy (1840-1928) The purpose of this article is to review the evolution

A
wareness that physical constitution and espe-
cially facial appearance are passed from one
generation to the next, or are somehow in-
herited, is as old as humankind. Since the inception of
Regents Professor, Department of Biomedical Sciences, Texas A&M Baylor Col-
lege of Dentistry, Texas A&M Health Science Center, Dallas, Tex.
Address correspondence to: David S. Carlson, 811 Berry Creek Cir, College
Station, TX 77845; e-mail, carlson@tamhsc.edu.
Submitted, July 2015; revised and accepted, September 2015.
0889-5406/$36.00
Copyright Ó 2015 by the American Association of Orthodontists.
http://dx.doi.org/10.1016/j.ajodo.2015.09.012
922
of concepts in orthodontics in relation to discoveries and
advances in genetics. Emphasis will be placed on discus-
sions about heredity and genetics that have appeared
primarily in the official journal of the American Associa-
tion of Orthodontists. The rationale for that approach is
threefold. First, consideration of the essential elements of
genetics, even limited to orthodontics, is far too extensive
to be covered adequately in this review. Comprehensive
reviews of the basic principles of genetics that are impor-
tant for modern orthodontists can be found in other
recent articles.1-4 Second, a major purpose of official
journals associated with learned professions, such as
Carlson
orthodontics, is to give the community of professionals,
in this case both practicing orthodontists and
orthodontic researchers, the most timely and relevant
information necessary to advance their specialty.
Therefore, it is reasonable to assume that the content
of the AJO-DO over its 100-year history provides a
bellwether for contemporary thought and opinion in
the orthodontic community for understanding
genetics. Lastly, this article is part of the centennial
celebration of the rich tradition of both scientific
research and clinical advances provided by the
American Association of Orthodontists through its
official journal, and it is appropriate to celebrate the
occasion by looking most closely at the AJO-DO to
appreciate those contributions.
The field of genetics emerged from the broader study
of heredity that was initiated by classically trained natural
scientists beginning in the first part of the 20th century.
At approximately the same time, pioneering dentists were
developing mechanical devices for correction of irregu-
larities of the occlusion and jaw deformities, marking
the beginning of orthodontics. From the start, orthodon-
tic pioneers understood at least intuitively that heredity
was a factor to be considered in determining the physical
constitution of progeny, including development of the
face and jaws. Moreover, early orthodontic thought
leaders such as Kingsley, Angle, and Case, among others,
were aware of the major concepts of heredity espoused by
the leading natural scientists of the late 19th century:
Darwin, Weismann, and Mendel. Although it was not un-
common to see the terms “inheritance” and “heredity” in
publications by early orthodontists, however, there was
little real appreciation of their actual concepts and prin-
ciples. Therefore, the orthodontic literature often
contained opinions about the role of heredity in the
development of overall constitution, dentofacial growth,
and malocclusion that would now be considered archaic
and in some instances fanciful. This is understandable,
since genetics was immature, and the education of early
dentists and orthodontists lacked the depth in biologic
sciences that became the norm in dental schools decades
later.5,6
Accepted concepts in genetics and orthodontics each
progressed chronologically through a series of concep-
tual stages as they evolved. Most of those stages can
be considered as definitive eras that arose from ground-
breaking discoveries and advancements, such as the
discovery of the structure of DNA and the completion
of the human genome, leading in some cases to new par-
adigms in the biologic sciences.7 Consideration of that
progression provides a convenient framework for under-
standing the evolution of concepts from genetics in the
field of orthodontics (Table).
American Journal of Orthodontics and Dentofacial Orthopedics
923
BRIEF HISTORY OF GENETICS
Aristotle and Hippocrates, in the 4th century BC, are
generally credited with the first scholarly efforts to
provide an explanation of the mechanisms of heredity.
Aristotle believed that physical traits are transmitted to
progeny through instructions found in seminal fluid
and menstrual blood. Hippocrates added that each phys-
ical trait is predetermined and contained in discrete par-
ticles derived separately from the various regions of the
bodies of the progenitors.
Pre-Mendelian Era (19th Century)
Nearly 2400 years after Aristotle and Hippocrates,
Charles Darwin (1809-1882) proposed that the inherited
particles passed from parents to offspring (“gemmules”)
are “blended” together in the zygote through the process
of pangenesis to produce a combination of discrete
physical traits inherited separately from each progenitor.
August Weismann (1834-1914), who is often called the
father of genetics, added that the traits programmed by
the units of heredity are predetermined and immutable;
ie, they cannot be altered in development and form by
environmental or other factors.
Classical Era (1900-1930)
The field of genetics began to emerge at the turn of
the 20th century with the rediscovery of experiments on
plant hybridization performed over 40 years earlier by
Gregor Mendel. With Mendel's laws of inheritance as a
foundation, quantitative methods were developed to
study traits across generations of animals and plants,
giving rise to the study of transmission genetics and
quantitative population genetics. Research in structural
genetics led to the discovery that genes located on chro-
mosomes are the principal units of heredity. Finally,
developmental genetics arose with recognition that
genes produce phenotypic traits through their expres-
sion during the process of development. Thus began
transformation of the study of heredity into the field
of genetics as the study of the transmission, structure,
and function of the genes.
DNA Era (1930-1970)
The DNA era of genetics was remarkable for ground-
breaking discoveries that had wide-ranging impacts in
all the biologic sciences. At the outset, the integration
of Mendel's laws of inheritance with paleontology in
the 1930s provided the basis for the synthetic theory
of evolution. Also at that time, quantitative population
geneticists developed approaches for analysis of the her-
itability of phenotypic traits.
December 2015  Vol 148  Issue 6
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Table. Major conceptual eras in genetics and orthodontics from late 19th century through the present; key
representative papers published in the AJO-DO are listed chronologically relative to major discoveries and conceptual
advancements in the study of heredity and the field of genetics
Major advances in the field of genetics
Pre-Mendelian era: particulate heredity; predetermination;
pangenesis
Particles (gemmules) as units of heredity (Darwin 1868)
Germ plasm as unit of heredity (Weismann 1892)
Classical era: chromosomes and genes
Rediscovery of Mendel’s laws (de Vries, 1900)
Chromosome as unit of heredity (Sutton, 1904)
Genetics (Bateson, 1905)
Genes located on chromosomes (Morgan, 1910)
Genes responsible for developmental program (Morgan, 1910)
First genetic map of a chromosome (Sturtevant, 1913)
Mendelian Laws applied to family pedigrees
Start of population genetics (Fisher, 1916)
The Physical Basis of Heredity (Morgan, 1918)
Theory of the Gene (Morgan, 1928)
DNA era: structure of DNA; genes; evolutionary genetics;
genetic code; epigenetics
DNA found in chromosomes (Brachet, 1932)
Synthetic theory of evolution (Haldane, 1932)
Genetics and Evolution (Dobzhanski, 1938)
Modern concept of epigenetics (Waddington, 1940)
Genes code for proteins: central dogma of genetics
(Beadle 1942)
Structure of DNA (Watson & Crick, 1953)
1st identified chromosomal abnormality, trisomy 21 (1959)
Operon Theory (Jacob & Monod, 1960)
Genetic code defined (Crick et al, 1964)
Genomics era: molecular biology of the gene; genetic
engineering
Beginning of molecular biology
Recombinant DNA (Berg 1970)
Transgenic animal technology (Boyer & Cohen,1972)
DNA sequenced (Sanger, 1977)
PCR amplification technique (1980)
December 2015  Vol 148  Issue 6
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Key papers on heredity and genetics in AJO-DO
Preorthodontia era: orthodontic mechanics and tooth movement
1860-1899 Kingsley (1880). Oral Deformities
Farrar (1889). Irregularities of the Teeth and Their Correction
Orthodontia era: Nature’s Plan and Biologic Laws
1900 Angle (1902). Art in relation to orthodontia
1905 Angle (1907). Malocclusion of the Teeth
Case (1908). Dental Orthopedia
1910 Angle, Case & Dewey: Extraction debate of 1911
1915 Zentler (1916). The factor of heredity in malocclusion
