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PERSPECTIVES
The Synthesis Paradigm in Genetics
William R. Rice1
Department of Ecology, Evolution and Marine Biology, University of California, Santa Barbara, California 93106
ABSTRACT Experimental genetics with model organisms and mathematically explicit genetic theory are generally considered to be the
major paradigms by which progress in genetics is achieved. Here I argue that this view is incomplete and that pivotal advances in
genetics—and other fields of biology—are also made by synthesizing disparate threads of extant information rather than generating
new information from experiments or formal theory. Because of the explosive expansion of information in numerous “-omics” data
banks, and the fragmentation of genetics into numerous subdisciplines, the importance of the synthesis paradigm will likely expand
with time.
AJOR advances in the field of genetics have been developed on a foundation supported by three major
pillars (i.e., paradigms, by which I mean a framework of
basic assumptions, logical approaches, and methodologies),
two of which are widely known and appreciated while the
third is rarely even acknowledged. The first major paradigm
is experimental genetics, especially in the context of model
organisms. The work of Thomas H. Morgan and his colleagues at Cal Tech during the early 20th century is a classic
example of this approach. A succession of elegant experimental studies by this research team led to the development
of the Drosophila melanogaster model system, which Morgan
et al. (1915) used to construct the first genomic map that
included genes assigned to precise locations on all of an
organism’s chromosomes. Their accumulated experimental
results also contributed importantly to their book, The Mechanism of Mendelian Heredity (1915), which many consider to
be the catalyst that launched the modern era of genetics.
The second paradigm is mathematically explicit genetic
theory. The succession of genetical theory papers published
throughout the first half of the 20th century by Ronald A.
Fisher is a classic example of this approach. Fisher’s work
reconciled a fundamental rift in the early history of modern
genetics—i.e., the genetic approaches of the Mendelians
(advocated by William Bateson and Hugo de Vries) vs. the
Galtonians (also known as the biometricians, represented in
particular by Karl Pearson and Walter F. Weldon)—by showing that Mendelian particulate inheritance could be unified
M
Copyright © 2014 by the Genetics Society of America
doi: 10.1534/genetics.113.160200
1
Address for correspondence: Department of Ecology, Evolution, and Marine Biology,
University of California, Santa Barbara, CA 93111. E-mail: [email protected]
with the quantitative genetics used to analyze continuously
varying traits such as height and weight (Fisher 1918). Although Darwin developed the basic framework of evolution,
it was Fisher—and contemporary theoreticians Sewall
Wright and J. B. S. Haldane—who integrated this qualitative
idea into a quantitatively explicit genetic theory that led to
the modern synthesis of evolution and launched the field of
evolutionary genetics (also known as population genetics
and summarized in Fisher’s now classic book, The Genetical
Theory of Natural Selection, first published in 1930). Of
course, some theory in genetics is not mathematically explicit, such as the “chromosomal theory of inheritance” or
the “central dogma.” But this form of theory usually represents the culmination of studies using the experimental genetics paradigm rather than a unique approach to genetics.
Most major advances in genetics have been achieved via one,
the other, or a combination of these experimental and theoretical paradigms. But there is a well-known exception: Watson
and Crick’s discovery of the structure of DNA (Watson and Crick
1953a,b, 11,000 combined citations—throughout, numbers of
citations are taken from Google Scholar—, and arguably the
pivotal publications that launched the modern field of molecular
genetics). Watson and Crick used no mathematical genetic
theory, nor did they do any critical experiments; instead, they
integrated many threads of established information (some unpublished) to deduce the chemical structure of the hereditary
material, i.e., the DNA double helix and how this structure could
explain gene replication. Although later experiments, such as
those of Meselson and Stahl (1958) on DNA replication, would
ultimately confirm the deduced structure and replication of DNA
that was proposed by Watson and Crick, the pivotal publications
of these researchers used neither the experimental nor the
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theory paradigms of genetics. Their approach exemplifies
what I will call the “synthesis paradigm.” Watson and Crick’s
work demonstrates that there is actually a trichotomy of
approaches—the experimental, theoretical-mathematical,
and theoretical-synthetic approaches—that combine like interwoven, reinforcing strands in a cord of historical advances in genetics.
In the next few sections I describe other instances in
which the synthesis paradigm has been of critical importance in the field of genetics. This set of examples is meant
to be illustrative and by no means exhaustive. Next I
illustrate how the synthesis paradigm has been of critical
importance in other fields of biology. Finally, I describe how
a fuller appreciation of the synthesis paradigm can influence
the training of the next cohort of geneticists and the career
trajectory of current geneticists.
