Autism Spectrum Disorder (ASD) is extremely heterogeneous clinically and genetically. There is a pressing need for a better understanding of the heterogeneity of ASD based on scientifically rigorous approaches centered on systematic evaluation of the clinical and research utility of both phenotype and genotype markers. This paper presents a holistic PheWAS-inspired method to identify meaningful associations between ASD phenotypes and genotypes. We generate two types of phenotype-phenotype (p-p) graphs: a direct graph that utilizes only phenotype (...) data, and an indirect graph that incorporates genotype as well as phenotype data. We introduce a novel methodology for fusing the direct and indirect p-p networks in which the genotype data is incorporated into the phenotype data in varying degrees. The hypothesis is that the heterogeneity of ASD can be distinguished by clustering the p-p graph. The obtained graphs are clustered using network-oriented clustering techniques, and results are evaluated. The most promising clusterings are subsequently analyzed for biological and domain-based relevance. Clusters obtained delineated different aspects of ASD, including differentiating ASD-specific symptoms, cognitive, adaptive, language and communication functions, and behavioral problems. Some of the important genes associated with the clusters have previous known associations to ASD. We found that clusters based on integrated genetic and phenotype data were more effective at identifying relevant genes than clusters constructed from phenotype information alone. These genes included five with suggestive evidence of ASD association and one known to be a strong candidate. (shrink)

Diseases causing inherited retinal degeneration in humans, such as retinitis pigmentosa and macular dystrophy, are genetically heterogeneous and clinically diverse. More than 40 genes causing retinal degeneration have been mapped to specific chromosomal sites; of these, at least 10 have been cloned and characterized. Mutations in two proteins, rhodopsin and peripherin/RDS, account for approximately 35% of all cases of autosomal dominant retinitis pigmentosa and a lesser fraction of other retinal conditions. This target article reviews the genes and mutations causing retinal (...) degeneration and proposes mechanisms whereby specific mutations lead to particular clinical consequences, that is, the relationship between genotype and phenotype. Retinitis pigmentosa and macular dystrophy are genetically heterogeneous diseases that cause retinal degeneration in humans and often result in severe visual impairment or blindness. Although many of the genes causing these diseases have not been identified, three photoreceptor-specific proteins have been implicated: rhodopsin, peripherin/RDS, and the P-subunit of rod phosphodiesterase. Mutations in the genes for these three proteins can cause either dominant retinitis pigmentosa, recessive retinitis pigmentosa, dominant congenital stationary night blindness, or dominant macular degeneration. Why this multiplicity of clinical phenotypes? Our target article summarizes the genetic and biochemical background to this question and proposes a number of possible explanations. Discussion focuses mainly on 73 distinct disease-causing mutations of rhodopsin. We feel that rhodopsin and other photoreceptor proteins can serve as model systems for unraveling the connection between genotype and phenotype, not only for inherited retinal diseases but for other degenerative disorders as well. (shrink)

Noting minimal philosophical attention to the shift of the meanings of “genotype” and “phenotype,” and their distinction, as well as to the variety of meanings that have co-existed over the last hundred years, this note invites readers to join in exploring the implications of shifts that have been left unexamined.

A number of debates in philosophy of biology and psychology, as well as in their respective sciences, hinge on particular views about the relationship between genotypes and phenotypes. One such view is that the genotype-phenotype relationship is relatively straightforward, in the sense that a genome contains the ?genes for? the various traits that an organism exhibits. This leads to the assumption that if a particular set of traits is posited to be present in an organism, there must be (...) a corresponding number of genes in that organism's genome to account for those traits. This assumption underlies what can be called the ?counting argument,? in which empirical estimates of the number of genes in a genome are used to support or refute particular hypotheses in philosophical debates about biology and psychology. In this paper, we assess the counting argument as it is used in discussions of the alleged massive modularity of the brain, and conclude that this argument cannot be upheld in light of recent philosophical work on gene concepts and empirical work on genome complexity. In doing so, we illustrate that there are those on both sides of the debate about massive modularity who rely on an incorrect view of gene concepts and the nature of the genotype-phenotype relationship. (shrink)

Charney's dismissal of well-established methods in behavioral genetic research is misguided. He claims that studies of heritability and genetic association depend for their validity on six assumptions, but he cites no sources to support this claim. We explain why none of the six assumptions is strictly necessary for the utility of either method of genetic analysis.

In a now classic paper published in 1991, Alberch introduced the concept of genotype–phenotype (G!P) mapping to provide a framework for a more sophisticated discussion of the integration between genetics and developmental biology that was then available. The advent of evo-devo first and of the genomic era later would seem to have superseded talk of transitions in phenotypic space and the like, central to Alberch’s approach. On the contrary, this paper shows that recent empirical and theoretical advances have (...) only sharpened the need for a different conceptual treat- ment of how phenotypes are produced. Old-fashioned metaphors like genetic blueprint and genetic programme are not only woefully inadequate but positively misleading about the nature of G!P, and are being replaced by an algorithmic approach emerging from the study of a variety of actual G!P maps. These include RNA folding, protein function and the study of evolvable soft- ware. Some generalities are emerging from these disparate fields of analysis, and I suggest that the concept of ‘developmental encoding’ (as opposed to the classical one of genetic encoding) provides a promising computational–theoretical underpinning to coherently integrate ideas on evolvability, modularity and robustness and foster a fruitful framing of the G!P mapping problem. (shrink)