Lischer (1916). Face facts
Lischer (1919). Variations and modifications of the facial features
1920 Case (1921) Laws of biology. in malocclusion
Case (1921). Practical application of biologic laws
Case (1921). Heredity and variation ethnologically considered
1925 Dewey (1925). Facial deformities
Morehouse (1926). Hereditary influences in orthodontics
Keeler (1929). Heredity and its relation to dentistry
Heredity vs environment era: racial admixture, atavisms &
habits as causes of malocclusion
1930 Korkhaus (1931) .inheritance of orthodontic malformations
Todd (1932). Heredity and environment.in facial development
Bery (1932). .etiology of malocclusion
1935 Berger (1938). Constitution, heredity and orthodontia
Rubbrecht (1939). .heredity of anomalies of the jaws
Sawin (1939). Application of .heredity to orthodontic
1940 Wilkinson (1940). .facial growth.inherent factors.
Moore (1944). Heredity as a guide in dentofacial orthopedics
Hughes (1944). Heredity . in the dentofacial complex
1945 Hughes (1945). Nature’s plan and orthodontics
Wylie (1948). Heredity and the orthodontist—..confusion
Snodgrasse (1948). Family line study in craniofacial growth
1950 Cheney (1950) Heredity, growth and extraction
Curtner (1953). Predetermination of the adult face
1955 Asbell (1957). .family line transmission of dental occlusion
Noyes (1958). A review of the genetic influence on malocclusion
Kraus et al (1959). Heredity and the craniofacial complex
1960 Publication hiatus
1965 Van der Linden (1966). Genetic and environmental factors ..
Nepola (1969). Intrinsic.extrinsic factors influencing growth.
Heritability era: pedigree analysis; prediction of dentofacial
growth
1970 Hunter (1972). The heritability of . growth of the human face
Salzmann (1972). . genetics and . the practice of orthodontics
Nakata (1973). .prediction of craniofacial growth
1975 Harris & Kowalski (1976). . familial [data] in . treatment .
Salzmann (1978). Genetic considerations in clinical orthodontics
Corruccini & Potter (1979). .occlusal variation in twins
1980 Harris & Smith (1980). .occlusion and arch widths in families
Watson (1980). Hereditary environment
Nakasima et al (1982). Heredity.in craniofacial morphology.
American Journal of Orthodontics and Dentofacial Orthopedics
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Table. Continued
Major advances in the field of genetics
Molecular Biology of the Gene (Watson et al, 1986)
Cystic fibrosis (CFTR) sequenced (Collins & Tsui, 1988)
Knockout mouse technology (Capecchi et al., 1988)
Epigenetic Mechanisms of Gene Regulation (Riggs, 1996)
Human DNA sequence variation (Collins et al, 1997)
Pharmacogenomics (Pirmohamed, 2001)
Human Genome Project completed (Collins, Venter 2003)
Detection of SNPs (Kwok & Chen, 2003)
HapMap Project completed (NIH, 2005)
Computational biology; bioinformatics (2006)
The epigenomic era opens (Boylan & Schuebel, 2007)
Postgenomic/epigenomic era: functional genomics; gene
regulation; SNPs; HapMap
Genome-wide association studies of polymorphisms
Roadmap Epigenomics Program (NIH, 2011)
Sequencing-based tests for Down syndrome (2013)
Precision medicine period: personalized medicine based on
genomics
Precision medicine (Collins & Varmus, 2015)
$213 M in federal budget for precision medicine
Discoveries in the 1940s and 1950s about the func-
tion and structure of the gene initiated a whole new
paradigm in genetics. Initially, discovery that genes
code for proteins provided the basis for the “central
dogma of genetics.” Subsequently, DNA was confirmed
as the basic chemical ingredient of genes. Finally, one
of the most important discoveries in the history of
science occurred when James Watson and Francis
Crick determined the structure of DNA as a double helix
and thus provided a biochemical and structural basis
for replication and transmission of genetic material to
progeny.
Genomics Era (1970-2010)
Another paradigm shift in genetics occurred in the
1970s, primarily as a result of advancements in molecu-
lar biology leading to the development of methods to
create recombinant DNA and sequence genes. In addi-
tion, new molecular methods for genetic engineering
of experimental animals, such as transgenic and
knockout mouse models, allowed for analysis of the
function of individual genes and groups of genes in
complex living animals. Advancement of molecular
technology culminated with the sequencing of the
American Journal of Orthodontics and Dentofacial Orthopedics
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Key papers on heredity and genetics in AJO-DO
1985 Publication hiatus
1990 Harris & Johnson (1991). Heritability of craniometric .
Suzuki & Takahama (1991). . data . to predict growth ..
King et al. (1993) Heritability of cephalometric . variables.
1995 Harris & Potter (1997). Sources of bias in heritability studies
Manfredi et al. (1997) Heritability of cephalometric parameters.
Moss (1997). The functional matrix hypothesis revisited.
Orthodontic genomics era: function of genes & gene products;
craniofacial anomalies
2000 Vastardis (2000). The genetics of human tooth agenesis.
Rabie et al. (2003) Functional appliance therapy [and] .growth
Mao & Nah (2004). .hereditary and mechanical modulations
2005 Iwasaki (2006) . tooth movement . IL-1 polymorphisms
Basto Lages et al. (2009) . polymorphism root resorption
Viecilli et al. (2009) .mechanotransduction and P2X7R .
Postgenomic/epigenomics period: gene variants & dentofacial
treatment
2010 Bowers et al. (2010) . importance of a genetic [DX] .
Ting et al. (2011) . genetic polymorphisms [and] crowding
He et al. (2012) . CYP19A1 genotype and . jaw growth
Precision orthodontics period (emerging): personalized
orthodontics based on genomics
2015 Enomoto et al. (2015) Mastication [and] gene expression
Huang et al. (2015) . orthodontic tooth movement: .
Ikuno et al. (2015) . [GWA] study for . prognathism
human genome in 2003; this made it possible to identify
genes and gene variants associated with a whole spec-
trum of genetic diseases and disorders.
Postgenomic/Epigenomic Era (2010- )
Equipped with new and ever more powerful molecu-
lar methods such as next-generation sequencing and ge-
netic engineering as well as knowledge of the human
and mouse genomes, the postgenomic/epigenomic era
is characterized by emphasis on application of the prin-
ciples of genomics in many interrelated areas. Those
areas include studies of the function of specific genes
and gene products (functional genomics); normal gene
variants such as single nucleotide polymorphisms as
the basis of normal phenotypic variability; intrinsic and
extrinsic environmental factors regulating gene expres-
sion (epigenomics); and patterns of human genetic vari-
ation and disease based on genetic polymorphisms
(haplotype mapping and genome-wide association
studies). In addition, mathematicians, biostatisticians,
and computer scientists together developed sophisti-
cated computer-based technologies for comparative
analysis of gene sequences and even whole genomes
(bioinformatics).
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Precision medicine period. The vast amount of
information emerging from research on the human
genome during the postgenomic/epigenomic era has
now advanced sufficiently to begin to realize a major
goal of biomedical research: understanding individual
susceptibility to certain diseases and response to treat-
ment. It is well known in medicine that the development,
progression, and treatment outcomes associated with
certain diseases and disorders vary considerably among
patients. It is now understood that this susceptibility
and variability may be due primarily to minor, typically
normal, genetic variations, or polymorphisms, including
single nucleotide polymorphisms (it is estimated that the
human genome contains over 2 million single nucleotide
polymorphisms). Awareness that there may be an under-
lying genomic basis for heterogeneity of response to
treatment of many diseases and disorders led naturally
to a still-evolving new paradigm in medicine referred
to initially as personalized medicine and now called
precision medicine.8 Precision medicine represents the
current culmination of research in genetics based on
application of information about individual genomes
to improve diagnosis, prevention, and treatment of dis-
eases and disorders with an underlying genomic basis on
a patient-by-patient basis.
CONCEPTS OF HEREDITY AND GENETICS IN
ORTHODONTICS
It was understood well before the 19th century that
forces applied to the teeth could cause them to be moved
to correct irregularities in dental alignment. Malocclu-
sion, the dental irregularity itself, was thought to be pre-
dominantly a result of “pressure habits” as well as dietary
deficiencies, endocrine malfunction, and even mental
degeneracy; few orthodontists considered malocclusion
to be hereditary.9,10
Orthodontia Era (1900-1930)
The orthodontia era (1900-1930) began with the
inception of orthodontics in the United States, generally
