The Synthesis Paradigm in Genetics

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.MAJOR 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 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 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.     

Introduction and Institutionalization of Genetics in Mexico Ana Barahona,Susana Pinar and Francisco J. Ayala

We explore the distinctive characteristics of Mexico’s society, politics and history that impacted the establishment of genetics in Mexico, as a new disciplinary field that began in the early 20th century and was consolidated and institutionalized in the second half. We identify about three stages in the institutionalization of genetics in Mexico. The first stage can be characterized by Edmundo Taboada, who was the leader of a research program initiated during the Cárdenas government (1934–1940), which was primarily directed towards improving the condition of small Mexican farmers. Taboada is the first Mexican post-graduate investigator in phytotechnology and phytopathology, trained at Cornell University and the University of Minnesota, in 1932 and 1933, respectively. He was the first investigator to teach plant genetics at the National School of Agriculture and wrote the first textbook of general genetics, Genetics Notes, in 1938. Taboada’s most important single genetics contribution was the production of “stabilized” corn varieties. The extensive exile of Spanish intellectuals to Mexico, after the end of Spain’s Civil War (1936–1939), had a major influence in Mexican science and characterizes the second stage. The three main personalities contributing to Mexican genetics are Federico Bonet de Marco and Bibiano Fernández Osorio Tafall, at the National School of Biological Sciences, and José Luis de la Loma y Oteyza, at the Chapingo Agriculture School. The main contribution of the Spanish exiles to the introduction of genetics in Mexico concerned teaching. They introduced in several universities genetics as a distinctive discipline within the biology curriculum and wrote genetics text books and manuals. The third stage is identified with Alfonso León de Garay, who founded the Genetics and Radiobiology Program in 1960 within the National Commission of Nuclear Energy, which had been founded in 1956. The Genetics and Radiobiology Program rapidly became a disciplinary program, for it embraced research, teaching, and training of academics and technicians. The Mexican Genetics Society, created by de Garay in 1966, and the development of strains and cultures for genetics research were important activities. One of de Garay’s key requirements was the compulsory training of the Program’s scientists for at least one or two years in the best universities of the United States and Europe. De Garay’s role in the development of Mexican genetics was fundamental. His broad vision encompassed the practice of genetics in all its manifestations.     

Genetics of mosquitoes

Beginning in the mid-1950s, much progress has been made in studying various aspects of the genetics of mosquitoes, particularly involving several species of three principal genera,Aedes, Culex andAnopheles, that transmit important human diseases. Here I discuss selected areas of research involving formal genetics; genome structure, organization and evolution at the interspecific and intraspecific level; and evolutionary genetics of theAedes scutellaris group. Information and insights gained from in-depth analyses of these areas, particularly transmission genetics, cytogenetics and genetics of chromosomal rearrangements, and of mutagen-induced sexual sterility, have proved invaluable for the development of the theory and evaluation of feasibility of genetic control of natural populations. As a result, mosquitoes represent some of the best studied taxa at various levels of genetic organization. Recent developments in molecular genetics offer exciting possibilities for extension of these concepts.     

Genetics of heart failure

Heart failure (HF) occurs when the cardiac output, no longer compensated by endogenous mechanisms, fails to meet the metabolic demands of the body. In most populations, the prevalence of heart failure continues to rise, constituting a major public health burden, especially in developed countries. There is some evidence that the risk of HF in the general population depends on genetic predisposition, necessarily characterised by a very complex architecture. In a small, but probably underestimated proportion, HF is caused by Mendelian inherited forms of myocardial disease. The genetic background of these genetic conditions is a matter of intensive research that is already shedding light onto the genetics of common sporadic forms of HF. In this review, we briefly review the insights provided by candidate gene and genome-wide association approaches in common HF and then describe the main genetic causes of inherited heart muscle disease. Finally we present the current challenges and future research needs for both forms of HF. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.     