Phenotype, whether conventional or extended, is defined as a reflectionof an underlying genotype. Adaptation and the natural selection thatfollows from it depends upon a progressively harmonious fit betweenphenotype and environment. There is in Richard Dawkins' notion ofthe extended phenotype a paradox that seems to undercut conventionalviews of adaptation, natural selection and adaptation. In a nutshell, ifthe phenotype includes an organism's environment, how then can theorganism adapt to itself? The paradox is resolvable through aphysiological, as opposed to (...) a genetic, theory of natural selection andadaptation. (shrink)

The distinction between phenotype and genotype is fundamental to the understanding of heredity and development of organisms. The genotype of an organism is the class to which that organism belongs as determined by the description of the actual physical material made up of DNA that was passed to the organism by its parents at the organism's conception. For sexually reproducing organisms that physical material consists of the DNA contributed to the fertilized egg by the sperm and egg (...) of its two parents. For asexually reproducing organisms, for example bacteria, the inherited material is a direct copy of the DNA of its parent. The phenotype of an organism is the class to which that organism belongs as determined by the description of the physical and behavioral characteristics of the organism, for example its size and shape, its metabolic activities and its pattern of movement. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:The Phenotype/Genotype Distinction and the Disappearance of the BodyGabriel GuddingThe discipline of genetics has long been a rhetorical and heuristic locus for social and political issues. As such, the science has influenced culture through the avenues of law, medicine, warfare, social work, and even, since 1972 in California, the education of kindergarten students. It has affected how we view the body, morality, romance, biography, and agency—not to (...) mention procreation and death.In many ways the delamination of genotype from phenotype was the first cut, so to speak, in this new cosmetics of life. The distinction between structure and expression arose from an interdisciplinary struggle for authority in the biological sciences at the turn of the century. This preceptual split in the organism between structure and expression came over time to fundamentally alter the percepts of the body, in terms of how the body is juridically, medicinally, and otherwise, generally perceived and understood. More importantly and interestingly, this delamination within the organism between its genotype and phenotype eventually led to a sense of the body’s fragility and its eventual “disappearance” as a seat of agency, morality, and identity; and in turn these three groundings of modernity have been redistributed to the gene, the genotype, and the genome. In one sense, then, this paper traces not so much the birth of a new view of the body (the genetic) but the drama of its disappearance, in which the body melts to a silhouette and is replaced by the genotype and its expression, the phenotype.In 1911 Wilhelm Johannsen of the University of Copenhagen published “The Genotype Conception of Heredity,” 1 which introduced to geneticists the ideas of “phenotype” and “genotype.” Johannsen coined these terms in objection to what he considered to be an erroneous conception of heredity, [End Page 525] which he called the “transmission view”: the idea that “personal qualities” (such as honesty or good looks) could themselves be or otherwise influence “the true heritable elements or traits” passed on from one generation to another. He called this transmission view “apparent heredity” and claimed that this idea relied upon an economic-juridical model of the transmission of property—and thereby provided no disciplined or profound understanding of true heredity. He asserted that in factthe transmission-conception of heredity represents exactly the reverse of the real facts, just as the famous Stahlian theory of “phlogiston” was an expression diametrically opposite to the chemical reality. The personal qualities of any individual organism do not at all cause the qualities of its offspring; but the qualities of both ancestor and descendent are in quite the same manner determined by the nature of the “sexual substances”—i.e., the gametes—from which they have developed. Personal qualities are then the reactions of the gametes joining to form a zygote; but the nature of the gametes is not determined by the personal qualities of the parents or ancestors in question. This is the modern view of heredity. 2This was indeed a profoundly new view of heredity: Johannsen quite boldly and deliberately intended his genotype-phenotype distinction to stand as a watershed between the old science of heredity—exemplified by Mendel, Galton, Weismann, and others—and the new science of genetics. He said, “The science of genetics is in a transition period, becoming an exact science just as the chemistry in the times of Lavoisier, who made the balance an indispensable implementation in chemical research.” 3 And he was right: genetics was indeed in a transition period, primarily due to the theoretically accommodating qualities of this new distinction. The science of genetics became radically simplified: the confusion which arose from the attempts to correlate characteristics to their corresponding units of hereditarian influence diminished. Viewing personal qualities and characteristics, in all their variation, as expressions of underlying structures instead of mutual correlates to them drastically simplified the theoretical and experimental aspects of heredity.Not only did this distinction revolutionize the science of heredity, it helped insinuate the new science of genetics into a position of autonomy and authority with respect to the other life sciences. Historians of science, such as Jan Sapp, have suggested that the genotype-phenotype distinction played a... (shrink)