considered to have taken place in the latter part of the
19th century with the work of Kingsley (1825-1896)
and Farrar (1839-1913). Although ideas about inheri-
tance of dentofacial growth and form often were
mentioned at the outset of discussions by these and
other early leaders in orthodontics, emphasis typically
shifted quickly to types and classifications of malocclu-
sions as well as different mechanical approaches to or-
thodontic tooth movement.
The well-known controversy in orthodontics, the
Great Extraction Debate of 1911, between followers of
Edward Angle and Calvin Case, epitomizes opinions
December 2015  Vol 148  Issue 6 American Journal of Orthodontics and Dentofacial Orthopedics
Carlson
about the role of heredity and malocclusion during the
orthodontia era.11 Edward Angle (1855-1930) and his
followers believed in what he referred to as “nature's
plan” for the normal function and form of the occlusal
plane. Angle was influenced by the work of Julius Wolff
(1836-1902), a German orthopedic surgeon best known
for development of Wolff's law, which simply stated
maintains that the form of a bone follows its function.
Wolff, in turn, was greatly influenced by Naturphiloso-
phie, which asserted that nature is essentially a mystical
power that provides a blueprint for skeletal form, and
that normal “function” is the process by which nature
ensured the genesis of normal form.12 Angle and his
many followers thus believed that abnormal growth of
the jaws leading to malocclusion and dentofacial defor-
mities is not inherited directly, but results from abnormal
function caused by “perverted” behavioral habits and
other external, environmental conditions.13 Further-
more, Angle asserted that orthodontic appliances can
“unpervert” forces on the developing jaws and thereby
stimulate normal growth of the occlusal arches.14,15
Calvin Case16-18 (1847-1923) believed strongly that
science must provide the foundation of the new field
of orthodontics. Accordingly, he relied on accepted
scientific beliefs of the time about heredity to assert
that the skeletal structures of the face and occlusal
arches are inherited in their final size and form
through what he referred to as biologic laws, by which
he primarily meant Darwin's concept of pangenesis
coupled with Weismann's belief in predetermined
inheritance of discrete traits. Case thus used then-
accepted scientific concepts such as pangenesis and pre-
determination of inherited traits to support his views
about atavism and the inability to influence growth of
the jaws. According to Case, “the fantastic claims [by
Angle and his followers] that ‘all malocclusions arise
from local causes,’ and ‘God does not make such mis-
takes in forming human anatomies,’ and so on must
be regarded as crass ignorance of the well established
principles of heredity.”16 (Ironically, those concepts
about heredity turned out to be erroneous.) Therefore,
tooth extraction is required to accommodate an in-
herited mismatch between tooth size and the size of
the jaws and occlusal arches.
Pangenesis was rejected by geneticists by the 1920s.
Nevertheless, Case,16-18 Kadner,19,20 and even later
orthodontic researchers continued to maintain that
the sizes of the maxilla and the mandible are
predetermined and inherited separately from the
mother and father.21,22 Thus, a prominent belief in the
orthodontic community through at least the first
3 decades of the 20th century was that malocclusion
occurs primarily as a result of “atavistic heredity from
Carlson
distant inharmonious progenitors” caused by
admixtures and blended inheritances with persons of
“lower races.” Acceptance of the ideas of atavism and
miscegenation was also undoubtedly fueled by
contemporary ideas of a hierarchy of racial “types” and
social prejudices regarding the mixing of certain ethnic
and racial groups.23-25
Hereditary vs Environment Era (1930-1970)
At the start of the hereditary vs environment era,
emphasis in the orthodontic literature centered on the
determining role of local environmental and behavioral
factors such as airway (tonsils and adenoids); endocrine
and metabolic disorders; disorders of the “blood
glands”; pressure from the lips, tongue, and cheeks
caused by “perverted” oral habits; and other “constitu-
tional factors.”21,22,26,27 According to Wylie,28 many
dentists and orthodontists at the time had an actual
bias against the idea that heredity might play a role in
the development and growth of the dentofacial region,
and certainly that heredity might be important to their
profession.
Nevertheless, in the aftermath of the Angle-Case
debate, there was growing recognition in the orthodon-
tic community at large of the need to become more
cognizant of the principles of heredity to improve under-
standing of dentofacial growth and malocclusion. That
trend is readily apparent by publication in the AJO-DO,
beginning in the late 1920s, of invited articles by scien-
tific experts from zoology, anthropology, and medicine
as primers of the new sciences of heredity and evolution
for orthodontists.20,29-34 For example, M. F. Guyer,
professor of zoology at the University of Wisconsin,
provided the first discussion of Mendelian inheritance
and use of the term “genetics” in the AJO-DO in
1924.23 The practical but still theoretic basis for
increased interest in the principles of heredity and their
potential relevance for understanding malocclusion
was well summarized by Salzmann: “Since rational
treatment of any [malocclusion and dentofacial] abnor-
mality necessitates a correct diagnosis and the determi-
nation and removal of underlying causes, the ability to
distinguish developmental influences of an inherent na-
ture, if they actually do exist, is imperative and such
knowledge should be applied to diagnosis and treat-
ment.”35 As evidence of this growing interest, by the
mid-1930s and continuing through the 1940s, there
was a burst of scholarly publications in the AJO-DO
dealing with the proportionate degree that heredity con-
trols dentofacial growth and form.
In the 1930s, a German orthodontist and a Belgian
physician introduced the orthodontic community to
the idea developed in quantitative population genetics
American Journal of Orthodontics and Dentofacial Orthopedics
927
that the study of twins provides a unique approach to
separate the relative contributions of heredity and envi-
ronment to physical constitution.33,36 From that point
on, during the late 1930s and throughout the 1950s,
much of orthodontic research focused on family
pedigrees and especially on the study of twins from
the perspectives of Mendelian genetics.37-43 Virtually
all of those studies tended to support the newly
popular opinion that heredity determines the size and
shape of the jaws in both normal and abnormal
development and growth.33,44,45 Thus, by the 1940s,
opinions among most orthodontic educators and
researchers had switched from abrogation of heredity
as the primary factor determining normal and
abnormal dentofacial growth and form to the position
that “today, the hereditary factors are considered first
in importance and [local environmental] factors second
in the process of growth and development.”46
During its first 25 years, the AJO-DO published over
20 articles that substantively addressed, positively and
negatively, the role of heredity in the etiology of
malocclusion (Fig 1). The number of articles increased
considerably through the end of the 1940s because
of enthusiasm for intrafamilial and twin studies. During
the next 10 years, however, studies on heredity and
genetics in orthodontics dropped dramatically, until
between 1960 and 1968 no substantive articles dealing
with heredity and genetics were published in the AJO-
DO. Although the hiatus in publications could have
been an anomaly of the AJO-DO alone, that does
not appear to be true. There also were no articles
dealing substantively with genetics published in the
Angle Orthodontist from 1960 through 1968 and
only 18 articles in all major journals between 1960
and 1965.
The hiatus of publications in the 1960s suggests
strongly that by the middle of the 20th century the
pendulum of opinion in the orthodontic community
had swung back toward the view that contemporary
concepts from genetics had questionable value for the
practice of orthodontics. Representing that point of
view, Harold Noyes, professor of orthodontics at the
University of Oregon, noted that from a practical stand-
point, knowledge that a patient's malocclusion is due to
genetics would not alter his treatment. Noyes most likely
spoke for most orthodontists when he stated that “while
I am intrigued with the science of genetics and im-
pressed with its tremendous growth in the past few
years, I feel that as yet it is essentially academic with
respect to the clinical practice of orthodontics and of
only occasional value as a tool in the diagnosis and
treatment of malocclusion” [italics added].47 According
to Kraus et al from the University of Washington, “The
December 2015  Vol 148  Issue 6
928 Carlson

