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
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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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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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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.
Literature Cited Arnqvist, G., and L. Rowe, 2005 Sexual Conflict. Princeton University Press, Princeton, NJ. Brandvain, Y., J., F. Van Cleve, Ubeda, and J. F. Wilkins, 2011 Demography, kinship, and the evolving theory of genomic imprinting. Trends Genet. 27: 251–257. Burt, A., and R. Trivers, 2006 Genes in Conflict: The Biology of Selfish Genetic Elements. Belknap Press, Cambridge, MA. Darwin, C., 1859 The Origin of Species by Means of Natural Selection: Or, the Preservation of Favored Races in the Struggle for Life. John Murray, London. Darwin, C., 1871 The Descent of Man and Selection in Relation to Sex. John Murray, London. Dawkins, R., 1976 The Selfish Gene. Oxford University Press, Oxford. Dobzhansky, T., 1973 Nothing in biology makes sense except in the light of evolution. Am. Biol. Teach. 35: 125–129. Doolittle, W. F., and C. Sapienza, 1980 Selfish genes, the phenotype paradigm and genome evolution. Nature 284: 601–603. Fisher, R. A., 1918 The correlation between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinb. 52: 399–433. Fisher, R. A., 1930 Sexual reproduction and sexual selection, pp. 135–162 in The Genetical Theory of Natural Selection. Clarendon Press, Oxford. Gillespie, J. H., 1991 The Causes of Molecular Evolution, Oxford University Press, Oxford. Hackett, J. A., and M. A. Surani, 2013 DNA methylation dynamics during the mammalian life cycle. Philos. Trans. R. Soc. Lond. B Biol. Sci. 368: 1–8. Haig, D., 1993 Genetic conflicts in human pregnancy. Q. Rev. Biol. 68: 495–532. Haig, D., and C. Graham, 1991 Genomic imprinting and the strange case of the insulin-like growth factor II receptor. Cell 64: 1045–1046. Haig, D., and M. Westoby, 1989 Parent-specific gene-expression and the triploid endosperm. Am. Nat. 134: 147–155. Haig, D., and M. Westoby, 1991 Genomic imprinting in endosperm: its effect on seed development in crosses between species, and between different ploidies of the same species, and its implications for the evolution of apomixis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 333: 1–13. Harris, H., 1966 Enzyme polymorphisms in man. Proc. R. Soc. Lond. B Biol. Sci. 164: 298–310. Hrdy, S. B., 1979 Infanticide among animals: a review, classification, and examination of the implications for the reproductive strategies of females. Ethol. Sociobiol. 1: 13–40. Kimura, M., 1955 Solution of a process of random genetic drift with a continuous model. Proc. Natl. Acad. Sci. USA 41: 144–150. Kimura, M., 1968 Evolutionary rate at the molecular level. Nature 217: 624–626. Kimura, M., 1984 The Neutral Theory of Molecular Evolution. Cambridge University Press, Cambridge, UK.
Kimura, M., and J. F. Crow, 1964 The number of alleles that can be maintained in a finite population. Genetics 49: 725–738. King, J. L., and T. H. Jukes, 1969 Non-Darwinian evolution. Science 164: 788–798. Köhler, C., P. Wolff, and C. Spillane, 2012 Epigenetic mechanisms underlying genomic imprinting in plants. Annu. Rev. Plant Biol. 63: 331–352. Lewontin, R. C., 1970 The units of selection. Annu. Rev. Ecol. Syst. 1: 1–18. Lewontin, R. C., and J. L. Hubby, 1966 A molecular approach to the study of genetic heterozygosity in natural populations. II. Amount of variation and degree of heterozygosity in natural populations of Drosophila pseudoobscura. Genetics 54: 595–609. McDonald, J. H., and M. Kreitman, 1991 Adaptive protein evolution at the Adh locus in Drosophila. Nature 351: 652–654. Meselson, M., and F. W. Stahl, 1958 The replication of DNA in Escherichia coli. Proc. Natl. Acad. Sci. USA 44: 671–682. Moore, T., and D. Haig, 1991 Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet. 7: 45–49. Morgan, T., A. Sturtevant, H. Muller, and C. Bridges, 1915 The Mechanism of Mendelian Heredity. Holt, New York. Ohta, T., and M. Kimura, 1971 On the constancy of the evolutionary rate of cistrons. J. Mol. Evol. 1: 18–25. Orgel, L. E., and F. H. Crick, 1980 Selfish DNA: the ultimate parasite. Nature 284: 604–607. Reik, W., and J. Walter, 2001 Genomic imprinting: parental influence on the genome. Nat. Rev. Genet. 2: 21–32. Rice, W., 2013 Nothing in genetics makes sense except in light of genomic conflict. Annu. Rev. Ecol. Evol. Syst. 44: 217–237. Tajima, F. 1989 Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123: 585– 595. Trivers, R. L., 1971 Evolution of reciprocal altruism. Q. Rev. Biol. 46: 35–57. Trivers, R., 1972 Parental investment and sexual selection, pp. 136–179 in Sexual Selection and the Descent of Man, 1871– 1971, edited by B. Campbell. Aldine Publishing, Chicago. Walker, P. M., 1979 Discussion of “Genes and non-coding DNA sequences,” pp. 39–45 in Symposium on Genetics and Human Biology: Possibilities and Realities, edited by R. Porter and M. O’Connor. Ciba Foundation, London. Watson, J. D., and F. H. C. Crick, 1953a Molecular structure of nucleic acids. Nature 171: 737–738. Watson, J. D., and F. H. C. Crick, 1953b Genetic implications of the structure of deoxyribonucleic acid. Nature 171: 964–967. Wright, S., 1931 Evolution in Mendelian populations. Genetics 16: 97. Zuckerkandl, E., and L. Pauling, 1965 Evolutionary divergence and convergence in proteins, pp. 97–165 in Evolving Genes and Proteins, edited by V. Bryson and H. J. Vogel. Academic Press, New York; London; San Diego. Communicating editor: A. S. Wilkins
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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,
368
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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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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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