DNA sequence variation is abundant in wild populations. While molecular biologists use genetically homogeneous strains of model organisms to avoid this variation, evolutionary biologists embrace genetic variation as the material of evolution since heritable differences in fitness drive evolutionary change. Yet, the relationship between the phenotypic variation affecting fitness and the genotypic variation producing it is complex. Genetic buffering mechanisms modify this relationship by concealing the effects of genetic and environmental variation on phenotype. Genetic buffering allows the build-up and (...) storage of genetic variation in phenotypically normal populations. When buffering breaks down, thresholds governing the expression of previously silent variation are crossed. At these thresholds, phenotypic differences suddenly appear and are available for selection. Thus, buffering mechanisms modulate evolution and regulate a balance between evolutionary stasis and change. Recent work provides a glimpse of the molecular details governing some types of genetic buffering. BioEssays 22:1095–1105, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Models of gene regulatory networks have proven useful for understanding many aspects of the highly complex behavior of biological control networks. Randomly generated non-Boolean networks were used in experimental simulations to generate data on dynamic phenotypes as a function of several genotypic parameters. We found that predictive relationships between some phenotypes and quantitative genotypic parameters such as number of network genes, interaction density, and initial condition could be derived depending on the strength of the topological genotype on specific phenotypes. (...) We quantitated the strength of the topological genotype effect on a number of phenotypes in multi-gene networks. For phenotypes with a low influence of topological genotype, derived and empirical relationships using quantitative genotype parameters were accurate in phenotypic outcomes. We found a number of dynamic network properties, including oscillation behaviors, that were largely dependent on genotype topology, and for which no such general quantitative relationships were determinable. It remains to be determined if these results are applicable to biological gene regulatory networks. (shrink)

Although undoubtedly it will be incomplete by the time it is published, the target article by Daiger et al. organizes mutations in genes that produce retinal degenerations in humans into categories of clinically relevant phenotypes. Such classifications should help us understand the link between altered photoreceptor cell proteins and subsequent cell death, and they may yield insight into methods for preventing consequent blindness.

Evolutionary biology is paying increasing attention to the mechanisms that enable phenotypic plasticity, evolvability, and extra‐genetic inheritance. Yet, there is a concern that these phenomena remain insufficiently integrated within evolutionary theory. Understanding their evolutionary implications would require focusing on phenotypes and their variation, but this does not always fit well with the prevalent genetic representation of evolution that screens off developmental mechanisms. Here, we instead use development as a starting point, and represent it in a way that allows genetic, environmental (...) and epigenetic sources of phenotypic variation to be independent. We show why this representation helps to understand the evolutionary consequences of both genetic and non‐genetic phenotype determinants, and discuss how this approach can instigate future areas of empirical and theoretical research. (shrink)

The Genotype-Phenotype (G-P) distinction was proposed in the context of Mendelian genetics, in the wake of late 19th century studies about heredity. In this paper, we provide a conceptual analysis that highlights that the G-P distinction was grounded on three pillars: observability, transmissibility, and causality. Originally, the genotype is the non-observable and transmissible cause of the phenotype, which is its observable and non-transmissible effect. We argue that the current developments of biology have called the validity of (...) such pillars into question. First, molecular biology has unveiled the putative material substrate of the genotype (qua DNA), making it an observable object. Second, numerous findings on nongenetic heredity suggest that some phenotypic traits can be directly transmitted. Third, recent organicist approaches to biological phenomena have emphasized the reciprocal causality between parts of a biological system, which notably applies to the relations between genotypes and phenotypes. As a consequence, we submit that the G-P distinction has lost its general validity, although it can still apply to specific situations. This calls for forging new frameworks and concepts to better describe heredity and development. (shrink)

The ArgumentMany associations have recently been discovered between phenotypic variation and genetic loci, causing some to advocate what Robert Sinsheimer has called “a new eugenics” that would treat genetic “defects” in individuals prone to a disease. The first premise of this vision is that genetic association studies reveal the biological cause of the phenotypic variation. Once the responsible genes are known, the second premise is that we should focus upon changing “nature” rather than “nurture” by correcting the “defective” genes.The first (...) premise is flawed because associations between genetic markers and phenotypes can be spurious, as shown by an example. Moreover, it is shown that using non-causative but associated genetic markers one at a time (the normal practice) can lead to incorrect predictions of disease risk for many individuals. Going from association to causation is a non-trivial step scientifically that has rarely been done in much of the human genetic research.Even when a particular locus does contribute to the phenotypic variation of interest, the first premise remains flawed because phenotypes in general arise from complex interactions among genes and between genes and environments as shown for genes associations with coronary artery disease (CAD). The ability of current molecular genetic tools to “fix” defective genotypes is extremely limited, but even if the technological problems could be overcome, the studies on CAD reveal no obvious “defective” gene to fix because the genetic effects are so context dependent (upon both other genes and environmental factors). Contrary to the second premise of the new eugenics, the more we learn about how different genotypes show variable responses to environments, themoreimportant the environment becomes for individual treatment.The paradigm of a “defective gene” may work for classical Mendelian genetic diseases that are due to loss-of-function mutations. However, such mutations affect only a small portion of humanity. When the focus is changed to common disease and behavioral phenotypes, the “defective gene” paradigm is biologically meaningless and often harmful when applied to individuals. Thus, even when genes clearly do influence common phenotypic variation, the premises of the “new eugenics” are biologically indefensible. (shrink)