25
GENOMICS ERA

20

15
HEREDITY V ENVIRONMENT ERA HERITABILITY ERA

10

X X
0
1930 1940 1950 1960 1970 1980 1990 2000 2010
X = No publicaƟons
A

500

450

400

350

300

250

200

150

100

50

0
1960 1970 1980 1990 2000
B

Fig 1. A, Number of articles published in the AJO-DO per decade at 5-year intervals from 1930 through
2014 that dealt substantively with heredity, genetics, and orthodontics; B, results of Web-based
searches for articles from all major scientific and clinical journals, 1960 through 2000, using the search
terms heredity or genetics and orthodontics or malocclusion. Sources: PubMed and Science Direct.

very nature of genic action, as far as geneticists under- or that, indeed, its heritability can be accurately as-
stand it at present time, precludes the notion that [the sessed” [italics added].48 Frans van der Linden, professor
dentofacial] complex has a simple genetic determinant of orthodontics at the University of Nijmegen in The

December 2015  Vol 148  Issue 6 American Journal of Orthodontics and Dentofacial Orthopedics
Carlson
Netherlands, similarly stated that “the effects of genetic
and environmental factors on the structure of the facial
complex have been oversimplified by many authors—
partly because of the limited information available on
hereditary influences and partly because of the typical
approach” of classical Mendelian analysis of family
pedigrees.49
Heritability Era (1970-2000)
After the hiatus of the 1960s, in the 1971 John V.
Mershon Memorial Lecture, J. A. Salzmann essentially is-
sued a “call to arms” to the orthodontic community
when he noted that “We do not at present have the
knowledge and the instruments to enable us to obtain
prediction on genetic growth and development in the
antenatal stage or in the continuing dynamic phases af-
ter birth. . . . [However, orthodontists must] perforce
keep up with newer developments in [genetics], as
well as orthodontic therapy, if they expect to obtain bet-
ter results in the prevention and treatment of malocclu-
sion in the future.”50 About the same time, the National
Institute of Dental Research organized 2 “state-of-the-
art” workshops to review the contemporary status of or-
thodontic research on the role of genetics in malocclu-
sion and occlusal variation.51,52 Both workshops
concluded that univariate analysis of twins and family
pedigrees in general using classical Mendelian models
of monogenic inheritance had failed to show genetic
mechanisms of dentofacial growth and malocclusion.
They also jointly called for the development of more
sophisticated multivariate statistical methods that
theoretically could be used to analyze polygenic
inheritance of dentofacial traits in human pedigrees to
determine the multifactorial basis of dentofacial form.
Beginning in the mid-1970s, a number of orthodon-
tic researchers adopted multivariate statistical methods
to study the variability of specific metric features of
the dentofacial complex to quantify proportionate de-
grees of genetic and environmental contributions to
dentofacial form: ie, the heritability of specific dentofa-
cial measurements. Researchers also continued to
emphasize pedigree analysis with the idea that if it was
done properly with multivariate statistical methods, in-
formation on heritability of dentofacial features would
allow orthodontists to predict dentofacial growth and
adult form with and without orthodontic treatment.53,54
Advances in computer technology permitted ortho-
dontic researchers to digitize radiographic cephalograms
and use multivariate statistical methods to explore pat-
terns of craniometric variation in families, again with the
goal of providing more accurate predictions of dentofa-
cial growth.54 It was apparent to some researchers, how-
ever, that even those more sophisticated methods for
American Journal of Orthodontics and Dentofacial Orthopedics
929
cephalometry and multivariate statistical approaches
largely depended on the variables selected and could
only provide a measure of statistical associations
without consideration of their underlying genetic
causes. Thus, according to Stuart Hunter and colleagues
in the Department of Orthodontics at the University of
Michigan,55 they are “of questionable value when used
to predict adult dimensions in the offspring.”
During the first 15 years of the heritability era, from
1970 through the mid-1980s, the AJO-DO published
approximately 20 articles that dealt substantively with
heredity and the genetics of dentofacial growth and
malocclusion. Then there was a second hiatus (1985-
1990) during which no substantive articles about hered-
ity and genetics appeared in the AJO-DO.
The reasons behind this second hiatus in research and
publication undoubtedly were similar in general to those
for the hiatus during the 1960s: ie, frustration with
contemporary approaches to research on the genetics
of dentofacial growth and malocclusion and a lack of
confidence in the orthodontic community regarding
the ability of the principles of genetics to predict dento-
facial growth with and without treatment. That sense of
frustration is readily apparent in an editorial entitled
“Hereditary environment” by Wayne Watson, then editor
of the American Journal of Orthodontics, who noted
that although the field of genetics has undergone an
“explosion” of research that “can be seen and heard
around the world.research on the genetics of dental
occlusion has had little effect on the daily practice of
clinical orthodontics.”56
By the mid-1980s, significant methodologic prob-
lems in contemporary studies of heritability overall had
become apparent to several researchers.57 For example,
Corruccini and Potter58 and Harris and Johnson,59 ex-
perts in quantitative genetics of dental and craniometric
data, identified significant problems regarding the selec-
tion of sample populations, cephalometric variables, and
overly simple assumptions about the meaning of esti-
mates of heritability for understanding the underlying
genetic mechanisms of craniometric and occlusal vari-
ables. They also admonished orthodontic researchers
that estimates of heritability should be just the first
step in understanding the role of genetics in malocclu-
sion; they are not ends in themselves.60 Studies of heri-
tability with cephalometrics and measurements of
occlusion even in twins provide little direct information
about the underlying genetic mechanisms and do not
address the possibility of altered genetic expression
caused by functional and other environmental factors.61
An additional issue prominent in orthodontics lead-
ing up to the 1985 to 1990 hiatus resulted in an even
more general sense of uncertainty about the value of
December 2015  Vol 148  Issue 6
930
research on the role of genetics in dentofacial growth.
Beginning in the 1960s and extending through the
1980s, Melvin Moss,62-64 a preeminent craniofacial
biologist from Columbia University, developed the
functional matrix hypothesis as an evolving conceptual
framework that provided an alternative explanation to
genetics for the factors influencing development and
growth of the craniofacial complex. Moss's position
about the growth of the cephalic cartilages and gene
functions during craniofacial development and growth,
as well as the significance of the functional matrix
hypothesis for treatment, was extreme and therefore
highly contentious. Nevertheless, the essentially all-
consuming debate in the entire orthodontic community
during the 1970s and 1980s related to the functional
matrix hypothesis had a significant impact because it
was a catalyst for a major shift of the prevailing concept
in craniofacial biology to what has been called the func-
tional paradigm as a theoretic basis for a broader consid-
eration of epigenetic-environmental factors as part of
orthodontic and dentofacial orthopedic treatment.7,65
It was also then that the name of the journal was
changed to the American Journal of Orthodontics and
Dentofacial Orthopedics, indicating that the
pendulum had again swung from focus on heredity
and genetics in dentofacial growth and malocclusion
to emphasis on function, biomechanical forces, and
other nongenetic factors that might affect dentofacial
growth as well as the etiology and treatment of
malocclusion.
Orthodontic Genomics Era (2000- )
The onset of the orthodontic genomics era at the
start of the 21st century marked the start of a paradigm
shift in orthodontic research, characterized most readily
by the rise of new prevailing questions and concerns
about the genetic basis of the specific molecular path-
ways underlying dentofacial development and defor-
mities. It was at that point in time that orthodontic
researchers adopted more fully the concepts and
methods developed 20 years earlier in genetics that
were now sufficiently understood so that they could be
applied in meaningful ways to problems of dentofacial
development and deformities.
Beginning in the 1990s, several orthodontic re-