The Process That Built Genetics
Darwin is generally credited as the father of the field of
evolution. But evolution is similarly acknowledged to be
both the source of, and dependent on, the action of the
hereditary material: evolution and heredity are inextricably
intertwined (see Dobzhansky 1973). For this reason, Darwin’s
discovery of the process of evolution by natural selection is
properly included in the realm of genetics. Darwin’s theory of
evolution was inspired by his natural history observations
while working as a commissioned naturalist on a voyage that
circumnavigated the globe. However, his landmark publication On the Origin of Species (Darwin 1859, 23,000 citations) was a synthesis of information from the fields of
domestic plant and animal breeding, embryology, geology,
geography, climatology, demography, ecology, and natural
history. Like the work of Watson and Crick (1953a,b), Darwin’s
landmark publication was the synthesis of diverse forms of
extant information (published and unpublished) that led to
a new and pivotal discovery: the ultimate process (adaptation by natural selection) that generates most biological
diversity and, thereby, most genetic diversity. Although
Darwin’s specific hypothesis of heredity, the idea of “pangenesis,” was wrong, Darwin’s work in On the Origin of
Species may be considered the first example of the “synthesis
paradigm.”
Genes That Do Not Code for “Phenotypes”
Dating back to Mendel’s early experiments, and the parallel
works by domestic plant and animals breeders on continuous traits, the focus of the field of genetics was to build an
understanding of how the hereditary material coded for the
phenotypic attributers of organisms and how this information was replicated and transmitted across generations. But
there was a paradigm shift that occurred during the third
quarter of the 20th century that expanded this view: the
existence of selfish DNA. Selfish genetic elements, such as
transposable elements, meiotic drivers, segregation distorters,
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W. R. Rice
B chromosomes, cytoplasmic sterility, and paternal genome
loss, were well documented in the first half of the 20th
century (reviewed in Burt and Trivers 2006), but the significance of these phenomena remained unappreciated by most
biologists. A shift in thinking, however, began with Richard
Dawkins’ book The Selfish Gene (1976, 16,000 citations).
This synthesis work championed the gene-centered view of
the heredity material as opposed to the organism-centered
view. Genomes and their constituent genes were conventionally viewed as a blueprint used to transform a fertilized
egg into a functional adult organism (e.g., Morgan et al.
1915). But from the selfish gene perspective, individual
genes were seen as the focal unit of genetics and evolution.
Genes were persistent and truly replicated themselves,
whereas organisms were little more than ephemeral, throwaway gene-transport machines coded by genes and enabling
their sequences to persist over vast periods of time. Many
biologists dismissed the significance of this view as an issue
of semantics because the mathematical models of evolution
developed during the modern synthesis were based on the
fitness of individual genes (albeit through the reproductive
performance of the organisms that carried them) and because previous articles (e.g., Lewontin 1970) had already
established the occurrence and significance of gene-based
selection.
The significance of the selfish DNA idea, however, was
soon bolstered by a pair of back-to-back articles published in
Nature trying to understand the genetic significance of vast
amounts of DNA (sometimes constituting most of a multicellular organism’s genome) that did not affect in in any visible
way the phenotypes of organisms (Doolittle and Sapienza
1980; Orgel and Crick 1980; 3000 citations collectively).
In this pair of complementary articles, many studies encompassing a wide diversity of enigmatic phenomena—e.g., the
C-value paradox, transposable elements, introns, middlerepetitive DNA, and simple reiterative DNA sequences—were
used to deduce that at least part of the genome of all species
gained a replicative advantage not by influencing the phenotypes of the organism as a whole, but by influencing only
subcellular phenotypes associated only with their DNA’s replication [termed “nonphenotypic selection” by Doolittle and
Sapienza (1980) and characterized as distinct because “it
makes no specific contribution to the phenotype” by Orgel
and Crick (1980)]. Of course the DNA did code for “phenotypes,” but these were subcellular traits that frequently had
no expression at the organismal level. The DNA was selfish
because its fitness advantage depended only on its own replication, irrespective of any collateral harm to the reproduction of other parts of the genome or the organism as
a whole. To be fair, the foundation for diverse forms of selfish DNA was established decades before these two highprofile publications in Nature (e.g., articles on selfish elements
like meiotic drivers and segregation distorters, as described
in the previous paragraph), and other contemporary biologists had also anecdotally proposed the idea of selfish DNA
[e.g., see the discussion in Walker (1979) on genes and
noncoding DNA sequences]. Nonetheless, the three publications described here—especially Doolittle and Sapienza
(1980) and Orgel and Crick (1980)—are generally credited
with synthesizing the diverse evidence needed to forge the
paradigm shift that significant parts of all genomes have
nothing to do with coding for aspects of the phenotype of
organisms and were instead a parallel genetic realm with
a form, function, and evolution that operated predominantly
at the suborganismal level. These publications relied exclusively on a synthesis of many threads of established information rather than on new insights from a pivotal experiment
with a model organism or a mathematically explicit genetical
theory. The selfish DNA paradigm also fostered a completely
new subdiscipline in genetics—the study of genomic conflict
(reviewed in Arnqvist and Rowe 2005; Burt and Trivers
2006), which influences virtually all subdisciplines of genetics
(Rice 2013).