The current implementation of the Neo-Darwinian model of evolution typically assumes that the set of possible phenotypes is organized into a highly symmetric and regular space. Most conveniently, a Euclidean vector space is used, representing phenotypic properties by real-valued variables. Computational work on the biophysical genotype-phenotype model of RNA folding, however, suggests a rather different picture. If phenotypes are organized according to genetic accessibility, the resulting space lacks a metric and can be formalized only in terms of a (...) relatively unfamiliar structure. Patterns of phenotypic evolution—such as punctuation, irreversibility, and modularity—result naturally from the properties of the genotype-phenotype map, which, given the genetic accessibility structure, define accessibility in the phenotype space. The classical framework, however, addresses these patterns exclusively in terms of natural selection on suitably constructed fitness landscapes. Recent work has extended the explanatory level for phenotypic evolution from fitness considerations alone to include the topological structure of phenotype space as induced by the genotype-phenotype map. Lewontin’s notion of “quasi-independence” of characters can also be formalized in topological terms: it corresponds to the assumption that a region of the phenotype space is represented by a product space of orthogonal factors. In this picture, each character corresponds to a factor of a region of the phenotype space. We consider any region of the phenotype space that has a given factorization as a “type”, i.e., as a set of phenotypes that share the same set of phenotypic characters. Thus, a theory of character identity can be developed that is based on the correspondence of local factors in different regions of the phenotype space. (shrink)

In this paper, I examine an experimental technique, gene targeting, used for establishing genotype/phenotype relationships. Through analyzing a case study, I identify many pitfalls that may lead to false conclusions about these relationships. I argue that some of these pitfalls may seriously affect gene targeting's usefulness for associating phenotypes with genes cataloged by the Human Genome Project. This case also shows the use of gene targeted mice as model systems for studying genotype/phenotype relationships in humans. Moreover, (...) I argue that it reveals the weakness of one attempt to draw conclusions about the biological determination of sexual and aggressive behaviors in humans. (shrink)

In 1941/42 Konrad Lorenz suggested that Kant's transcendental categories ofa priori knowledge could be given an empirical interpretation in Darwinian material evolutionary terms: a priori propositional knowledge was an organ subject to natural selection for adaptation to its specific environments. D. Campbell extended the conception, and termed evolution a process of knowledge. The philosophical problem of what knowledge is became a descriptive one of how knowledge developed, the normative semantic questions have been sidestepped, as if the descriptive insights would automatically (...) resolve them. This came at a time when the traditional concept of knowledge as universally true, justified beliefs had been challenged by subjectivist, intercommunicative coherence frameworks. Much of the literature on evolutionary epistemology claimed that knowledge in general, and science as its epitome in particular, evolved along lines analogous to organic biological evolution. I refer here only to the view of knowledge as an extension of material biological evolution. These theories of evolutionary epistemology, contrary to the relativist notions of naturalized epistemology, adopted strict realist positions.Although there is no contention with the claim that biological evolution provided the raw material and the constraints for human knowledge, cognition is not knowledge and knowledge is not constrained by it beyond some trivial truisms. The view that sees evolution as a knowledge/cognition process is coercing a loosely defined term into the status of a phenotypic trait on which selection could act. This disregards the intricate many-to-many relationship between correlates of knowledge and biological capacities. But even if we grant the correlates of knowledge the status of selectable traits, the heritability of alternative phenotypes would be low and unpredictable due to the high, open-ended environmental malleability of such complex characters in the course of development. Such concepts are therefore biologically inconsequential. (shrink)

Mehlman and Li offer a framework for approaching the bioethical issues raised by the military use of genomics that is compellingly grounded in both the contemporary civilian and military ethics of medical research, arguing that military commanders must be bound by the two principles of paternal- ism and proportionality. I agree fully. But I argue here that this is a much higher bar than we may fully realize. Just as the principle of proportionality relies upon a thorough assessment of harms (...) caused and military advantage gained, the use of genomic research, on Mehlman and Li’s view, will require an accurate understanding of the connection between genotypes and phenotypes – accurate enough to ameliorate the risk undertaken by our armed forces in being subject to such research. Recent conceptual work in evolutionary theory and the philosophy of biology, however, renders it doubtful that such knowledge is forthcoming. The complexity of the relationship between genotypic factors and realized traits (the so-called ‘G→P map’) makes the estimation of potential military advantage, as well as potential harm to our troops, incredibly challenging. Such fundamental conceptual challenges call into question our ability to ever satisfactorily satisfy the demands of a sufficiently rigorous ethical standard. (shrink)

The analysis of genetic and epigenetic mechanisms of the genotype–phenotypic connection has, so far, only been possible in a handful of genetic model systems. Recent technological advances, including next‐generation sequencing methods such as RNA‐seq, ChIP‐seq and RAD‐seq, and genome‐editing approaches including CRISPR‐Cas, now permit to address these fundamental questions of biology also in organisms that have been studied in their natural habitats. We provide an overview of the benefits and drawbacks of these novel techniques and experimental approaches that can (...) now be applied to ecological and evolutionary vertebrate models such as sticklebacks and cichlid fish. We can anticipate that these new methods will increase the understanding of the genetic and epigenetic factors influencing adaptations and phenotypic variation in ecological settings. These new arrows in the methodological quiver of ecologist will drastically increase the understanding of the genetic basis of adaptive traits – leading to a further closing of the genotype–phenotype gap. -/- . (shrink)