searchers, dentist-scientists, and craniofacial biologists
achieved considerable prominence in the broader field
of genetics as a result of their significant contributions
published in the scientific literature outside of ortho-
dontics to understanding the developmental biology
and genetic basis of the spectrum of craniofacial anom-
alies.66-77 As a result of that research, tooth
development, cleft lip and palate, and craniofacial
December 2015  Vol 148  Issue 6 American Journal of Orthodontics and Dentofacial Orthopedics
Carlson
dysmorphology became model systems that have
proven to be especially relevant for understanding the
basic processes of the genomics and epigenomics of
development overall.78-80
The number of articles published in the orthodontic
literature underscores once again the new emphasis by
orthodontic researchers on the genomics of craniofacial
and dentofacial development. During the 30 years from
1970 to the end of the 20th century, over 400 articles on
the combined topics of genetics or heredity and ortho-
dontics were published in major scientific and clinical
journals worldwide; over 30 of those articles, an average
of about 1 per year, appeared in the AJO-DO. The begin-
ning of the 21st century saw a significant increase in
research on craniofacial genomics as indicated by more
than double the number of articles published on genetics
and craniofacial development in all scientific and clinical
journals. This trend is mirrored closely by an increase in
the number of articles dealing substantively with ge-
netics published in the AJO-DO from the end of the
1990s, to an average of 5 per year in the 4 years from
2010 to 2014.
Despite the new focus on the molecular basis of
development, analysis of heritability through quantita-
tive genetics remained an important part of the overall
research approach in orthodontics.81,82 However,
researchers in dental genetics and craniofacial growth
now emphasized that it is a mistake to assume that
heritability can be used in a meaningful way to assist
in the treatment of each patient because genomic
research has demonstrated that the environment
coupled with genetic variants plays a far greater role in
the determination of intrafamilial variations of even
common traits.83-86 For example, as noted by James
Hartsfield and colleagues in the Department of
Orthodontics at the University of Kentucky, “There is a
common perception that knowing a trait's heritability
should affect how a patient is to be treated. This is a
misconception. The ability of the patient to respond to
changes in the environment (including treatment),
which has nothing to do with estimates of heritability
for the trait, will define this.”3
An incredible amount of information was generated
on the basic genetics of craniofacial and dental develop-
ment with the shift in emphasis in orthodontic and
craniofacial research during the late 1990s and early
2000s. The greatest progress in areas of primary impor-
tance to orthodontics, as evidenced in the AJO-DO dur-
ing this period, took place in the identification of the
genes for craniofacial dysmorphologies, including
growth factors and transcription factors controlling
morphogenesis and growth of craniofacial tissues,87,88
candidate genes for midfacial deformities,89 and genes
Carlson
affecting growth of the condylar cartilage of the
mandible both normally and during treatment.90-96
With advances in molecular analysis of genes from
both animals and humans, orthodontic researchers also
began to address the specific effects of gene variants
for growth factors and cytokines as they might affect
dental development,97 tooth movement,98 root resorp-
tion,99-103 temporomandibular joint pain,103 and assess-
ment of skeletal maturation.104,105
Postgenomic/epigenomic period. In the postge-
nomic/epigenomic period, during the late 1990s and
early 2000s, orthodontic and other craniofacial re-
searchers began to make significant advances in genetic
research by adopting the approaches and molecular
methods of developmental biology generally common
in genetics.106,107 The most obvious area for emphasis
in research at that time was craniofacial
dysmorphogenesis, both because it is a major clinical
problem that demands attention and because
dysmorphology is often associated with single-gene mu-
tations and thus provides an excellent model system for
the study of developmental processes in general and for
the complex craniofacial region in particular. However,
during the first decade or more of the 21st century, ma-
jor interest in both genetic and orthodontic research had
grown to include greater consideration of the role of
gene variants, such as single nucleotide polymorphisms,
and regulatory molecules, such as microRNAs, as well as
more complex groups of genes, or haplotypes, in dento-
facial development and growth.108-110
The current postgenomic/epigenomic period of or-
thodontic research is a continuation of the orthodontic
genomics era, but with 2 notable advancements. First
and foremost, researchers have begun to consider
genomic information to improve diagnosis and treat-
ment of dental disorders and dentofacial deformities in
orthodontic patients.111,112 Second, recent orthodontic
research has moved toward greater emphasis on the
genetic factors underlying clinical problems that are
seen more regularly in orthodontic practices, such as
malocclusion, tooth movement, and dental
crowding,108 rather than on less common, genomically
less complex craniofacial anomalies.3
Precision orthodontics period. As noted previously,
precision medicine is based on the idea that each pa-
tient's genome as well as the way epigenomic factors
affect gene expression can vary from person to person.
The key principle of precision medicine is that even mi-
nor gene variants such as single nucleotide polymor-
phisms, which exist normally in the genome of
everyone, are largely responsible for variations in devel-
opment, growth, and response to environmental pertur-
bations. As a result, individual genomes may vary with
American Journal of Orthodontics and Dentofacial Orthopedics
931
respect to susceptibility and progression of diseases
and disorders as well as to response to clinical treatment.
Shortly after the Human Genome Project was
completed, articles began to appear in the dental litera-
ture addressing the need to improve education in ge-
netics so that new generations of dentists can take
advantage of the significant advances that would inevi-
tably emerge from detailed knowledge of the human
genome.107,113-116 Several articles also extolled
“personalized” dentistry.114,117-119 As with precision
medicine, virtually all of those articles tended to focus
on prevention and treatment of acquired diseases that
may have an underlying genomic component: eg,
caries, periodontal disease, and oral cancer.120,121
Although dentofacial disorders associated with
monogenic defects, such as dental agenesis and certain
craniofacial syndromes, are sometimes mentioned,
there has been little substantive consideration
regarding complex, polygenic developmental disorders.
This is unfortunate, since the principles of precision
medicine are ideally suited to basic and applied clinical
research on the etiology, differential diagnosis, and
treatment of developmental disorders such as
malocclusion and dentofacial deformities.
An example of how the central concepts and principles
that make up precision medicine can be used to account
for variations in dentofacial growth and orthodontic
treatment response can be found in an article published
in the AJO-DO at the start of the orthodontic genomics
era.122 In a theoretical discussion of the role of genetics
in the treatment of a developing dentofacial deformity,
a heuristic model was proposed based on the idea that
the orthodontic patient population could be considered
a continuum that can be stratified loosely into 3 broad
and overlapping groups, each with a number of substrata,
based on individual genomes (Fig 2). At one end of the
continuum is a group characterized by definitive defects
related to mutations of key genes that affect the develop-
ment of core craniofacial tissues and organs. These sub-
jects' craniofacial deformities are principally a direct
consequence of significant abnormalities in their ge-
nomes. In addition, it should be expected that standard
clinical approaches to change the growth of affected tis-
sues and regions based on assumptions of normal growth
processes are likely to be compromised because of the
same underlying genetic abnormalities. The population
at the other end of the broader continuum includes per-
sons with a range of “standard” or “normal” genomes.
Those in the “standard” group would be expected to ex-
press a range of normal phenotypic variation because of
their spectrum of standard polymorphisms. Conse-
quently, the process of dentofacial growth would be
“normal”—the way it is supposed to occur according to
December 2015  Vol 148  Issue 6
932 Carlson