植物化学遗传学：一种崭新的植物遗传学研究方法

化学遗传学（chemical genetics,也称为化学基因组学,chemical genomics）研究方法是利用生物活性小分子扰动蛋白分子互作过程来研究有关的生命现象,是常规遗传学研究方法的补充和延伸。化学遗传学在植物科学中的应用——植物化学遗传学的研究在短短几年内,凭借其作为一种新的遗传学研究方法所具备的独特优势（如能够克服常规遗传学研究中的遗传冗余、突变致死难题及可提供特异强度、作用时间点上的条件性遗传扰动等）,已开始解决一些植物分子生物学中长期存在的研究难题。本文就植物化学遗传学的一般原理及其方法,以及它作为一种新的遗传学研究方法的优势及特点作一个综述．     

Key questions in the genetics and genomics of eco-evolutionary dynamics

Increasing acceptance that evolution can be ‘rapid'' (or ‘contemporary'') has generated growing interest in the consequences for ecology. The genetics and genomics of these ‘eco-evolutionary dynamics'' will be—to a large extent—the genetics and genomics of organismal phenotypes. In the hope of stimulating research in this area, I review empirical data from natural populations and draw the following conclusions. (1) Considerable additive genetic variance is present for most traits in most populations. (2) Trait correlations do not consistently oppose selection. (3) Adaptive differences between populations often involve dominance and epistasis. (4) Most adaptation is the result of genes of small-to-modest effect, although (5) some genes certainly have larger effects than the others. (6) Adaptation by independent lineages to similar environments is mostly driven by different alleles/genes. (7) Adaptation to new environments is mostly driven by standing genetic variation, although new mutations can be important in some instances. (8) Adaptation is driven by both structural and regulatory genetic variation, with recent studies emphasizing the latter. (9) The ecological effects of organisms, considered as extended phenotypes, are often heritable. Overall, the study of eco-evolutionary dynamics will benefit from perspectives and approaches that emphasize standing genetic variation in many genes of small-to-modest effect acting across multiple traits and that analyze overall adaptation or ‘fitness''. In addition, increasing attention should be paid to dominance, epistasis and regulatory variation.     

Genetics and Lineage-Specific Evolution of a Lethal Hybrid Incompatibility Between Drosophila mauritiana and Its Sibling Species

The Dobzhansky–Muller model posits that intrinsic postzygotic reproductive isolation—the sterility or lethality of species hybrids—results from the evolution of incompatible epistatic interactions between species: favorable or neutral alleles that become fixed in the genetic background of one species can cause sterility or lethality in the genetic background of another species. The kind of hybrid incompatibility that evolves between two species, however, depends on the particular evolutionary history of the causative substitutions. An allele that is functionally derived in one species can be incompatible with an allele that is functionally derived in the other species (a derived-derived hybrid incompatibility). But an allele that is functionally derived in one species can also be incompatible with an allele that has retained the ancestral state in the other species (a derived-ancestral hybrid incompatibility). The relative abundance of such derived-derived vs. derived-ancestral hybrid incompatibilities is unknown. Here, we characterize the genetics and evolutionary history of a lethal hybrid incompatibility between Drosophila mauritiana and its two sibling species, D. sechellia and D. simulans. We show that a hybrid lethality factor(s) in the pericentric heterochromatin of the D. mauritiana X chromosome, hybrid lethal on the X (hlx), is incompatible with a factor(s) in the same small autosomal region from both D. sechellia and D. simulans, Suppressor of hlx [Su(hlx)]. By combining genetic and phylogenetic information, we infer that hlx-Su(hlx) hybrid lethality is likely caused by a derived-ancestral incompatibility, a hypothesis that can be tested directly when the genes are identified.     