Emphatic claims of a “microbiome revolution” aside, the study of the gut microbiota and its role in organismal development and evolution is a central feature of so-called postgenomics; namely, a conceptual and/or practical turn in contemporary life sciences, which departs from genetic determinism and reductionism to explore holism, emergentism and complexity in biological knowledge-production. This paper analyses the making of postgenomic knowledge about developmental symbiosis in Drosophila melanogaster by a specific group of microbiome scientists. Drawing from both practical philosophy of (...) science and Science and Technology Studies, the paper documents epistemological questions of artefactuality and representativeness of model organisms as they emerge in the day-to-day labour producing and being produced by the “microbiome revolution." Specifically, the paper builds on all the written and editorial exchanges involved in the troubled publication of a research paper studying the symbiotic role of the microbiota in the flies’ development. These written materials permit us to delimit the network of justifications, evidence, standards of knowledge-production, trust in the tools and research designs that make up the conditions of possibility of a postgenomic fact. More than reframing the organism as a radically novel multiplicity of reactive genomes, we conclude, doing postgenomic research on the microbiota and symbiosis means producing a story that deviates from the scripts embedded into the sociotechnical experimental systems of post-Human Genome Project life sciences. (shrink)

In this article we examine the “phenotype” concept in light of recent technological advances in Genome-Wide Association Studies . By observing the technology and its presuppositions, we put forward the thesis that at least in this case genotype and phenotype are effectively coidentifled one by means of the other. We suggest that the coidentiflcation of genotype-phenotype couples in expression-based GWAS also indicates a conceptual dependence, which we call “co-deñnition.” We note that viewing these terms as (...) codeflned runs against possible expectations, viz., that genotypes and phenotypes could ultimately be expressed independently from one another. In addition, the co-definition of genotypes and phenotypes in this context emphasizes the correlative character of both genotypes and phenotypes in GWAS. (shrink)

Embryonic development and ontogeny occupy whatis often depicted as the black box betweengenes – the genotype – and the features(structures, functions, behaviors) of organisms– the phenotype; the phenotype is not merelya one-to-one readout of the genotype. Thegenes home, context, and locus of operation isthe cell. Initially, in ontogeny, that cell isthe single-celled zygote. As developmentensues, multicellular assemblages of like cells(modules) progressively organized as germlayers, embryonic fields, anlage,condensations, or blastemata, enable genes toplay their roles in development and (...) evolution.As modules, condensations are fundamentaldevelopmental and selectable units ofmorphology (morphogenetic units) that mediateinteractions between genotype and phenotype viaevolutionary developmental mechanisms. In ahierarchy of emergent processes, gene networksand gene cascades (genetic modules) link thegenotype with morphogenetic units such ascondensations, while epigenetic processes suchas embryonic inductions, tissue interactionsand functional integration, link morphogeneticunits to the phenotype. To support theseconclusions I distinguish units of heredityfrom units of transmission and discussepigenetic inheritance by tracing the historyof relationship between embryology andevolution, especially the role(s) assigned tocells or to cellular components in generatingtheories of morphological change in evolution.The concept of cells as modular morphogeneticunits is modeled and illustrated using themammalian dentary bone. (shrink)

In this paper I discuss one possible extension of Richard Lewontin’s proposal in The Triple Helix. After reviewing the theoretical commitments common to discussions that assume we will be able to compute an organism from its genes, I turn to Lewontin’s arguments that we will never be able to compute phenotype from genotype because the genotype specifies an organism’s phenotype relative to a range of environments. The focus of the discussion in this paper, however, is on (...) what might follow if we take seriously the claim that genetic structure does not determine phenotypic structure. The question is: What becomes causally efficacious in an explanation of the development of a heritable trait if genes are not sufficient? Any answer to this question, and even the question itself, is central to an understanding of the types of relations and structures into which humans enter and which they create in an environment. (shrink)

The ‘phenotypic gambit,’ the assumption that we can ignore genetics and look at the fitness of phenotypes to determine the expected evolutionary dynamics of a population, is often used in evolutionary game theory. However, as this paper will show, an overlooked genotype to phenotype map can qualitatively affect evolution in ways the phenotypic approach cannot predict or explain. This gives us reason to believe that, even in the long-term, correspondences between phenotypic predictions and dynamical outcomes are not robust (...) for all plausible assumptions regarding the underlying genetics of traits. This paper shows important ways in which the phenotypic gambit can fail and how to proceed with evolutionary game theoretic modeling when it does. (shrink)

The ArgumentEugenics, in whatever form it may be articulated, is based on the idea that phenotypic characteristics of particular individuals can be predicted in advance. This paper argues that biology's capacity to predict many of the characteristics exhibited by an individual, especially behavioral or cognitive attributes, will always be very limited. This stems from intrinsic limitations to the methodology for relating genotypes to phenotypes, and from the nature of developmental processes which intervene between genotypes and phenotypes. While genetic studies may (...) generate valid population predictions for conditions which impact human health, neither genetics nor developmental biology are likely to generate useful individual predictions about variation in non-disease-related human behavioral and cognitive phenotypes in the foreseeable future. (shrink)

The great majority of phenotypic characteristics are complex traits, complicating the identification of the genes underlying their expression. However, both methodological and theoretical progress in genome‐wide association studies have resulted in a much better understanding of the underlying genetics of many phenotypic traits, including externally visible characteristics (EVCs) such as eye and hair color. Consequently, it has become possible to predict EVCs from human samples lacking phenotypic information. Predicting EVCs from genetic evidence is clearly appealing for forensic applications involving the (...) personal identification of human remains. Now, a recent paper has reported the genetic determination of eye and hair color in samples up to 800 years old. The ability to predict EVCs from ancient human remains opens up promising perspectives for ancient DNA research, as this could allow studies to directly address archaeological and evolutionary questions related to the temporal and geographical origins of the genetic variants underlying phenotypes. (shrink)

Studies of the role of imprinted genes in psychological phenomena are long overdue. The target article is comprehensive, presenting a wealth of important and convergent evidence, and provides an excellent point of departure for further research. However, the authors' evidentiary grasp exceeds the explicatory capacity of the proposed model. Greater genotypic and phenotypic precision would significantly enhance its predictive power.