• Possible mutations and/or unfavorable polymorphisms

• Unknown intrinsic epigenetic effects
UNPREDICTABLE growth and treatment response

Abnormal Clinical Standard

• Mutation of key developmental genes • Favorable polymorphisms

• Abnormal development/growth • Positive extrinsic epigenetic effects
UNSATISFACTORY growth and SATISFACTORY growth and
treatment response treatment response

Fig 2. Heuristic model illustrating the basis and rationale for consideration of genomics in the treatment
of malocclusion and dentofacial deformities (adapted from Carlson122,123).

textbooks on craniofacial growth. Similarly, response to
orthodontic treatment to correct a malocclusion or a
developing maxillomandibular discrepancy in this group
should for the most part conform to expectations for
“normal” growth processes.
The population in the middle of the continuum, the
“clinical population,” overlaps to some extent with the
abnormal population and to a considerably greater
extent with the standard population. The clinical popu-
lation thus is characterized by a greater range of varia-
tions in dentofacial growth and form because of a
wider spectrum of polymorphisms that affect skeletal
growth and orofacial function. Persons toward the
“abnormal” end of the clinical population spectrum
may have true genetic abnormalities that are not readily
apparent. Those toward the “normal” end may have a
number of different standard polymorphisms that could
affect dentofacial growth and thus should be considered
to a greater or lesser extent with respect to alternative
options for treatment.
Based on this theoretical model of the orthodontic
patient population and taking into account the princi-
ples of precision medicine, it would be extremely useful
for the orthodontist to have information related to 2 ma-
jor areas. The first area, which would come from basic
and translational orthodontic research, is understanding
of the key genes and gene variants that affect the overall
rate and amount of growth as well as the responses of
key tissues and components of the craniofacial complex
during treatment. Those components might include var-
iations associated with polymorphisms for the molecular
factors affecting growth and adaptation of bone and
muscle in general and more specifically in the unique tis-
sues of the craniofacial complex, such as sutures, pri-
mary cartilages of the cranial base and midface, and
secondary cartilage of the mandibular condyle. The sec-
ond area necessary to determine, which would come
from clinical laboratory testing, is the genome of each
patient with respect to the presence, absence, or modi-
fied expression of critical gene variants. With specific un-
derstanding about the significance of key gene variants
for dentofacial growth and treatment response as well as
about the underlying genomic variations of each patient,
it may then be possible to adapt the orthodontic treat-
ment plan to achieve the optimum result most efficiently
for the patient.122,123
Hartsfield,124 who was perhaps first to use the term
“personalized orthodontics” for scientific purposes,
similarly concluded that patient outcomes in orthodon-
tics may be affected by polymorphic genes, which makes
it important to understand gene variants in quantitative
terms. To achieve that goal, Hartsfield stressed the need
to incorporate modern genomic methodologic ap-
proaches to clinical research in orthodontics, such as
large genome-wide association studies that could then
be linked with follow-up randomized clinical trials,
but, importantly, using appropriately stratified samples
based on the genomic profile. Michael Glick,120 editor
of the Journal of the American Dental Association,
also stressed the need for dental researchers to partici-
pate in large genome-wide association studies, through
practice-based research networks to validate the normal