Ecological studies of polyploidy in the 100 years following its discovery

Polyploidy is a mutation with profound phenotypic consequences and thus hypothesized to have transformative effects in plant ecology. This is most often considered in the context of geographical and environmental distributions—as achieved from divergence of physiological and life-history traits—but may also include species interactions and biological invasion. This paper presents a historical overview of hypotheses and empirical data regarding the ecology of polyploids. Early researchers of polyploidy (1910s–1930s) were geneticists by training but nonetheless savvy to its phenotypic effects, and speculated on the importance of genome duplication to adaptation and crop improvement. Cytogenetic studies in the 1930s–1950s indicated that polyploids are larger (sturdier foliage, thicker stems and taller stature) than diploids while cytogeographic surveys suggested that polyploids and diploids have allopatric or parapatric distributions. Although autopolyploidy was initially regarded as common, influential writings by North American botanists in the 1940s and 1950s argued for the principle role of allopolyploidy; according to this view, genome duplication was significant for providing a broader canvas for hybridization rather than for its phenotypic effects per se. The emphasis on allopolyploidy had a chilling effect on nascent ecological work, in part due to taxonomic challenges posed by interspecific hybridization. Nonetheless, biosystematic efforts over the next few decades (1950s–1970s) laid the foundation for ecological research by documenting cytotype distributions and identifying phenotypic correlates of polyploidy. Rigorous investigation of polyploid ecology was achieved in the 1980s and 1990s by population biologists who leveraged flow cytometry for comparative work in autopolyploid complexes. These efforts revealed multi-faceted ecological and phenotypic differences, some of which may be direct consequences of genome duplication. Several classical hypotheses about the ecology of polyploids remain untested, however, and allopolyploidy—regarded by most botanists as the primary mode of genome duplication—is largely unstudied in an ecological context.     

Genetics of complex disorders

The success stories of identifying genes in Mendelian disorders have stimulated research that aims at identifying the genetic determinants in complex disorders, in which both genetics, environment and chance affect the pathogenetic processes. This review summarizes the brief history and lessons learned from genetic analysis of complex disorders and outlines some landscapes ahead for medical research.     

The use of racial, ethnic, and ancestral categories in human genetics research

The global dispersal of anatomically modern humans over the past 100,000 years has produced patterns of phenotypic variation that have exerted—and continue to exert—powerful influences on the lives of individuals and the experiences of groups. The recency of our common ancestry and continued gene flow among populations have resulted in less genetic differentiation among geographically distributed human populations than is observed in many other mammalian species. Nevertheless, differences in appearance have contributed to the development of ideas about “race” and “ethnicity” that often include the belief that significant inherited differences distinguish humans. The use of racial, ethnic, and ancestral categories in genetics research can imply that group differences arise directly through differing allele frequencies, with little influence from socially mediated mechanisms. At the same time, careful investigations of the biological, environmental, social, and psychological attributes associated with these categories will be an essential component of cross-disciplinary research into the origins, prevention, and treatment of common diseases, including those diseases that differ in prevalence among groups.     

“One Health” or Three? Publication Silos Among the One Health Disciplines

The One Health initiative is a global effort fostering interdisciplinary collaborations to address challenges in human, animal, and environmental health. While One Health has received considerable press, its benefits remain unclear because its effects have not been quantitatively described. We systematically surveyed the published literature and used social network analysis to measure interdisciplinarity in One Health studies constructing dynamic pathogen transmission models. The number of publications fulfilling our search criteria increased by 14.6% per year, which is faster than growth rates for life sciences as a whole and for most biology subdisciplines. Surveyed publications clustered into three communities: one used by ecologists, one used by veterinarians, and a third diverse-authorship community used by population biologists, mathematicians, epidemiologists, and experts in human health. Overlap between these communities increased through time in terms of author number, diversity of co-author affiliations, and diversity of citations. However, communities continue to differ in the systems studied, questions asked, and methods employed. While the infectious disease research community has made significant progress toward integrating its participating disciplines, some segregation—especially along the veterinary/ecological research interface—remains.     