While the definition of the ‘genotype’ has undergone dramatic changes in the transition from classical to molecular genetics, the definition of the ‘phenotype’ has remained for a long time within the classical framework. In addition, while the notion of the genotype has received significant attention from philosophers of biology, the notion of the phenotype has not. Recent developments in the technology of measuring gene-expression levels have made it possible to conceive of phenotypic traits in terms of (...) levels of gene expression. We demonstrate that not only has this become possible but it has also become an actual practice. This suggests a significant change in our conception of the phenotype: as in the case of the ‘genotype’, phenotypes can now be conceived in quantitative and measurable terms on a comprehensive molecular level. We discuss in what sense gene expression profiles can be regarded as phenotypic traits and whether these traits are better described as a novel concept of phenotype or as an extension of the classical concept. We argue for an extension of the classical concept and call for an examination of the type of extension involved. (shrink)

This paper describes the historical background and early formation of Wilhelm Johannsen's distinction between genotype and phenotype. It is argued that contrary to a widely accepted interpretation his concepts referred primarily to properties of individual organisms and not to statistical averages. Johannsen's concept of genotype was derived from the idea of species in the tradition of biological systematics from Linnaeus to de Vries: An individual belonged to a group - species, subspecies, elementary species - by representing a (...) certain underlying type. Johannsen sharpened this idea theoretically in the light of recent biological discoveries, not least those of cytology. He tested and confirmed it experimentally combining the methods of biometry, as developed by Francis Galton, with the individual selection method and pedigree analysis, as developed for instance by Louis Vilmorin. The term "genotype" was introduced in W. Johannsen's 1909 treatise, but the idea of a stable underlying biological "type" distinct from observable properties was the core idea of his classical bean selection experiment published 6 years earlier. The individual ontological foundation of population analysis was a self-evident presupposition in Johannsen's studies of heredity in populations from their start in the early 1890s till his death in 1927. The claim that there was a "substantial but cautious modification of Johannsen's phenotype-genotype distinction" from a statistical to an individual ontological perspective derives from a misreading of the 1903 and 1909 texts. The immediate purpose of this paper is to correct this reading of the 1903 monograph by showing how its problems and results grow out of Johannsen's earlier work in heredity and plant breeding. Johannsen presented his famous selection experiment as the culmination of a line of criticism of orthodox Darwinism by William Bateson, Hugo de Vries, and others. They had argued that evolution is based on stepwise rather than continuous change in heredity. Johannsen's paradigmatic experiment showed how stepwise variation in heredity could be operationally distinguished from the observable, continuous morphological variation. To test Galton's law of partial regression, Johannsen deliberately chose pure lines of self-fertilizing plants, a pure line being the descendants in successive generations of one single individual. Such a population could be assumed to be highly homogeneous with respect to hereditary type, and Johannsen found that selection produced no change in this type. Galton, he explained, had experimented with populations composed of a number of stable hereditary types. The partial regression which Galton found was simply an effect of selection between types, increasing the proportion of some types at the expense of others. (shrink)

Observing adaptive evolution is difficult. In the fossil record, phenotypic evolution happens much more slowly than in artificial selection experiments or in experimental evolution. Yet measures of selection on phenotypic traits, with high heritabilities, suggest that phenotypic evolution should also be rapid in the wild, and this discrepancy often remains even after accounting for correlations between different traits (i.e. making predictions using the multivariate version of the breeder's equation). Are fitness correlations with quantitative traits adequate measures of selection in the (...) wild? We should instead view fitnesses as average properties of genotypes, while acknowledging that they can be environment‐dependent. Populations will tend to remain at fitness equilibria, once these are attained, and phenotypes will then be stable. Thus, studying the causes of adaptive change at a genotypic rather than phenotypic level may reveal that, typically, it is occurring too slowly to be easily observed. (shrink)

Selection operates at many levels. Robert Brandon has distinguished the question of the level of selection from the unit of selection, arguing that the phenotype is commonly the target of selection, whatever the unit of selection might be. He uses "screening off" as a criterion for distinguishing the level of selection. Cave animals show a common morphological pattern which includes hypertrophy of some structures and reduction or loss of others. In a study of a cave dwelling crustacean, Gammarus minus, (...) we find evidence for selection for both increased antennal size and reduction of eyes. The genetic structure of the population does not support the view that the phenotype screens off the genotype in explaining the differences in fitness. Nonetheless, the results do indicate that the level of selection is at least at the level of the phenotype in both cases. (shrink)