December 2015  Vol 148  Issue 6 American Journal of Orthodontics and Dentofacial Orthopedics
Carlson
variability of biomarkers for dental diseases and thereby
advance personalized oral health care through the
“-omic” evolution.
Three examples of orthodontic research published in
the AJO-DO illustrate the recent emergence of the prin-
ciples of precision medicine in orthodontics. In studies
focusing on the relevance of genetic diagnosis for ortho-
dontic treatment planning, Frazier-Bowers et al111
found that mutations in parathyroid hormone receptor
were diagnostic for primary failure of eruption. With
such genomic information, in this case, the orthodontist
could then adjust the orthodontic treatment plan by
avoiding early treatment with a continuous archwire: a
“treatment-planning recommendation [that] is meant
to be in sharp contrast to an ex post facto diagnosis of
[primary failure of eruption] after unsuccessful ortho-
dontic extrusion of the teeth.”
A series of clinical and animal studies on the genetics
of mandibular growth in the laboratory of A. B. M. Rabie
in the Department of Orthodontics at the University of
Hong Kong has revealed associations between a number
of single nucleotide polymorphisms located in the type II
collagen gene and variations in the growth of the
mandibular condylar cartilage, potentially leading to
mandibular prognathism in a Chinese population.125 It
was concluded that awareness of these gene variants
in orthodontic patients “could allow the clinician to
select early courses of dentofacial and orthodontic treat-
ments that are aimed at preventing the development of
Class III malocclusion.”126
Finally, research studies from the laboratories of
James Sciote at the Department of Orthodontics of
Temple University in Philadelphia, as well as colleagues
in France and the United Kingdom, described genetic var-
iants of myosin isoforms, contractile regulatory proteins,
and a-actin of certain fibers of the masseter muscle in as-
sociation with variations in dentofacial form. Both those
gene variants in the muscles of mastication and associ-
ated variations in mechanical properties of the muscles
could be epigenetic factors that affect dentofacial growth
in general and specifically in the etiology of Class II, Class
II deepbite, and Class III malocclusions. The authors
concluded that “If [single nucleotide polymorphisms]
[for muscle gene variants] are detected as part of a routine
diagnosis and treatment planning, a more personalized
and specific treatment plan might be developed to
enhance a more favorable treatment result.”127
CONCLUSIONS FOR THE FUTURE IMPORTANCE OF
GENETICS IN ORTHODONTICS
Opinions regarding the relative importance of hered-
ity and the environment in the etiology and treatment of
American Journal of Orthodontics and Dentofacial Orthopedics
933
malocclusion and dentofacial deformities have swung
back and forth in a pendulum-like fashion throughout
the history of orthodontics. There are 2 fundamental
reasons behind this oscillation. The first is that most
earlier orthodontic researchers and clinicians saw the
heredity-environment debate as a dichotomy, which de-
notes a conflict between 2 diametrically opposed pro-
cesses. It has been common to assume that if a feature
is thought to be the result of heredity and is therefore
referred to as “genetic,” its development and growth
cannot be altered to any clinically significant extent by
local environmental factors, including orthodontic
treatment. On the other hand, early orthodontists who
focused solely on local environmental factors, such as
oral habits, endocrine factors, and even mental degener-
acy, as being responsible for malocclusion and dentofa-
cial deformities were hard-pressed to account for
obvious familial similarities and heterogeneous treat-
ment outcomes. Contemporary understandings of geno-
mics and epigenomics support the view that the
relationship between heredity and environment is
actually a duality—a yin and yang—where apparently
opposing and contradictory processes are complemen-
tary and necessary for each other.
The second reason for the pendulum effect is
related to the asymmetric nature of discoveries in a
fundamental science such as genetics on the one
hand, and the feasibility of advancing those discoveries
in orthodontic research, especially with respect to
development of meaningful clinical applications, on
the other. Basic scientific discoveries are often initially
far removed from applied and clinical sciences. As a
result, impractical and inappropriate attempts to apply
discoveries from the study of heredity and the field of
genetics in orthodontic research and practice contrib-
uted ultimately to the opinion that concepts of hered-
ity are insufficient in general to advance
understanding in orthodontics. This caused a swing
of opinion within orthodontics away from heredity
and toward environmental factors. For example, the
concepts and methods in quantitative population ge-
netics based on classical Mendelian genetic studies
used for craniometric studies of families during the he-
redity vs environment era of orthodontic research dur-
ing the 1930s through the 1960s were based on the
assumption that malocclusion and dentofacial defor-
mities are simple monogenic traits. The lack of signif-
icantly meaningful results from that research with
respect to understanding of normal and abnormal
dentofacial growth and form, and especially options
for practical applications in clinical orthodontics, was
inevitably a significant factor in the swing of the
pendulum leading up to the hiatus in orthodontic
December 2015  Vol 148  Issue 6
934
research on heredity in the 1960s. Once it became
clear in the heritability era of the 1970s and 1980s
that malocclusion and dentofacial deformities are
complex polygenic and multifactorial characteristics,
new approaches based on intrafamilial multivariate
statistical analysis of craniometric data once again
caused the pendulum to swing toward emphasis in or-
thodontic research on heredity.
The swing from heredity seen with the trend toward
research on craniofacial function and related local envi-
ronmental factors in the 1980s and early 1990s most
likely resulted from 2 factors. First, there was improved
understanding based on contemporary orthodontic
research in quantitative population genetics that esti-
mates of heritability can vary depending on environ-
mental influences; therefore, they are not as useful for
prediction of dentofacial growth and form as had been
originally thought. Second, the 1980s saw the peak of
debate in orthodontics about the functional matrix hy-
pothesis, which led to considerable disquietude
throughout the orthodontic community about the prac-
tical importance of heredity with respect to the etiology
and treatment of malocclusion and dentofacial defor-
mities. The result was a strong emphasis on laboratory
research related to the effect of function and other local
environmental factors on craniofacial growth. Heredity
was essentially considered to be a “black box”; whatever
could not be explained by environment must be
“genetic.”7,128
The field of genetics was completing the develop-
ment of molecular techniques and approaches for
detailed analyses of gene sequences and gene func-
tions precisely when orthodontic researchers were
moving largely toward emphasis on studies of exper-
imental morphology in 1980s. It was just after that,