Genetics of Biomphalaria glabrata and its effect on the outcome of Schistosoma mansoni infection

The genetics of the snail Biomphalaria glabrata is better characterized than that of any other intermediate host of schistosomes of humans. Using techniques of selective breeding, several snail stocks have been developed that consistently display resistant or susceptible phenotypes. Investigators using these stocks have learned that several snail and parasite genes influence the course of parasite development. Here, Charles Richards, Matty Knight and Fred Lewis discuss the importance of the snail's genetics in categorizing resistance in this complex invertebrate, some recent molecular evidence that may help us understand several of the problems that still remain, and some challenges lying ahead for investigators in this field.     

Rational Extension of the Ribosome Biogenesis Pathway Using Network-Guided Genetics

Biogenesis of ribosomes is an essential cellular process conserved across all eukaryotes and is known to require >170 genes for the assembly, modification, and trafficking of ribosome components through multiple cellular compartments. Despite intensive study, this pathway likely involves many additional genes. Here, we employ network-guided genetics—an approach for associating candidate genes with biological processes that capitalizes on recent advances in functional genomic and proteomic studies—to computationally identify additional ribosomal biogenesis genes. We experimentally evaluated >100 candidate yeast genes in a battery of assays, confirming involvement of at least 15 new genes, including previously uncharacterized genes (YDL063C, YIL091C, YOR287C, YOR006C/TSR3, YOL022C/TSR4). We associate the new genes with specific aspects of ribosomal subunit maturation, ribosomal particle association, and ribosomal subunit nuclear export, and we identify genes specifically required for the processing of 5S, 7S, 20S, 27S, and 35S rRNAs. These results reveal new connections between ribosome biogenesis and mRNA splicing and add >10% new genes—most with human orthologs—to the biogenesis pathway, significantly extending our understanding of a universally conserved eukaryotic process.     

Valine-Resistance, a Potential Marker in Plant Cell Genetics. I. Distinction between Two Types of Valine-Resistant Tobacco Mutants Isolated from Protoplast-Derived Cells

In previous experiments, seven lines of valine-resistant plants were regenerated from protoplast-derived haploid tobacco mesophyll cells which had been UV mutagenized and submitted to selection by toxic concentrations of valine. In this study we described the transmission of valine-resistance to progeny and a preliminary phenotypical and biochemical characterization of the resistant plants.—Two types were thus distinguished among the seven mutant lines. Valine-resistance of the mutants of the first type (three lines) was transmitted as a single Mendelian dominant character (Vr1), whereas valine-resistance of the second type (four lines) was transmitted as a digenic recessive character (vr2 and vr3). Allelism tests revealed that the four recessive mutant lines yielded resistant progeny when intercrossed and, therefore, bear recessive mutant alleles at the same two unlinked loci.—When cultured at a density of 100 cell/ml, protoplast-derived cells of mutants of the first type had a low level of resistance to valine, whereas protoplast-derived cells of mutants of the second type displayed a high level of resistance to valine and to other amino acids.—According to the results of ¹⁴C-labelled amino acid uptake experiments, the amino acid resistance of mutants of the second type, but not valine-resistance of the first type, could be accounted for by reduced uptake of several amino acids. Possible uses of valine-resistance as a marker in plant cell genetics are discussed.     

Facultative parthenogenesis discovered in wild vertebrates

Facultative parthenogenesis (FP)—asexual reproduction by bisexual species—has been documented in a variety of multi-cellular organisms but only recently in snakes, varanid lizards, birds and sharks. Unlike the approximately 80 taxa of unisexual reptiles, amphibians and fishes that exist in nature, FP has yet to be documented in the wild. Based on captive documentation, it appears that FP is widespread in squamate reptiles (snakes, lizards and amphisbaenians), and its occurrence in nature seems inevitable, yet the task of detecting FP in wild individuals has been deemed formidable. Here we show, using microsatellite DNA genotyping and litter characteristics, the first cases of FP in wild-collected pregnant females and their offspring of two closely related species of North American pitviper snakes—the copperhead (Agkistrodon contortrix) and cottonmouth (Agkistrodon piscivorus). Our findings support the view that non-hybrid origins of parthenogenesis, such as FP, are more common in squamates than previously thought. With this confirmation, FP can no longer be viewed as a rare curiosity outside the mainstream of vertebrate evolution. Future research on FP in squamate reptiles related to proximate control of induction, reproductive competence of parthenogens and population genetics modelling is warranted.     