There is at present uneasiness about the conceptual basis of genetics. The gene concept has become blurred and there are problems with the distinction between genotype and phenotype. In the present paper I go back to their role in the creation of modern genetics in the early twentieth century. The terms were introduced by the Danish botanist and geneticist Wilhelm Johannsen in his big textbook of 1909. Historical accounts usually concentrate on this book and his 1911 paper “The (...) Genotype Conception of Heredity.” His bean selection experiment of 1900–1903 is generally assumed to be the source of his genotype theory. The present paper examines the scientific context and meaning of this experiment, how it was received, and how the genotype theory became securely established by the early 1910s. I argue in conclusion that the genotype/phenotype distinction, which provides the empirical basis for Johannsen's gene, was scientifically well founded when introduced and still is. Keith Baverstock's criticism does not consider the force of the bean selection experiment at the time and as a paradigm for following investigations of heredity. (shrink)

This paper describes the historical background and early formation of Wilhelm Johannsen's distinction between genotype and phenotype. It is argued that contrary to a widely accepted interpretation his concepts referred primarily to properties of individual organisms and not to statistical averages. Johannsen's concept of genotype was derived from the idea of species in the tradition of biological systematics from Linnaeus to de Vries: An individual belonged to a group - species, subspecies, elementary species - by representing a (...) certain underlying type. Johannsen sharpened this idea theoretically in the light of recent biological discoveries, not least those of cytology. He tested and confirmed it experimentally combining the methods of biometry, as developed by Francis Galton, with the individual selection method and pedigree analysis, as developed for instance by Louis Vilmorin. The term "genotype" was introduced in W. Johannsen's 1909 treatise, but the idea of a stable underlying biological "type" distinct from observable properties was the core idea of his classical bean selection experiment published 6 years earlier. The individual ontological foundation of population analysis was a self-evident presupposition in Johannsen's studies of heredity in populations from their start in the early 1890s till his death in 1927. The claim that there was a "substantial but cautious modification of Johannsen's phenotype-genotype distinction" from a statistical to an individual ontological perspective derives from a misreading of the 1903 and 1909 texts. The immediate purpose of this paper is to correct this reading of the 1903 monograph by showing how its problems and results grow out of Johannsen's earlier work in heredity and plant breeding. Johannsen presented his famous selection experiment as the culmination of a line of criticism of orthodox Darwinism by William Bateson, Hugo de Vries, and others. They had argued that evolution is based on stepwise rather than continuous change in heredity. Johannsen's paradigmatic experiment showed how stepwise variation in heredity could be operationally distinguished from the observable, continuous morphological variation. To test Galton's law of partial regression, Johannsen deliberately chose pure lines of self-fertilizing plants, a pure line being the descendants in successive generations of one single individual. Such a population could be assumed to be highly homogeneous with respect to hereditary type, and Johannsen found that selection produced no change in this type. Galton, he explained, had experimented with populations composed of a number of stable hereditary types. The partial regression which Galton found was simply an effect of selection between types, increasing the proportion of some types at the expense of others. (shrink)

Much research on color representation and categorization has assumed that relations among color terms can be proxies for relations among color percepts. We test this assumption by comparing the mapping of color words with color appearances among different observer groups performing cognitive tasks: an invariance of naming task; and triad similarity judgments of color term and color appearance stimuli within and across color categories. Observer subgroups were defined by perceptual phenotype and photopigment opsin genotype analyses. Results suggest that (...) individuals rely on at least two different representational models of color experience: one lexical, conforming to the culture's normative linguistic representation, and another individual perceptual representation organizing each observer's color sensation experiences. Additional observer subgroup analyses suggest that perceptual phenotype variation within a language group may play a greater role in the shared color naming system than previously thought. A reexamination of color naming data in view of these findings may reveal influences on color naming important to current theories. (shrink)

Recombination is often considered a disruptive force for well‐adapted phenotypes, but recent evidence suggests that this cost of recombination can be small. A key benefit of recombination is that it can help create proteins and regulatory circuits with novel and useful phenotypes more efficiently than point mutation. Its effectiveness stems from the large‐scale reorganization of genotypes that it causes, which can help explore far‐flung regions in genotype space. Recent work on complex phenotypes in model gene regulatory circuits and proteins (...) shows that the disruptive effects of recombination can be very mild compared to the effects of mutation. Recombination thus can have great benefits at a modest cost, but we do not understand the reasons well. A better understanding might shed light on the evolution of recombination and help improve evolutionary strategies in biochemical engineering. (shrink)

Organisms that share the capability of storing information about experiences in the past have an actively generated background resource on which they can compare and evaluate more recent experiences in order to quickly or even better react than in previous situations. This is an essential competence for all reaction and adaptation purposes of living organisms. Such memory/learning skills can be found from akaryotes up to unicellular eukaryotes, fungi, animals and plants, although until recently, it had been mentioned only as a (...) capability of higher animals. With the rise of epigenetics, the context-dependent marking of experiences at both the phenotype and the genotype level is an essential perspective to understand memory and learning in all organisms. Both memory and learning depend on a variety of successful communication processes within the whole organism. (shrink)

Polygenic score (PGS) computations assume an additive model of gene action because associations between phenotypes and alleles at different loci are compounded, ignoring interactions between alleles or loci let alone between genotype and environment. Consequently, PGSs are subject to the same objections that invalidated traditional heritability analyses in the 1970s. Thus, PGSs should not be used in the social sciences.