in the 1990s, that the research approaches of genetics
and orthodontics began to converge, and a strong
new tradition emerged using the considerable
technical and conceptual advances made in genetics
during the genomics era for research on the develop-
mental biology of the craniofacial region. That new
molecular genetic approach led first to the transition
in orthodontic research toward a focus on the identi-
fication and function of the genes most important for
prenatal craniofacial development, with an emphasis
on craniofacial anomalies. It also led eventually to
the application of the approaches of molecular
biology and genomics to questions concerning the
function of specific genes and gene variants associ-
ated with variations in normal postnatal dentofacial
growth and in the etiology and treatment of maloc-
clusion and dentofacial deformities. This can be
considered as the benchmark for the start of the
December 2015  Vol 148  Issue 6 American Journal of Orthodontics and Dentofacial Orthopedics
Carlson
orthodontic genomics era as distinct from the geno-
mics era in genetics early in the 21st century.
Over the past 5 years alone, orthodontic research and
publications on the effect of normal polymorphisms for
key genes on dentofacial growth and orthodontic treat-
ment increased greatly in the AJO-DO as well as in or-
thodontic journals worldwide. That is a clear indication
that orthodontics is on the brink of the same emphasis,
for both translational research and clinical treatment,
seen over the past few years that gave rise to precision
medicine. As the pace of precision medicine now demon-
strates, the length of time for progress from bench to
bedside—from fundamental research discoveries, to
translational clinical studies, and finally to clinical appli-
cations of genomic research—is becoming exponentially
shorter. The same is true for research and clinical treat-
ment in orthodontics more broadly, especially with
respect to the etiology and treatment of dentofacial de-
formities and malocclusion.
The concepts and principles of molecular genetics
have become major components in understanding of
the genesis of variations in the development, growth,
and form of the entire craniofacial complex. Moreover,
those concepts and principles are now sufficiently un-
derstood that they can provide a firm foundation for
future advances with respect to options for orthodontic
treatment, ranging from enhancement of approaches for
simply moving teeth, to preventing, ameliorating, and
treating malocclusion, developing dentofacial defor-
mities, and perhaps eventually even major craniofacial
anomalies.
From the perspective of orthodontic research, future
advancements in orthodontics must include continued
discovery research related to the key genes and gene var-
iants responsible for craniofacial development and
growth, of the epigenetic factors that influence gene
expression, and of the molecular factors that affect
treatment response in the dentofacial complex. This
will require large genome-wide association studies to
find candidate genes for a spectrum of developmental
variations, ranging from tissue reactions affecting or-
thodontic tooth movement and stability as well as
growth patterns and treatment responses associated
with defined dentofacial deformities, identification of
candidate genes for developmental variations, and
implementation of properly designed randomized
controlled trials based on stratification of clinical
populations according to appropriately defined genomic
variants.
The ongoing evolution of the concepts and methods
of genetics applied in orthodontics will lead to greater
understanding of the genomic and epigenomic factors
that affect normal and abnormal growth of the
Carlson
dentofacial complex. Such developments will inevitably
lead to further incorporation of the concepts and princi-
ples that are now part of precision medicine to establish
precision orthodontics as a principal clinical approach.
That approach will not necessarily lead to more funda-
mental changes in the way orthodontists treat patients;
orthodontic biomechanics and appliances undoubtedly
will continue to be the main approach for treatment of
malocclusions and dentofacial deformities. The primary
change will be seen in the diagnosis and treatment plan-
ning related to options for the most effective way to
treat malocclusions and dentofacial deformities, from
dental irregularities to major jaw discrepancies, on a
patient-by-patient basis.
Clinical orthodontic records obviously include such
phenotypic variables as age, sex, and developmental sta-
tus, as well as radiographic cephalograms, panoramic ra-
diographs, and dental casts as the primary bases for
diagnosis and treatment planning. Orthodontists in the
future will also take samples of saliva or other bodily
fluids for assessment of biomarkers for gene variants
that might affect, positively and negatively, orthodontic
treatment, whether for simple tooth movement and post-
orthodontic stability or for dentofacial orthopedic treat-
ment of a developing malocclusion and dentofacial
deformity. In this respect, individual genomes and specif-
ically the potential for expression of key growth factors
and signaling molecules related to specific gene variants,
for example, will simply become part of the phenotype
that the orthodontist assesses as part of the process of
diagnosis and planning treatment. As suggested previ-
ously,122 assessment of each patient's genome to deter-
mine the most effective options for treatment will
perforce become incorporated into orthodontic practice,
and, in the words of Frazier-Bowers et al,111 orthodon-
tists will “shift the emphasis in diagnosis and treatment
planning from a wholly phenotypic or clinical perspective
to greater consideration of a patient's genotype.”
The specialty of orthodontics has a long and fasci-
nating history with respect to how it has interfaced
with the early study of heredity and the modern field
of genetics. From its inception, the leaders in orthodon-
tics have recognized the need to understand heredity as
it relates to normal and abnormal development of face,
jaws, and teeth. Although understanding of heredity and
genetics, historically in orthodontics, has been naïve and
even fanciful in some instances, this has been more a
result of the level of scientific maturity and understand-
ing, as well as translation, of the principles of genetics.
Genetics did not become generally applicable in a mean-
ingful way to issues and concerns in orthodontics until
late in the 20th century. However, with advances in ge-
netics over the past 20 years or more, conditions are ideal
American Journal of Orthodontics and Dentofacial Orthopedics
935
for orthodontics to make a quantum leap into a
modern precision orthodontics era. The members
of the entire orthodontic community—researchers,
clinician-scientists, and practitioners alike—should be
incredibly excited as they look forward to use the discov-
eries and conceptual advancements that continue to be
made in basic and applied clinical genetics as well as in
current orthodontic research in modern genetics that
will lead to greater understanding not only of dentofa-
cial development and growth but also of the highly sig-
nificant advances that will be made toward the most
efficacious approaches for treatment of malocclusion
and dentofacial deformities for orthodontic patients.
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