Phenotypic-dependent variability and the emergence of tolerance in bacterial populations

Ecological and evolutionary dynamics have been historically regarded as unfolding at broadly separated timescales. However, these two types of processes are nowadays well-documented to intersperse much more tightly than traditionally assumed, especially in communities of microorganisms. Advancing the development of mathematical and computational approaches to shed novel light onto eco-evolutionary problems is a challenge of utmost relevance. With this motivation in mind, here we scrutinize recent experimental results showing evidence of rapid evolution of tolerance by lag in bacterial populations that are periodically exposed to antibiotic stress in laboratory conditions. In particular, the distribution of single-cell lag times—i.e., the times that individual bacteria from the community remain in a dormant state to cope with stress—evolves its average value to approximately fit the antibiotic-exposure time. Moreover, the distribution develops right-skewed heavy tails, revealing the presence of individuals with anomalously large lag times. Here, we develop a parsimonious individual-based model mimicking the actual demographic processes of the experimental setup. Individuals are characterized by a single phenotypic trait: their intrinsic lag time, which is transmitted with variation to the progeny. The model—in a version in which the amplitude of phenotypic variations grows with the parent’s lag time—is able to reproduce quite well the key empirical observations. Furthermore, we develop a general mathematical framework allowing us to describe with good accuracy the properties of the stochastic model by means of a macroscopic equation, which generalizes the Crow-Kimura equation in population genetics. Even if the model does not account for all the biological mechanisms (e.g., genetic changes) in a detailed way—i.e., it is a phenomenological one—it sheds light onto the eco-evolutionary dynamics of the problem and can be helpful to design strategies to hinder the emergence of tolerance in bacterial communities. From a broader perspective, this work represents a benchmark for the mathematical framework designed to tackle much more general eco-evolutionary problems, thus paving the road to further research avenues.     

Genetics of Heading Time in Wheat (TRITICUM AESTIVUM L.). II. the Inheritance of Vernalization Response

The inheritance of vernalization response was studied in crosses involving four spring wheats (Sonora 64 (S), Pitic 62 (P), Justin (J) and Thatcher (T)) and three winter wheats (Blackhull (B), Early Blackhull (E) and Extra Early Blackhull (EE)).—All winter cultivars were highly responsive to vernalization, and Pitic 62 was the only spring cultivar whose time to heading was significantly accelerated following cold treatments. When vernalized and grown under long days, spring and winter cultivars became comparable in their heading response, indicating that cold requirement is the major attribute differentiating the heading behavior of true spring and true winter wheats.—Inheritance of growth habit in the F₁ generation of a five-parent diallel cross showed dominance of the spring character in all spring x winter crosses. Depending on the cross, one or two duplicate major genes governing growth habit were detected in F₂, F₃ and backcross generations grown in the field under long days in the absence of vernalizing temperatures. In some spring x winter crosses most of the variation in heading time among spring segregates could be attributed to the effects of major genes conditioning growth habit. In other crosses the heading patterns appeared more complex, indicating that genes with smaller effects are also involved in the control of heading response under spring or summer environments.—Evidence was presented supporting the hypothesis that the cultivar Pitic 62 carries a different allele at one of the two major loci governing its spring habit. This allele was associated with some response to vernalization and acted as a dominant gene determining earliness under low temperature vernalization, but as a partially recessive gene determining lateness in the absence of vernalizing temperatures. Genotypes were assigned to five cultivars as follows: S, CC DD; P, CC D'D'; J, cc DD; B and EE, cc dd.—The presence of major and minor genes and of multiple alleles governing response to photoperiod and vernalization was discussed in relation to the genetic manipulation of the heading response and to breeding wheat cultivars with specific or broad adaptation.