The Neo‐Darwinian concept of natural selection is plausible when one assumes a straightforward causation of phenotype by genotype. However, such simple 1:1 mapping must now give place to the modern concepts of gene regulatory networks and gene expression noise. Both can, in the absence of genetic mutations, jointly generate a diversity of inheritable randomly occupied phenotypic states that could also serve as a substrate for natural selection. This form of epigenetic dynamics challenges Neo‐Darwinism. It needs to incorporate the (...) non‐linear, stochastic dynamics of gene networks. A first step is to consider the mathematical correspondence between gene regulatory networks and Waddington's metaphoric ‘epigenetic landscape’, which actually represents the quasi‐potential function of global network dynamics. It explains the coexistence of multiple stable phenotypes within one genotype. The landscape's topography with its attractors is shaped by evolution through mutational re‐wiring of regulatory interactions – offering a link between genetic mutation and sudden, broad evolutionary changes. (shrink)

Sociotype is a concept that allows a more comprehensive understanding about biosociology of undiagnosed rare diseases (URD). Sociotype is related to a genotype and a phenotype and it is an expression of the individual life world in society. In this paper, semiotic and hermeneutic analysis of papers published and selected about URD is developed. Te perspective followed in this research is aligned with the works of Barbieri and Peirce. Papers with the most social content have been selected and (...) those with a more biomedical content have been rejected. Te semiotics analysis has been divided in genotypic, phenotypic and sociotypic, and related to the hermeneutical perspective. It has been possible to understand the basis of semiotics elements of URD. Te general conclusion is that URD is a particular sociotype with a determined set of social characteristics. Tis paper opens research on the biosemiotic and hermeneutic perspective about URD. (shrink)

Nelson and Winter’s An Evolutionary Theory of Economic Change (1982) was the foundational work of what has become the thriving sub-discipline of evolutionary economics. In attempting to develop an alternative to neoclassical economics, the authors looked to borrow basic ideas from biology, in particular a concept of economic “natural selection.” However, the evolutionary models they construct in their seminal work are in many respects quite different from the models of evolutionary biology. There is no reproduction in any usual sense, “mutation” (...) is directed as opposed to blind, and there is no meaningful distinction between phenotype and genotype. Despite these substantial departures from the conceptions of evolutionary biology, I argue that the “evolutionary” economics of Nelson and Winter is indeed a legitimate extension of Darwinian evolutionary principles to a novel domain, and that the traditional conception of evolution by natural selection must be revised. The novel features of evolutionary economics models reflect the distinctive theoretical requirements faced by economists. I further contend that reproduction, heredity, blind variation, and the genotype/phenotype distinction are all inessential to evolutionary theory, and that their role in evolutionary biology is a domain-specific feature of biological theory. (shrink)

Can heritability estimates provide causal information? This paper argues for an affirmative answer: since a non-nil heritability estimate satisfies certain characteristic properties of causation (i.e., association, manipulability, and counterfactual dependence), it increases the probability that the relation between genotypic variance and phenotypic variance is (at least partly) causal. Contrary to earlier proposals in the literature, the argument does not assume the correctness of any particular conception of the nature of causation, rather focusing on properties that are characteristic of causal relationships. (...) The argument is defended against Lewontin's (1974) locality objection and Kaplan and Turkheimer's (2021) recent critique of Genome-Wide Association Studies (GWAS). (shrink)

Most models of generational succession in sexually reproducing populations necessarily move back and forth between genic and genotypic spaces. We show that transitions between and within these spaces are usually hidden by unstated assumptions about processes in these spaces. We also examine a widely endorsed claim regarding the mathematical equivalence of kin-, group-, individual-, and allelic-selection models made by Lee Dugatkin and Kern Reeve. We show that the claimed mathematical equivalence of the models does not hold. *Received January 2007; revised (...) April 2008. †To contact the authors, please write to: Elisabeth Lloyd, Department of History and Philosophy of Science, 130 Goodbody Hall, Indiana University, Bloomington, IN 47405; e-mail: [email protected]; Richard Lewontin, Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138; Marcus Feldman, Department of Biological Sciences, Stanford University, Stanford, CA 94305; e-mail: [email protected]. (shrink)

Two prevailing paradigms explain the diversity of sex-determining modes in reptiles. Many researchers, particularly those who study reptiles, consider genetic and environmental sex-determining mechanisms to be fundamentally different, and that one can be demonstrated experimentally to the exclusion of the other. Other researchers, principally those who take a broader taxonomic perspective, argue that no clear boundaries exist between them. Indeed, we argue that genetic and environmental sex determination in reptiles should be seen as a continuum of states represented by species (...) whose sex is determined primarily by genotype, species where genetic and environmental mechanisms coexist and interact in lesser or greater measure to bring about sex phenotypes, and species where sex is determined primarily by environment. To do otherwise limits the scope of investigations into the transition between the two and reduces opportunities to use studies of reptiles to advance understanding of vertebrate sex determination generally. © 2004 Wiley Periodicals, Inc. (shrink)

I consider recent uses of the notion of neutrality in evolutionary biology and ecology, questioning their relevance to the kind of explanation recently labeled ‘topological explanation’. Focusing on fitness landscapes and genotype-phenotype maps, I explore the explanatory uses of neutral subspaces, as modeled in two perspectives: hyperdimensional fitness landscapes and RNA sequence-structure maps. I argue that topological properties of such spaces account for features of evolutionary systems: respectively, capacity for adaptive evolution toward global optima and mutational robustness of (...) genotypes. Thus many models appealing to “neutral” manifolds provide topological alternatives to hypothetical mechanisms. (shrink)