The Wild-Type Allele
Until the 1960s, the conventional view of allelic diversity
was that most gene loci were represented by a single
predominant “wild-type” allele with rare alternative alleles
maintained by mutation-selection balance. Some loci, such
as those controlling ABO and Rh+/Rh2 blood types were
well established to be highly polymorphic, but these were
considered to be rare exceptions to a more general rule. This
monolithic “wild-type” paradigm was shattered by a series of
articles showing widespread polymorphism at many gene
loci (Zuckerkandl and Pauling 1965; Harris 1966; Lewontin
and Hubby 1966). But what was the process responsible
for maintaining the newly uncovered and widespread
polymorphism?
Kimura (1955) built a genetic foundation for one possible
explanation for widespread polymorphism by adapting
a complex mathematical approach—diffusion theory (employing the Fokker–Planck equation or Kolmogorov forward equation), which was originally developed in the context of
chemistry and particle physics—to quantify the frequency
spectrum of neutral and weakly selected genetic variation
in finite populations. Next, Kimura and Crow (1964) extended this approach, and that of Wright (1931), to predict
the potential widespread polymorphism of neutral variation
in large finite populations. This theoretical foundation set
the stage for a radical hypothesis: the vast majority of the
recently uncovered allelic polymorphisms (and fixed differences between species) represented selectively neutral
alleles rather than being due to balancing selection on
alleles producing alternative, selectively relevant phenotypes or transient polymorphisms associated with one allele
being selectively replaced by another (Kimura 1968; King
and Jukes 1969; Ohta and Kimura 1971). At this point in
time, the paradigm shift (that polymorphisms were common)
and the hypothesized new explanation (neutral theory) were
based on the traditional paradigms of experimental and theoretical genetics. But the next phase in understanding this
new view of genetic variation was strongly influenced by
the synthesis paradigm.
Over the decade following the publications proposing the
neutral theory of molecular evolution, a torrent of empirical
and theoretical articles were published both supporting and
refuting neutral theory, with no clear consensus. To break
the impasse, Kimura devoted 3 years of his career to write
his seminal book entitled The Neutral Theory of Molecular
Evolution” (Kimura 1984). The book was a synthesis of the
previous two decades of theoretical research on genetic variation in finite populations and empirical work in molecular
genetics. It was widely cited (it currently has 7000 citations, approaching the level of Watson and Crick’s synthesis
study on the structure of DNA), and it led to a widespread
acceptance of neutral theory by much of the biological community. It was not until a second seminal book by John
Gillespie entitled The Causes of Molecular Evolution (Gillespie
1991, 1000 citations) that the tide began to turn. Gillespie
synthesized a broad spectrum of biochemical studies to
provide compelling evidence that, when the requisite empirical data were available, there was consistently strong
evidence that a substantial proportion of substitutions between species and polymorphisms within species had function consequences that were unlikely to be selectively
neutral.
It is now clear from more recently developed analytical
tests for neutrality [e.g., Tajima’s D test (Tajima 1989) and
the McDonald–Kreitman test (McDonald and Kreitman
1991)] and their application to an ever-expanding digital
tome of DNA sequences that both selectively neutral and
non-neutral genetic variation contribute importantly to the
widespread polymorphisms first uncovered in the 1960s.
Tracing the history of the neutral theory controversy demonstrates how synthesis studies like those of Kimura (1984)
and Gillespie (1991) can play as large a role, or a larger one,
as studies based on experimentation with model organisms
and mathematically explicit genetical theory in propelling
scientific advance in the field of genetics. This example also
illustrates how some controversies in genetics are too big
and complex to be resolved by a critical experiment or theoretical study and how advance requires a synthesis of extensive and disparate extant information.
Genomic Imprinting
The discovery that hereditary information can be silent in
some generations and expressed in others dates back to the
classic experiments of Mendel on dominant and recessive
alleles. But in the 1980s a new form of silent allele was
discovered: genomic imprinting. Experiments with mice and
corn demonstrated that the expression of some genes
depended not on their dominant/recessive interaction but
instead on their parent of origin (reviewed in Reik and
Walter 2001). This early work was followed by a succession
of experiments that revealed the molecular processes underlying genomic imprinting (reviewed in Köhler et al. 2012;
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Hackett and Surani 2013). These experiments led to
a mechanistic understanding of genomic imprinting but told
us nothing about its functional underpinning; i.e., what
purpose did imprinting achieve and why did imprinting
evolve? In a series of synthesis articles written by David
Haig and his collaborators (Haig and Westoby 1989,
1991; Haig and Graham 1991; Moore and Haig 1991; Haig
1993), a convincing case was made that genomic imprinting evolved in large part due to a tug-of-war between paternal and maternal genes in offspring influencing the level
of maternal investment that they receive, and 20 years
of subsequent studies strongly support this conclusion
(Brandvain et al. 2011). In the case of genomic imprinting,
its discovery and advances in underlying its molecular mechanisms were accomplished via the paradigm of experimentation in model systems, but an understanding of the functional
significance of imprinting was achieved via the synthesis
paradigm.
Other Disciplines
The synthesis paradigm has also been important outside the
field of genetics. Here I briefly summarize a few examples.
The phenomenon of sexual selection occurs when some
individuals (usually males) are better at securing mates
and/or excel in sperm competition within multiply mated
females. Sexual selection sometimes favors counterintuitive
phenotypes, such as a peacock’s tail, that reduce survival
when there is a counterbalancing advantage in mating or
fertilization success. The existence, prevalence, and importance of sexual selection was first articulated in a synthesis
publication by Charles Darwin [The Descent of Man and Selection in Relation to Sex (1871), 13,000 citations], and its
first major advance was also via a synthesis work by Ronald
Fisher (“Sexual reproduction and sexual selection,” in The
Genetical Theory of Natural Selection 1930, 14,000 citations). In the areas of animal behavior, synthesis works by
Robert Trivers on reciprocal altruism (Trivers (1971, 7000
citations) and parental investment (Trivers 1972, 9000
citations) had a paradigm-setting influence on our understanding of how levels of cooperation are structured between unrelated individuals and within families. From my
perspective, Trivers’ work equals or surpasses in importance
that of any experimental or mathematically explicit study in
the field of ethology. For this work, Trivers received the
2007 Crafoord Prize from the Royal Swedish Academy of
Sciences. This prize is the equivalent of a Nobel Prize for
scientific disciplines outside of physics, chemistry, physiology, and medicine. An example of a paradigm-setting synthesis publication in anthropology is Sarah Hrdy’s 1979
article on the relationship between sexual selection and infanticide. Infanticide was originally viewed by anthropologists as an aberrant mistake of displaced aggression, but
Hrdy’s synthesis article showed that it is instead a predicted
and adaptive behavior that evolved across many diverse taxa
in response to sexual selection.
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W. R. Rice
The Next Generation of Geneticists and the Already
Established Ones
I think that an understanding and an appreciation of the
synthesis paradigm is important when planning how we
train our students. As the amount of new information in all
disciplines of science expands at an accelerating rate, there
is a natural tendency to narrow curricula so that students
are better trained in their area of specialization. But we are
now experiencing a qualitatively new era in which data
banks for genes, genomes, transcriptomes, epigenomes,
proteomes, micromes, microbiomes, and genetic networks
are accumulating far more rapidly than our analysis and
understanding of these behemoth archives. The backlog of
analysis and interpretation of these ever-expanding databases makes it all the more likely that the synthesis
paradigm will become even more important in generating
major advances in genetics and other fields of biology. The
people who will make these synthetic discoveries will be like
Watson and Crick: capable of integrating threads of disparate information across multiple scientific disciplines. For
this reason I think that it will be the more broadly trained
students—who are capable of participating in interdisciplinary collaborations—who will make many of the major genetic discoveries in the near future.
Another way to envision the crucial role of the synthesis
paradigm during an explosive period of information expansion in genetics is to compare it with the design of search
engines and other information technologies needed to
process the exponentially increasing amount of digital
information. Most advances are a consequence of specialists
producing new hardware or software (metaphorically analogous to empiricists and mathematically explicit theoreticians). But there is also a crucial role for “big picture”
individuals who find connections and integrate across structural subdivisions to make major advances via a synthesis of
extant technologies and information. To be the architect of
such big picture advances, one needs to be sufficiently
trained in and knowledgeable about several subdisciplines.
Almost all senior, well-established geneticists began their
careers as experimentalists or mathematical theoreticians,
and our laboratories and grants are structured around these
approaches. However, as our careers progress, our knowledge
and experience continually accrue. In parallel, our capacity to
successfully utilize the synthesis paradigm continually increases.
As a consequence, our approach to research may also need to
adapt to this changing balance, with ever greater emphasis on
the synthesis paradigm as our careers mature.
Acknowledgments
I thank Urban Friberg for his comments and suggestions on
an early draft of this manuscript and Kathryn Schoenrock for
copyediting assistance. I also thank the “Perspectives” editor,
Adam Wilkins, and two anonymous referees for helpful comments on the manuscript and suggestions for improvements.
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